The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
DNA and RNA Structure
Central Dogma of Life
Protein Engineering (Brief)
Introduction to microRNA (miRNA)
History of miRNA
Biogenesis of miRNA
Conservation of miRNA
Impact of miRNA
miRNA Therapy
Conclusion
DNA and RNA Structure
Central Dogma of Life
Protein Engineering (Brief)
Introduction to microRNA (miRNA)
History of miRNA
Biogenesis of miRNA
Conservation of miRNA
Impact of miRNA
miRNA Therapy
Conclusion
This is a presentation slide about cellular RNA interference process and RNA interference technology. Contains basic information about biology of cellular RNA interference processes and its discovery, and RNA interference technology. Also gives you the history and development of in-vitro and in-vivo technologies for applicability of RNA interference technology.
siRNA synthesis, siRNA libraries, siRNA delivering techniques, Electroporation, viral transfection methods, Advantages and disadvantages of RNA interference technology.
details about the preliminary and pre-clinical experiments of RNA interference as well as clinical trials of RNA interference.
Transcriptomics is the study of RNA, single-stranded nucleic acid, which was not separated from the DNA world until the central dogma was formulated by Francis Crick in 1958, i.e., the idea that genetic information is transcribed from DNA to RNA and then translated from RNA into protein.
Almost 98 of the human genome does not encode proteins
o The non coding transcripts less than 200 bases are called small non
coding RNA and comprise of tRNA, rRNA, miRNA, snoRNA, piwi
interacting RNA (pi RNA)
o RNA molecules that are of more than 200 bases in length are known
as long non coding RNA (
o lncRNAs are more than 200 nucleotides in length and also can be
more than 2 Kb
o Such long noncoding RNAs usually have limited coding potential due
to the absence of open reading frames, 3 UTR and termination
region while their coding potential is less than 100 amino acids
RNAi is a powerful, conserved biological process through which the small, double-stranded RNAs specifically silence the expression of homologous genes, largely through degradation of their cognate mRNA.
Alternative splicing is a deviation from the conventional splicing as it removes introns in a different manner. It has a lot of significance in the development of diseases like cancers and in plants adapting to various stress conditions.
This is a presentation slide about cellular RNA interference process and RNA interference technology. Contains basic information about biology of cellular RNA interference processes and its discovery, and RNA interference technology. Also gives you the history and development of in-vitro and in-vivo technologies for applicability of RNA interference technology.
siRNA synthesis, siRNA libraries, siRNA delivering techniques, Electroporation, viral transfection methods, Advantages and disadvantages of RNA interference technology.
details about the preliminary and pre-clinical experiments of RNA interference as well as clinical trials of RNA interference.
Transcriptomics is the study of RNA, single-stranded nucleic acid, which was not separated from the DNA world until the central dogma was formulated by Francis Crick in 1958, i.e., the idea that genetic information is transcribed from DNA to RNA and then translated from RNA into protein.
Almost 98 of the human genome does not encode proteins
o The non coding transcripts less than 200 bases are called small non
coding RNA and comprise of tRNA, rRNA, miRNA, snoRNA, piwi
interacting RNA (pi RNA)
o RNA molecules that are of more than 200 bases in length are known
as long non coding RNA (
o lncRNAs are more than 200 nucleotides in length and also can be
more than 2 Kb
o Such long noncoding RNAs usually have limited coding potential due
to the absence of open reading frames, 3 UTR and termination
region while their coding potential is less than 100 amino acids
RNAi is a powerful, conserved biological process through which the small, double-stranded RNAs specifically silence the expression of homologous genes, largely through degradation of their cognate mRNA.
Alternative splicing is a deviation from the conventional splicing as it removes introns in a different manner. It has a lot of significance in the development of diseases like cancers and in plants adapting to various stress conditions.
INTERFERENCE means the act of interfering with something, here, with RNA. RNAi is an evolutionarily conserved mechanism triggered by dsRNA molecules, to prevent the expression of specific genes or the translation, causes sequence-specific degradation of the targeted mRNA molecules of that particular gene. It was also known as CO-SUPPRESSION, POST TRANSCRIPTIONAL GENE SILENCING [PTGS] in plants and QUELLING in fungi.
RNA interference (RNAi) is a mechanism that inhibits gene expression at the stage of translation or by hindering the transcription of specific genes.
RNAi targets include RNA from viruses and transposons.
COMPETENCY 3Integrate credible and relevant sources into coursewLynellBull52
COMPETENCY 3
Integrate credible and relevant sources into coursework to enhance clarity and support claims.
CRITERION
Reflect on how credibility and relevance of a chosen resource were determined.
Your result: Non-Performance
Distinguished
Reflects on how credibility and relevance of a chosen resource were determined. Notes how specific aspects of the assessment were used to determine relevance.
Proficient
Reflects on how credibility and relevance of a chosen resource were determined.
Basic
Explains the concepts of credibility and relevance in general terms, but does not specifically address how this was used to determine if the specific resource was credible and relevant.
Non-Performance
Does not explain the concepts of credibility and relevance in general terms.
Faculty Comments:
I did not see a discussion of source credibility/relevance. For this assignment you were are also required to locate an article in the library about time organizing strategies (outlined in Part I). Then, you were asked in Part II to reflect on how you determined the credibility and relevance of your chosen library resource to support your task prioritization.
ONCOLOGY LETTERS 19: 595-605, 2020
Abstract. Numerous types of molecular mechanisms mediate
the development of cancer. Non-coding RNAs (ncRNAs) are
being increasingly recognized to play important role in medi-
ating the development of diseases, including cancer. Long
non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are
the two most widely studied ncRNAs. Thus far, lncRNAs are
known to have biological roles through a variety of mecha-
nisms, including genetic imprinting, chromatin remodeling,
cell cycle control, splicing regulation, mRNA decay and
translational regulation, and miRNAs regulate gene expres-
sion through the degradation of mRNAs and lncRNAs.
Although ncRNAs account for a major proportion of the total
RNA, the mechanisms underlying the physiological or patho-
logical processes mediated by various types of ncRNAs, and
the specific interaction mechanisms between miRNAs and
lncRNAs in various physiological and pathological processes,
remain largely unknown. Thus, further research in this field
is required. In general, the interaction mechanisms between
miRNAs and lncRNAs in human cancer have become
important research topics, and the study thereof has led to
the recent development of related technologies. By providing
examples and descriptions, and performing chart analysis, the
present study aimed to review the interaction mechanisms and
research approaches for these two types of ncRNAs, as well
as their roles in the occurrence and development of cancer.
These details have far‑reaching significance for the utilization
of these molecules in the diagnosis and treatment of cancer.
Contents
1. Introduction
2. Interactions between lncRNAs and miRNAs
3. Methods of research in to lncRNAs and miRNAs
4. lncRNAs and miRNAs in cancer
5. Conclusion
1. Introduction
In 1993, Lee e ...
RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules. Two types of small ribonucleic acid (RNA) molecules – microRNA (miRNA) and small interfering RNA (siRNA) – are central to RNA interference.
Congenital Agenesis Of The Corpus Callosum With Intracerebral Lipoma And Fron...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
“Hemodynamic and recovery profile with Dexmedetomidine and Fentanyl in intrac...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Correlation of Estrogen and Progesterone Receptor expression in Breast Canceriosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Analytical Study of Urine Samples for Epidemiology of Urinary Tract Infection...iosrphr_editor
The current study was carried out in District Abbottabad aimed to determine the common urinary
tract infections in local community to determine the epidemiology of significant diseases in asymptomatic patients
of renal disorder. In this study a total of 1000 urine samples were examined during 3rd February to 1st April 2015
from patients attending Ayub Teaching Hospital Abbottabad by using dipstick and microscopic analysis of urine.
There were 638 females and 362 males patients examined during this period. The range of age groups is between
1.5 years to 80 years. Results of this study was reported as Pyuria 11%, Proteinuria 21.1%, Hematuria 10.4%,
Epithelial Cells 8.2%, pH 7.8 %, Granular casts 7.3%, Triple phosphate 6.6%, Calcium oxalate 6.4%, Glycosuria
6.3%, Bacteria 6.2% and mucous 4.1%. This study concludes that routing urinalysis should be performed for all
individuals to diagnose the asymptomatic diseases that will help in simple therapeutic measurements as urinalysis
is a simple step to determine the root of Urinary tract disorders.
Chest sonography images in neonatal r.d.s. And proposed gradingiosrphr_editor
BACKGROUND : Lung sonography has been used to monitor the patients of R.D.S. in
N.I.C.U. in recent times.
AIMS : To Describe and Grade the changes of R.D.S. by lung sonography.
SETTING & DESIGN : Tertiary care institutional set up in a rural medical college.
STUDY DURATION : September 2014 to May 2015. Follow-up variable, upto 2 weeks.
PROSPECTIVE, ANALYTICAL STUDY.
MATERIALS AND METHODS -This was a single institute study approved by the institutional ethics
committee. Prior informed consent was obtained from the parents. 100 consecutive patients admitted in
N.I.C.U. WITH gestational age < 36 weeks with respiratory complaints were enrolled. Chest x-ray was
obtained within few hours of admission and lung sonography was performed within 24 hours. Follow – up
sonography was performed as and when necessary. Sonography image was graded and correlated with chest
xray and clinical picture
The Comprehensive Review on Fat Soluble Vitaminsiosrphr_editor
This review article deals with brief description of fat soluble vitamins with figures and tables
showing statistical analytical data duly quoting the references wherever necessary. The word “soluble” actually
means “able to be dissolved.” Whether a vitamin is classified as 'fat-soluble' or 'water-soluble' has to do with
how the vitamin is absorbed, stored and removed from the body. Vitamins are tiny organic compounds with a
huge impact on the health and well-being of the body. The body needs a small amount of fat soluble vitamins in
order to stay in optimal health. Fat soluble vitamins play an important role in keeping the body healthy and
functioning from immune system and muscle and heart function, easy flow and clotting of blood as well as eye
health. They are critical to health and wellness–particularly reproductive health and wellness. Low-fat, no-fat
and vegan diets are woefully lacking in fat soluble vitamins. However a diet based on traditional foods can
naturally provide these vitamins. Science is still learning about many of the functions of vitamins. "Too much
vitamin A, D, or K can lead to increased levels that are unhealthy and can cause serious health consequences.
Diseased conditions leading to decreased fat absorption leads to decreased absorption of vitamins. The fatsoluble
vitamins work most safely and effectively when obtained them from natural foods within the context of a
diet rich in all their synergistic partners. If fat soluble vitamins are stored for lengthy time they generate threat
for toxicity than water soluble vitamins and such situation even aggravated, provided they are consumed in
excess. Vitamin products, above the legal limits are not considered food supplements and must be registered as
prescription or non-prescription (over-the-counter drugs) due to their potential side effects. Vitamin A and E
supplements do not provide health benefits for healthy individuals, instead they may enhance mortality, and it is
held proved that beta-carotene supplements can be harmful to smokers
Sulphasalazine Induced Toxic Epidermal Necrolysis A Case Reportiosrphr_editor
Toxic Epidermal Necrolysis (TEN) is a rare and life threatening mucocutaneous reaction
characterized by extensive necrosis and detachment of epidermis. The Worldwide incidence of TEN is 0.9 to 1.4
per million populations per year [1]. Here we have discussed a case of Toxic Epidermal Necrolysis secondary
to Sulfasalazine managed with fluid replacement, analgesics, anti-infective therapy aggressive nutritional
support and intravenous high dose steroid therapy.
Keywords- Toxic Epidermal Necrolysis, Sulfasalazine
Evaluation the efficacy of IVIgG in treatment of Hemolytic Disease of Newborniosrphr_editor
Hemolytic disease of newborn (HDN) is an important cause of hyperbilirubinemia in the
neonatal period,and delayed diagnosis and treatment may lead to permanent brain damage. Traditional
neonatal treatment of HDN is intensive phototherapy and exchange transfusion.Intravenous
immunoglobulin(IVIgG) has been introduced as an alternative therapy to exchange transfusion. This study was
conducted to assess the effect of IVIG in HDN .
FIBROLIPOMATOUS HAMARTOMA OF ULNAR NERVE: A RARE CASE REPORT.iosrphr_editor
Nervous fibrolipomatous hamartoma is said to be a rare tumor-like condition involving the peripheral
nerves,in which the epineurium and perineurium are enlarged and distorted by excess of fatty and fibrous tissue
s that infiltrate between and around nerve boundaries. The median nerve is more likely to develop a hamartoma
than other nerves with a predilection for the carpal tunnel.
A fibrolipomatous hamartoma – is a rare, benign, congenital lesion most commonly found in the median nerve,
usually at the level of the wrist or hand.
We report a case of this rare condition in ulnar nerve.
SELF MEDICATION PRACTICES FOR ORAL HEALTH PROBLEMS AMONG DENTAL PATIENTS IN B...iosrphr_editor
Introduction: Self‑ medication is commonly practiced all over the world. Self-medication is defined as the use
of medication by a patient on his own initiative or on the advice of a pharmacist or a lay person instead of
consulting a medical practitioner. The present study was aimed to estimate the prevalence of self-medication for
oral health problems among dental patients in Bengaluru city; to identify triggering factors that could influence
self-medication practices; to identify sources of medications used; to identify sources of information about
medications used; and to identify reasons for self-medication.Study Design: A Cross sectional Study.Methods:A
survey was conducted among 175 subjects among dental patients in Bengaluru city. Data were collected
through a specially designed proforma using a closed‑ ended, self‑ administered questionnaire containing 15
questions, in five sections.
Results: The prevalence of
Clinico-haematological Profile of Falciparum Malaria in a Rural Hospital of T...iosrphr_editor
Aim: To study the clinico-haematological profile malaria in a rural hospital of Tripura.
Material and methods: A cross-sectional hospital-based study was done from at Kulai District
Hospital,Tripura. This hospital based cross sectional study was done on 60 confirmed cases of falciparum
malaria (either by peripheral smear or rapid diagnostic test) admitted in Kulai District Hospital. A case sheet
proforma was prepared and data (demographic profile,clinical feature, investigation, treatment, and
complication) from all indoor patients was collected and analyzed.
Result: Out of 60 patients, 40(66.6%) were males and 20 (33.4%) were females. Most of the patients were
between the age group 21-40 years with the highest prevalence between the age group of 21-30. Fever was the
most common symptom. Anemia was present in 42(70%) patients, out of which 6(10%) patients had severe
anemia. Thrombocytopenia was present in 36(60%) patients.Abnormal liver function tests were observed in
26(43.3%) subjects while abnormal kidney function tests were observed in16(26.6%) patients. All the 60
patients received Artemisinin based antimalarial drugs.
Conclusion: Early detection, prompt management, and adequate supportive therapy may reduce mortality due
to falciparum cerebral malaria.
Indonesian Wild Ginger (Zingiber sp) Extract: Antibacterial Activity against ...iosrphr_editor
Lempuyang gajah (Zingiber zerumbet (L.) Smith), lempuyang pahit (Zingiber amaricans BL.), and
lempuyang wangi (Zingiber aromaticum Vahl.) are used as traditional medicine (jamu) in Indonesia. It is also
used for treatment of microbial infections, helps to increase appetite and stimulate digestion in chickens.
Information on their uses are available, but only limited in the scientific data on their bioactivity. The study was
conducted on the antibacterial effect of organic extracts of these plants with Mycoplasma gallisepticum as the
agent of chronic respiratory disease in chickens. Juice and extracts of fresh and dried rhizome are evaluated
through the disc diffusion assay and minimum inhibitory concentration. Oxytetracyclin (30 µg) are used as
standards. All extracts are individually exhibited as antibacterial activity against Mycoplasma gallisepticum (7
± 0.11 mm to 21 ± 0.86 mm). The minimum inhibitory concentration (MIC) determination of plants extracts are
ranged from 7.8 mg/ml to 31.2 mg/ml. The preliminary results suggested promising antibacterial properties of
wild ginger from Indonesia, and probably could be used in management of chronic respiratory disease in
chickens.
A case of allergy and food sensitivity: the nasunin, natural color of eggplantiosrphr_editor
Abstract: Allergies and food sensitivities can both be considered as "adverse reactions individualistic" to food.
Are pathological and individual forms because they affect a few individuals in way rather serious; immediate
or delayed reactions occur instead with simple effects histamine, or, in severe cases with respiratory and
anaphylactic shock
The eggplant (Solanum melongena L.) is known to cause food allergies in some Asian countries, but detailed
studies on allergies caused by eggplant are lacking, however, it was highlighted the presence of allergens in
edible parts of eggplant with preponderance in the peel .
The purpose of this study was to propose an extraction method rapid, efficient and cost of natural dye from
waste products from the food industry, such as the peels of eggplant, from which it was extracted, isolated and
purified the nasunin,a colored molecule in red-fuchsia.
Nasusin was tested on 58 patients to evaluate the potential sensitizing effect on the skin. The results demonstrate
that allergenic effects are negligible and therefore the nasunin can be used as a colorant in various industrial
sectors with a certain safety margin
Complete NMR Assignment of MogrosidesII A2, II E andIII A1Isolated from Luo H...iosrphr_editor
NMR analysis allowed complete assignments of three known mogrol glycosides, Mogroside IIA2 (1),
II E (2)and IIIA1 (3), isolated from the extracts of Luo Han Guo. Herein, complete 1H and 13C NMR
assignmentsof all threemogrosidesare described based on NMR experiments (1H NMR, 13C NMR, COSY,
HSQC-DEPT, HMBC, NOESY and 1DTOCSY) and mass spectral data.
Nanoemulsion and Nanoemulgel as a Topical Formulationiosrphr_editor
: Nanoemulsion is referred type of emulsion with uniform and extremely small droplet size in the range
of 20-200 nm. Nanoemulsion provides numerous advantages over other carrier such as polymeric nanoparticle
and liposomes, including low cost preparation procedure, high hydrophilic and lipophilic drug loading system
to enhance the longer shelf live upon preserving the therapeutic agents. Incorporating the preparation of
nanoemulsion with hydrogel matrix to produce nanoemulgel exhibited by the two separate systems that forming
it. Nanoemulgel possesses the properties of thixotropic, non-greasy, effortlessly spreadable, easily be removed,
emollient, not staining, soluble in water, longer shelf life, bio-friendly, translucent and agreeable appearance.
Pharmacokinetics of High-Dose Methotrexate in Egyptian Children with Acute Ly...iosrphr_editor
Aim:Since several factors have been shown to influence the clearance of methotrexate, the purpose of this study
was to identify potential relationships between patient covariates and the methotrexate clearance estimates and
deduce a pharmacokinetic model for the estimation of methotrexate clearance in Egyptian pediatric ALL
patients that may help dosage adjustment and achieve target steady-state plasma concentrations in a similar
sittings.
Patients and methods: A total of 94 pediatric patients with B-cell ALL, of whom 70 were the studied population
and 24 were the test population, were treated with four courses of HDMTX doses 2.5 gm/m2
(low-risk arm) or 5
gm/m2
(standard-/high-risk arm) given every other week by intermittent intravenous infusions over 24 hours as
a part of their treatment protocol. Patients were monitored for the 24 hour MTX concentration and the systemic
methotrexate clearance was calculated for each methotrexate dose
Epidemiology of Tuberculosis (TB) in Albania 1998-2009iosrphr_editor
Abstract : In Albania, many people erroneously think that tuberculosis (TB) is a disease of the past-an illness
that no longer constitutes a public health threat. Surveillance is an integral part of tuberculosis (TB) control.
Albania has a highTB notification rate and there are doubts about underreporting. The evolution of the
incidence of tuberculosis is presented, together with more detailed figures over the period 1998-2009. These
figures were obtained by the monthly forms (called 14/Sh) compared with the individual notification data.
Objective: To examine the distribution and sources of increased tuberculosis (TB) morbidity and reporting
system deficiencies in the Albania from 1998 through 2009. Metodology: The study is descriptive one conductet
during the period 1998-2009. The statistical analysis is based on data reported from regional level (regional
epidemiological departments) to the central level (Public Health Institute). Results: The main findings were:
discordance between the collected data (individual form) and reported data (monthly form); tuberculosis
incidence rate shows little oscillations which ranges from 6.67 to 9.2 cases/100.000 population; 50% of the
regions show a lack of information on the confirmation of diagnosis and laboratory examination type used for
confirmation. Conclusion: TB disease in high-risk populations where it is difficult to detect, diagnose, and treat;
limitations of current control measures and the need for new tests and treatments, including an effective
vaccine; improving information system, regulation of individual form and personnel training.
Total Phenol and Antioxidant from Seed and Peel of Ripe and Unripe of Indones...iosrphr_editor
Study on total phenol and antioxidantactivity ofsugar apple fruits of various solvent, part of fruits, and level of ripening. Solvent extraction used were 80% (v/v) methanol, 50% (v/v) acetone, boiling water, and 50% (v/v) ethanol. Part of fruits thatbeen used for samples were seed and peel which are normally by products of sugar apple processing, level of ripening were unripe, and ripe sugar apple fruits. Total phenol was determined by Folin-ciocalteau method. Total antioxidant was quantified by 1,1-diphenyl-2-picrylhydrazyl(DPPH) method.Therewas a difference in type of solvent, part of fruits, and level of ripeningon total phenol and antioxidant concentration of sugar apple fruits. Seeds have higher total phenol concentration than peels of this fruits. Unripe sugar apple fruits have higher total phenol and antioxidant than ripe fruit. The best solvent for phenol extraction was ethanol 50%butthe best solvent for antioxidant extraction was acetone 50%.
A Review on Step-by-Step Analytical Method Validationiosrphr_editor
When analytical method is utilized to generate results about the characteristics of drug related samples it is essential that the results are trustworthy. They may be utilized as the basis for decisions relating to administering the drug to patients. Analytical method validation required during drug development and manufacturing and these analytical methods are fit for their intended purpose. To comply with the requirements of GMP pharmaceutical industries should have an overall validation policy which documents how validation will be performed. The purpose of this validation is to show that processes involved in the development and manufacture of drug, production and analytical testing can be performed in an effective and reproducible manner. This review article provides guidance on how to perform validation characteristics for the analytical method which are utilized in pharmaceutical analysis.
A Cross Sectional Study of Ethnic Differences in Occurrence and Severity of A...iosrphr_editor
Non-steroidal anti-inflammatory drugs are the most widely used "over the counter" medication all over the world despite their complications in different major organs. Present studies envisaged for knowing the occurrence and severity of adverse drug reactions from NSAIDs in different ethnic communities of Sikkim. A cross sectional study was undertaken in the medicine outpatients department of a secondary and tertiary care hospital. The patients belonging to Nepalese, Bhutias, Lepchas ethnic communities and others community (settlers from other parts of India) were included to analyzed the data based on the age and gender, ethnicity and ADRs, drugs and ADRs. Severity assessment was done using Hartwing and Siegel scale and causality assessment by Naranjo scale. Total 109 cases of ADRs, predominating in female were detected. Nepalese were the most affected and Gastrointestinal tract (GIT) being the most affected organ in them. Diclofenac showed maximum number of ADRs in all the communities. Maximum number of cases occurred on single day use (40.36%) of drugs. All the cases were belonging to the "possible category" and the maximum being the mild (72.48%) in nature. It is advisable to consider the ethnic/racial differences equally with other factors, to improve the safety and efficacy of a drug.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
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Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journey
MICRORNAs: A REVIEW STUDY
1. IOSR Journal Of Pharmacy
(e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219
www.iosrphr.org Volume 5, Issue 6 (June 2015), PP. 33-42
33
MICRORNAs: A REVIEW STUDY
Shirsa Udgata1
, Rutuja Sheth2
, Vijendra Rane3
1
(Department of Biotechnology, MGM’s College of Engineering and Technology, India)
2
(Department of Biotechnology, MGM’s College of Engineering and Technology, India)
3
(Department of Biotechnology, MGM’s College of Engineering and Technology, India)
ABSTRACT: MicroRNAs (miRNAs) are endogenous short (20–22 nucleotides) non-coding RNA molecules
that mediate gene expression. This is an important regulatory mechanism to modulate fundamental cellular
processes such as differentiation, proliferation, death, metabolism, and pathophysiology of many diseases. The
miRNA expression profile of the kidney differs greatly from that of other organs, as well as between the different
regions in the kidney. In kidneys, miRNAs are indispensable for development and homeostasis. In this review,
we explore the involvement of miRNAs in the regulation of blood pressure, hormone, water, and ion balance
pertaining to kidney homeostasis. We also highlight their importance in renal pathophysiology, such as in
polycystic disease, diabetic nephropathy, nephrogenic diabetes insipidus, hypertension, renal cancer, and
kidney fibrosis (epithelial–mesenchymal transition). In addition, we highlight the need for further investigations
on miRNA-based studies in the development of diagnostic, prognostic, and therapeutic tools for renal diseases.
[1]
KEYWORDS: miRNAs, siRNAs, Cancer, Immune system, therapeutic method.
I. INTRODUCTION
Gene expression in cells and tissues of every complex organism is precisely controlled and largely
dependent on different conditions (such as development, changes in the environment, diseases or drugs).
Various cells and organ systems within such organism (including humans) contain different gene expression
profiles, thus proper understanding of regulatory mechanisms involved in such expression represents one of the
key issues in genomic medicine.
Non-coding RNA molecules have a role in plethora of regulatory events – from controlling the number
of copies in bacterial division to X-chromosome inactivation in mammals. Recent analyses of the human and
animal genomes have shown that most of RNA transcripts do not code for proteins (i.e. they are messenger
RNAs or mRNAs), but are instead noncoding RNAs (ncRNAs).
MicroRNAs (or miRNAs) comprise a novel class of small, non-coding endogenous RNAs that regulate
gene expression by directing their target mRNAs for degradation or translational repression. Their discovery
added a new dimension to the understanding of complex gene regulatory networks in humans and animals alike.
1. History of microRNAs:
MicroRNA (miRNA) was initially discovered in Caenorhabditis elegans by Victor Ambros' laboratory
in 1993 while studying the gene lin-14. At the same time, Gary Ravkun identified the first miRNA target gene.
Those two groundbreaking discoveries identified a novel mechanism of posttranscriptional gene regulation.
However, the importance of miRNA was realized seven years later when Ravukon and Horvitz
laboratories identified a second miRNA in the same model nematode species (named let-7), and when another
class of short RNA (siRNA) involved in the process of RNA interference was discovered. Only then it became
obvious that short non-coding RNA molecule identified in 1993 was part of a much bigger phenomenon.
Since then, an increasing number of miRNAs have been recognized in mammals. In humans alone over
700 miRNAs have been identified and fully sequenced, and the estimated number of miRNA genes in a human
genome is more than one thousand. Based on computer models, miRNAs in humans have a direct influence on
at least 30% of the genes in the whole genome. [1]
2. MICRORNAs: A REVIEW STUDY
34
2. What are microRNAs?
miRNAs represent small RNA molecules encoded in the genomes of plants and animals. These highly
conserved 22 nucleotides long RNA sequences regulate the expression of genes by binding to the 3'-untranslated
regions (3'-UTR) of specific mRNAs. A growing body of evidence shows that miRNAs are one of the key
players in cell differentiation and growth, mobility and apoptosis (programmed cell death).
Differentiating miRNAs from other classes of small RNAs that are present in the cell is often
cumbersome – particularly the distinction from endogenous small interfering RNAs (siRNAs). The most
significant distinction between miRNAs and siRNAs is whether they silence their own expression. Almost all
siRNAs (regardless of their viral or other origin) silence the same locus from which they were derived. On the
other hand, most miRNAs do not silence their own loci, but other genes instead.
miRNAs regulate diverse aspects of development and physiology, thus understanding its biological role is
proving more and more important. Analysis of miRNA expression may provide valuable information, as
dysregulation of its function can lead to human diseases such as cancer, cardiovascular and metabolic diseases,
liver conditions and immune dysfunction. [2]
II. DIFFERENCE BETWEEN SIRNA AND MICRORNA
The process by which double-stranded RNAs initiate the degradation of homologous RNA is known as
RNA interference. In 2006, the Nobel Prize in Medicine and Physiology was awarded to Drs Andrew Fire and
Craig Mello for their discovery of siRNA, which guides the cleavage of mRNA. siRNAs regulate the
degradation of mRNA molecules identical in sequence to that of the corresponding siRNA, resulting in the
silencing of the corresponding gene and the shutting down of protein synthesis. The main mechanism of action
of siRNA is the mRNA cleavage function. There are no genes that encode for siRNAs. siRNAs can also silence
gene expression by triggering promoter gene methylation and chromatin condensation.
In contrast with siRNAs, miRNAs are encoded by specific miRNA genes as short hairpin pri-miRNAs
in the nucleus. miRNAS are also small noncoding RNAs, but they seem to require only a 7- to 8-base-pair
"seed" match between the 5' region of the miRNA and the 3'UTR of the target. It would seem that the majority
of miRNA targets are translationally repressed; however, degradation of the target mRNA can also occur. The
main mechanism of action of miRNA may be the inhibition of mRNA translation, although the cleavage of
mRNA is also an important role siRNAs are synthesized from double-stranded segments of matched mRNA via
RNA-dependent RNA polymerase. miRNAs are synthesized from an unmatched segment of RNA precursor
featuring a hairpin turn. siRNAs are often derived from repetitive DNA sequences and associated transposons
and centromeres, forming heterochromatin structures. Both siRNAs and miRNAs are produced by Dicer-
mediated cleavage of longer double-stranded RNA precursors. However, miRNAs are entirely endogenous,
whereas siRNAs may be endogenous or exogenously derived from viruses. Also, miRNAs cluster in "families"
closely related as far as the sequence is concerned or as individual units. siRNAs can exist as repeated elements.
[3]
Attribute siRNA miRNA
Primary mode of action Inhibition of translation mRNA cleavage
Secondary mode of action mRNA cleavage Chromatin silencing
Synthesis Endogenous Endogenous or exogenous of dsRNA
Hairpin Structure No Yes
Length 19-23 bases 19-24 base pairs
Impact on protein synthesis Indirect Indirect
Potential use in cancer diagnosis Unknown Yes
Table 1.[4]
Hundreds of miRNAs have now been identified in various organisms, and the RNA structure and
regulatory mechanisms that have been characterized in lin-4 and let-7 still provide unique molecular signatures
as to what defines miRNAs. miRNAs are generally 21–25nucleotide, non-coding RNAs that are derived from
larger precursors that form imperfect stem-loop structures. The mature miRNA is most often derived from one
arm of the precursor hairpin, and is released from the primary transcript through stepwise processing by two
ribonuclease-III (RNase III) enzymes.At least in animals, most miRNAs bind to the target-3′ UTR with
imperfect complementarity and function as translational repressors.
3. MICRORNAs: A REVIEW STUDY
35
Almost coincident with the discovery of the second miRNA, let-7, small RNAs were also characterized
as components of a seemingly separate biological process, RNA interference (RNAi). RNAi is an evolutionarily
conserved, sequence-specific gene-silencing mechanism that is induced by exposure to dsRNA. In many
systems, including worms, plants and flies, the stimulus that was used to initiate RNAi was the introduction of a
dsRNA (the trigger) of ~500 bp.The trigger is ultimately processed in vivo into small dsRNAs of ~21–25 bp in
length, designated as small interfering RNAs (siRNAs). It is now clear that one strand of the siRNA duplex is
selectively incorporated into an effector complex (the RNA-induced silencing complex; RISC). The RISC
directs the cleavage of complementary mRNA targets, a process that is also known as post-transcriptional gene
silencing (PTGS).The evolutionarily conserved RNAi response to exogenous dsRNA might reflect an
endogenous defense mechanism against virus infection or parasitic nucleic acids. Indeed, mutations of the RNAi
components greatly compromise virus resistance in plants, indicating that PTGS might normally mediate the
destruction of the viral RNAs. In addition, siRNAs can also regulate the expression of target transcripts at the
transcriptional level, at least in some organisms.Not only can siRNAs induce sequence-specific promoter
methylation in plants, but they are also crucial for heterochromatin formation in fission yeast, and transposon
silencing in worms. [5]
III. FUNCTIONS OF MICRORNAS
1. Involvement of microRNAs in the control of gene expression
The basic mechanism leading to alteration of gene expression is based on the recruitment of mature
miRNA at the level of the RISC silencing complex. This process occurs in the cytoplasm, where the pre-miRNA
hairpin is cleaved by the RNase III enzyme Dicer, which interacts with the 30 end of the hairpin and cuts away
the loop joining the 30 and 50 arms, yielding an imperfect miRNA/ miRNA duplex. One of the strands is
incorporated into the RISC, where it binds to target mRNA sequences. Animal miRNAs are usually
complementary to a site in the 30UTR. Perfect or near perfect base pairing with the target RNA promotes
cleavage of the RNA. It is proposed that in the case of partially complementary microRNAs, in order to
recognize their targets, nucleotides 2–7 of the miRNA (the ‘seed region’) are important. This is the key process
permitting mature miRNAs to exert their effects in gene regulation. The final effect of miRNAs activity is the
inhibition of the synthesis of the protein(s) encoded by the target mRNA(s). This has of course important
biological implications depending on the role of the protein in the cellular network. Since a single 30UTR of a
given mRNA contains signal sequences for several microRNAs, applied biological studies are needed to
determine which microRNA should be targeted to achieve alteration of gene expression. Possible effects on the
expression of other mRNA targets should be considered. An alteration of a single microRNA may exhibit
multiple effects, possibly in combination with the targeting activity of other miRNAs, enabling the achievement
of strong biological effect. [4]
2. Biogenesis of microRNAs and drug design
Some miRNAs are encoded by unique genes (intergenic miRNAs) and others are embedded into the
intronic regions of protein-coding genes (intragenic miRNAs). Examples of intergenic miRNA are miR-210,
miR-10a, miR-21, and miR-222/miR-221, which are encoded by unique genes located in the chromosome 11,
17, 17, 6 and X, respectively. The transcription is controlled, as protein-coding genes, by a promoter which is
regulated by specific interactions with transcription factors. The transcription by RNA polymerase II of these
miR genes gives rise to long primary miRNAs (pri-miRNAs) with typical stem-loop structures. These are
rapidly processed by the nuclear RNase endonuclease-III Drosha, which, removing the branches, gives rise to
precursor miRNAs (pre-miRNA) of around 60–100 nts in length. An example of intragenic miRNA is miR-301.
Its genomic sequences are embedded into the intronic regions of ska2. In this specific case, the transcription of
miRNA sequences depends on the cellular promoter of the host gene. The miR sequences follow the splicing
pathways giving rise to a ‘‘Mirtron’’ (microRNA/ intron) sequence further processed by debranch enzymes to
generate a pre-miRNA. The microRNA transcription can be controlled by targeting regulatory transcription
factors, the microRNA promoter itself, or the promoter of the host gene. An example is that reported by Xi et
al., showing that knocking-down of C-EBP-b induces a decrease of the recruitment of this transcription factor
on the promoter of the LOC554202 gene (hosting miR-31) and down-regulation of miR-31. [4]
4. MICRORNAs: A REVIEW STUDY
36
Fig. 1 MicroRNA (miRNA)—biogenesis and function. The biosynthesis of miRNAs, as well as their activity
in translational repression (RNA interference (RNAi)) and transcriptional modulation (RNAa or RNAi), is
represented diagrammatically. Pre-miRNA, precursor miRNA; RISC, RNA-induced silencing complex; RNAa,
RNA activation. [6]
3. Post-transcriptional repression by miRNAs
The precise molecular mechanisms that underlie posttranscriptional repression by miRNAs still remain
largely unknown. One of the best-studied examples is lin-4, which negatively regulates its target, lin-14, by
repressing its translation16. Base pairing between lin-4 and lin-14 has proved to be crucial for their interaction
in vivo, as mutations that affect their complementarity compromise or abolish this negative regulation.
Interestingly, lin-4 only inhibits the synthesis of the LIN-14 protein but fails to affect the synthesis,
polyadenylation state or abundance of lin-14mRNA. Furthermore, the initiation of lin-14 translation seems to
occur normally in the presence of lin-4, because lin-14 mRNAs are efficiently incorporated into polyribosomes
regardless of lin-4 expression16.Therefore, it is reasonable to speculate that the translational repression by lin-4
occurs after translational initiation, probably during translational elongation and/or the subsequent release of the
LIN-14 protein. Translational repression of target genes is not specific to lin-4; in fact, it turns out to be the
predominant mechanism by which miRNAs negatively regulate their targets throughout the animal kingdom.
let-7 and Bantam (which encodes an anti-apoptotic miRNA) bind to the 3′ UTRs of their targets and negatively
regulate their translation in worms and flies, respectively. In addition,miR-30, a mammalian miRNA, inhibits
protein synthesis of a reporter gene that bears an artificial 3′ UTR with miR-30 complementary sites. Although
most animal miRNAs repress target translation, one miRNA, mir-196, was found recently to direct mRNA
cleavage of its target, Hoxb8. In plants, however, most miRNAs that have been studied so far mediate the
destruction of their target mRNAs.
Despite progress in identifying protein and RNA components of the RISC, the biochemical mechanism
by which this complex functions still remains unknown. Genetic screens combined with biochemical
purification have pinpointed several important components. Argonaute (AGO) proteins belong to an
evolutionarily conserved family that is defined by the presence of a PAZ domain and a Piwi domain. AGO-
family proteins have been consistently co-purified with RISC activity in many organisms, and mutations in
AGO homologues have been associated with distinct developmental and/or RNAi phenotypes. As a core
component of the RISC, the AGO family has multiple homologues in each metazoan species (24 for C. elegans,
5 for D. melanogaster and 8 for mammals). Given the diverse mutant phenotypes and expression patterns of
AGO homologues, RISCs might come in different flavours and act in a tissue-specific or a developmentally
regulated manner. [4]
5. MICRORNAs: A REVIEW STUDY
37
4. Functional characterization of miRNAs
Although the studies of lin-4 and let-7 shaped our understanding of miRNA molecular structures and
functional mechanisms, their roles in temporal regulation of development only revealed one of many possible
aspects of miRNA function.Mutations in Dicer homologues disrupt the biogenesis of miRNAs, and cause
diverse developmental defects, including germline defects in C. elegans, abnormal embryogenesis in A.
thaliana, developmental arrest in zebrafish and depletion of stem cells in mice. Mutations in AGO family
proteins are also associated with pleiotropic developmental phenotypes, such as premature MERISTEM
differentiation in A. thaliana zwille mutants, defective embryogenesis and larval development in C. elegans alg-
1 and alg-2mutants and decreased stem-cell self-renewal during oogenesis in Drosophila piwi mutants. Because
Dicer and AGO are essential components in miRNA and siRNA biogenesis and function, these defects might
reflect the collective functions of multiple miRNAs and/or siRNAs that are expressed during early development.
[4]
IV. MICRORNAS AND CANCER
MicroRNAs play a pivotal role in cancer. The literature on this specific issue is impressive (see the
Human MicroRNA Disease Database. MicroRNAs play a double role in cancer, behaving both as oncogenes or
tumor suppressor genes. In general, miRNAs promoting cancer target mRNA coding for tumor-suppression
proteins, while microRNAs exhibiting tumor-suppression properties usually target mRNAs coding oncoproteins.
MicroRNAs which have been demonstrated to play a crucial role in the initiation and progression of human
cancer are defined as oncogenic miRNAs (oncomiRs). Moreover, microRNAs have been definitely
demonstrated to be involved in cancer metastasis (metastamiRs. For instance, miR-372 and miR-373 were
identified as oncogenes, after the screening of hundreds of miRNAs. The mechanism of action of these
microRNAs is to negatively regulate the expression of the LAST2 tumor suppressor gene, thus blocking the
pathway of one of the key tumor suppressors, p53. Using breast cancer MCF7 as a model system, Huang et al.
were able to demonstrate that miR-373 promotes tumor invasion and metastasis. A similar tumor-promoting
activity is exhibited by miR-221 and miR-222, able to stimulate proliferation following inhibition of the
expression of the tumor suppressor p27Kip1. An opposite effect on tumor development is displayed by other
miRNAs; for instance miR-31 expression levels correlate inversely with the metastatic ability of breast tumor
cell lines, and the inhibition of miR-31 promotes metastasis. Further studies have revealed that miR-31 blocks
several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and
metastatic colonization. Another interesting feature of the miRNA life was found by studying cancer associated
miRNAs in different experimental model systems, i.e. that cancer-specific miRNAs are present in extracellular
body fluids, and may play a very important role in the cross-talk between cancer cells and surrounding normal
cells [5]. The extracellular miRNA are protected by exosome-like structures, small intraluminal vesicles shed
from a variety of cells (including cancer cells), with a biogenesis connected with the endosomal sorting complex
required for transport (ESCRT) machinery in multivesicular bodies (MVB). These extracellular structures,
originally considered as a ‘‘garbage bag’’ devoted to discard degraded proteins, are now considered of interest
as an intercellular communication tool. It is still unclear whether these exosome-associated miRNAs are the
result of tumor cell death and lyses, or are actively excreted from tumor cells into the microenvironment.
However, this novel secretory machinery of miRNAs may be involved in tumorassociated features, such as
enhancement of angiogenesis, increase of cytokine secretion and migration to a pre-metastatic niche [7]. In
conclusion, miRNAs are deeply involved in tumor onset and progression, so that therapeutic strategies involving
miRNA silencing have been proposed. Since miRNAs can behave as tumor suppressor genes, miRNA
replacement therapy has been also proposed as a possible therapy of cancer. [5]
V. MIRNA IN INFLAMMATORY DISEASES AND IMMUNE RESPONSE SYSTEM
Recently miRNAs have emerged as fine-tune regulators of innate and acquired immune response
systems. The recognition on miRNAs in inflammation has in turn furthered our understanding of the molecular
pathogenesis of autoimmune diseases, cancers, asthma to name a few. However, due to inherent complexities of
miRNA regulation of targets, we are still in an early stage of exploring the functional roles of miRNAs in
inflammatory diseases. Certain miRNAs serve as important components of negative feedback loops in the
immune system (miR-146a), whereas others serve to amplify the response of the immune system (miR-155). In
addition, role of miRNA can be cell- or tissue- specific. It is likely that multiple miRNAs rather than single
miRNAs, synergistically act together to regulate gene expression and thus biological networks in response to
stress. Thus, a better understanding about how miRNAs regulate gene networks in general may provide insights
into novel regulatory mechanisms. [8]
6. MICRORNAs: A REVIEW STUDY
38
VI. MICRORNAS IN VIRAL DISEASES
Viral genes encode miRNAs and these miRNAs have a regulatory effect on the viral protein-coding
genes .Hepatitis B Virus (HBV) has been found to encode a candidate pre-miRNA, suggesting that HBV has the
capacity to use viral miRNAs to regulate its own gene expression. miRNAs from the host cells may also play a
role in regulating viral genes. It has recently been reported that miRNA-122 facilitates the replication of
Hepatitis C Virus (HCV) by targeting the viral 5’ non-coding region. Expression of a total of 30 cellular
miRNAs in hepatocytes has been influenced by IFN-α/β or IFN-γ. In this , eight of the miRNAs (miR-1, miR-
30, miR-128, miR-196, miR-296, miR-351, miR-431 and miR-448) were shown to be upregulated which also
have an almost perfect complementarity with HCV RNA genomes. This suggests that these miRNAs are
capable of inhibiting HCV replication and infection.
VII. MICRORNAS IN NEURODEVELOPMENTAL DISEASES
MicroRNAs are highly expressed in human and other mammalian brains relative to other organs. The
results of high-throughput sequencing experiments suggest that the number of miRNAs expressed in human
brain should be over 1000, although currently this number stands at about 550 in all humans. The expression of
miRNAs in brain changes during brain MicroRNAs in Cardiovascular Disease development. Therefore, some
miRNAs are expressed more abundantly during early development in the mammalian brain, and some are
expressed less during later development. The changes in miRNA expression levels in brain during development
may represent biochemical signals for cell fate determination, apoptosis and/or cell division programming.
Some miRNAs are differentially expressed in neuronal nuclei, and/or different cell populations in brain.
Because miRNAs are known to be dynamically regulated in neurogenesis and brain development, it is believed
that miRNAs are also involved in neural development and play an important role in mediating neuronal
plasticity. One of the major common traits linking many of the neurodevelopmental disorders [e.g. intellectual
disability, autism, Attention Deficit Hyperactivity Disorder (ADHD) and epilepsy] is that disease onset occurs
during periods of maturation and development. Therefore miRNAs contribute significantly to the pathogenesis
of neurodevelopmental disorders at the molecular level.
VIII. MICRORNAS IN NEURODEGENERATIVE DISEASES
Neurodegenerative diseases (ND) such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) have
placed substantial social-economic burdens on countries with aging populations. As the pathogeneses of NDs on
molecular levels remain poorly understood, successful treatments are still unavailable. A systemic miRNA
profiling in peripheral blood mononuclear cells from PD patients revealed miR-30b, miR-30c, and miR-26a to
be associated with the susceptibility of the disease. Deregulation of miR-133b expression may contribute to the
pathogenesis as the miR-133b-Pitx3 feedback loop is essential for maintaining dopaminergic neurons in the
brain. An analysis of miRNA and mRNA expression in brain cortex from AD and age-matched control subjects
demonstrated strong correlations between the expression levels of miRNAs and predicted mRNA targets,
implying functional relevance of microRNA-mediated regulations in AD pathogenesis. The expression of miR-
29a, miR-29b-1 and miR-9 was significantly decreased in AD patients, resulting in abnormally high expression
of their target BACE1, a protein playing an important role in AD pathogenesis. These findings highlight the
importance of miRNA research in understanding ND pathogenesis.
IX. MICRORNAS IN CARDIOVASCULAR DISEASE
MicroRNAs play an important role in regulation of heart function and Cardiovascular Diseases.
miRNAs are important regulators of cardiovascular growth, proliferation, cell differentiation, and apoptosis.
Three mirRNAs (miR-1, miR-133, and miR-208) are highly expressed in the heart and are important regulators
of heart development and myocyte differentiation. Deregulated expression of miR-1 and miR-133 were reported
in human heart failure .miR-23a, miR-23b, miR-24, miR-195, miR-199a, and miR-214 were upregulated during
cardiac hypertrophy, and their over-expression in cardiomyocytes in vitro caused an induction of hypertrophic
growth. Interestingly, miR-24, miR-125b, miR-195, miR-199a, and miR-214 were similarly upregulated in the
tissue of patients with end-stage failing human hearts. The investigation into the role of miRNAs as a novel
class of gene regulators in cardiovascular disease is a new frontier for research.
7. MICRORNAs: A REVIEW STUDY
39
Fig 2
DISEASE MI-RNA
Cancer B-CLL miR-15, miR-16
Breast cancer miR-125b, miR-145, miR-21, miR-155, miR-
210
Lung cancer miR-155, let-7a
Gastric cancer miR-145
Liver cancer miR-29b
Viral diseases HCV miR-122, miR-155
HIV-1 miR-28, miR-125b, miR-150, miR-223, miR-
382
Influenza virus miR-21, miR-223
Immune-related diseases Multiple sclerosis miR-145, miR-34a, miR-155, miR-326
Systemic lupus
erythematosus
miR-146a
Type II diabetes miR-144, miR-146a, miR-150, miR-182,
miR-103, miR-107
Nonalcoholic fatty liver
disease
miR-200a, miR-200b, miR-429, miR-122,
miR-451, miR-27
Non-alcoholic
steatohepatitis
miR-29c, miR-34a, miR-155, miR-200b
Neurodegenerative
diseases
Parkinson’s disease miR-30b, miR-30c, miR-26a, miR-133b,
miR-184∗, let-7
Alzheimer’s disease miR-29b-1, miR-29a, miR-9
Table 2.
X. MICRORNAS FOR CLASSIFICATION OF DISEASE
MicroRNA expression signatures often reflect embryonic or developmental origin of the tumor type.
This greatly facilitates tumor classification based on microRNAs: a blind study of 22 different tumor types
showed microRNA expression classified tumors according to tissue of origin with accuracy higher than 90%.
WHO classification of leukemia is done according to progenitor cell lineage, and microRNA expression across
leukemia subtypes also reflects the cell of origin. Association of expression signatures in acute myeloid
leukemia (AML) revealed specific microRNA expression patterns in each disease subtype. Similarly, in prostate
cancer, microRNA patterns were distinct between different cellular subsets when stem/progenitor cells were
isolated from prostate tumors, showing that microRNA expression patterns are indicative of the cellular
populations in a tumor. Distinct micro-RNA expression patterns have also recently been identified in luminal
8. MICRORNAs: A REVIEW STUDY
40
(epithelial origin), basal-like (myoepithelial origin), and human epidermal growth factor receptor 2 (HER2)
breast cancers. The classification of breast cancer is better defined that most malignancies; however, meta-
analyses of recent clinical trials have shown incorrect classification of a substantial number of tumors in
laboratories with high volume testing (fluorescence in situ hybridization and immunohistochemistry-based
tests), and therefore microRNA analysis may add robustness to current testing. Various cancer subtypes have
been identified using the huge body of data at TCGA, and microRNAs are either associated with these changes
or have been used to create subtypes. The identification of microRNAs that target current biomarkers may pave
the way for microRNA-based tests as an alternative to mRNA/protein expression for prognosis assessment.
MicroRNAs have been shown to have a role in cancer progression and might be useful for the prediction of
metastatic outcomes for patient management. Specific microRNAs have been shown to support endothelial
recruitment to metastases in breast cancer and might serve as efficient biomarkers for predicting this event.
MicroRNA signatures associated with known inducers of EMT have also been developed and shown to be
relevant in both in vitro and in vivo models of EMT in endometrial cancer.[9]
XI. MICRORNAS AS DRUGS
Efforts are ongoing to develop miRNA-based drugs, either in the form of miRNA mimics, amplifying
the impact of a miRNA, or miRNA inhibitors, essentially quenching the effect of a miRNA. miRNA drugs have
the advantage that one miRNA may target and modify the expression of several genes with different roles in the
same pathway. The most advanced miRNA drug to date is a miRNA inhibitor which targets miR-122 in liver to
treat hepatitis C virus (HCV). One challenge as such drugs approach clinical use is testing for interactions
between the novel miRNA drugs and traditional drugs already in the market. The link from miRNAs to drugs
allows Pharmaco-miR to predict putative interactions between novel miRNA drugs and more traditional drugs,
which can then be tested experimentally. miR-122 is for instance predicted to target estrogen receptor 1 (ESR1),
whose gene product is essential for the important drug families of estrogens (e.g. estradiol) and anti-estrogens
(e.g. tamoxifen). If this predicted target is functional, treating patients for HCV with miR-122 may cause
adverse drug effects if the patient is also undergoing treatment with estrogens or anti-estrogens.[10]
1. Discovering the first micro-RNA trageted drug:
MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process
in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery
programs that focus on developing miRNA-based therapeutics. The most advanced of these programs targets the
liver-expressed miRNA-122 using the locked nucleic acid (LNA)–modified antisense oligonucleotide
miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for
treatment of hepatitis C virus (HCV) infection.
2. MicroRNAs as predictors of drug efficacy:
Although not yet used in clinical decision making, several studies have associated microRNAs with
well-known biomarkers for treatment therapy decisions. For example, in chronic myeloid leukemia (CML),
levels of cells with the BCR-ABL rearrangement, which characterizes this dis-ease, decrease over time with
imatinib treatment. It has been discovered that miR-451 levels inversely correlate with BCR-ABL levels at both
the time of diagnosis and on treatment. SNPs in microRNA target sites may also be predictors of response; the
LCS6 polymorphism in the let-7 binding site in the 30UTR of KRAS predicted response to anti-EGFR-based
therapy in 100 metastatic CRC cancer patients. Base excision repair genes have been associ-ated with treatment
resistance, and variations in the microRNA binding sites of the 30UTRs of these genes have been shown to
reflect CRC cancer prognosis and treatment response. A notable and interesting example of altered target sites in
cancer is the creation of an illegitimate target site for miR-191 in the 30UTR of MDM4 by the presence of
SNP34091, which affects chemosensitivity in ovarian cancer. MicroRNA polymorphisms predisposing cancer
Aside from treatment resistance, it is worth noting that a number of SNPs in microRNA binding sites are
involved in cancer risk and may be markers for genetic susceptibility studies in some cancers. They can be used
as markers to predict subsets of patients at risk of poor outcome or lack of treatment response. These SNPs may
be present in microRNA target sites, in the processing machinery, or in the microRNA sequence, altering the
target of the microRNA and its ability to be processed.[9]
9. MICRORNAs: A REVIEW STUDY
41
3. MicroRNAs as non-invasive biomarkers
The use of circulating microRNAs as markers in different cancer types is a rapidly developing area.
Tumor cells can release microRNAs, stabilized by their incorporation into microvesicles, which have shown
stability in the cir-culation following multiple freeze–thaw cycles and pro-longed exposure to room temperature.
MicroRNAs have also shown stability in other bodily fluids, such as urine and saliva; however, most studies
have centered around serum microRNAs as biomarkers. A study of 391 patients with non-small cell lung cancer
(NSCLC) identi-fied 35 highly expressed microRNAs with predicted bind-ing sites for at least one of 11 genes
of the TGF-b pathway, which were significantly differentially expressed at the extremes of survival. Of these,
17 were associated with patient survival and were combined into a risk score that significantly predicted
survival in advanced NSCLC. Furthermore, isolation of exosomes from serum showed that a signature involving
two microRNAs and one small non-coding RNA can be used for non-invasive diagnosis of glioblastoma. The
detection of microRNAs in the blood presents some challenges, and there is an overwhelming discordance
between reports in well-studied cancers. Appropriate endogenous controls for microRNA quantification in
serum are under debate because many mRNA and rRNA species are absent in blood due to circulating RNases.
Clini-cally, fluctuations of circulating microRNAs can occur as a result of treatment, diet, and other factors,
increasing noise in these assays. The presence of myeloid and lymphoid cells can alter the levels of certain
microRNAs, and viral infections of the patient might also affect endogenous microRNA expression. Expression
changes of microRNAs are rapid in blood, and even a traumatic venepuncture may have the potential to
influence expression. Despite these hurdles, it is clear that further study is warranted for detection of the
presence of microRNAs in the blood for future non-invasive biomarker development, and the field is moving
rapidly towards that goal.
4. MicroRNA-based therapeutics and clinical trials
Most current clinical trials are for the use of microRNAs as biomarkers for patient stratification,
prognosis, and drug efficacy, and breast cancer seems to be the cancer under the most study. In few cases are
specific microRNAs stated, and a global expression-profiling platform has been employed for the mining of
appropriate biomarkers. In addition to biomarker studies, microRNAs and anti-micro- RNA constructs are now
under investigation as potential therapeutic agents for cancer. Despite the challenges pre-sented by delivery of
these types of molecule, there are currently two clinical trials for microRNA-based therapeutics. Targeting
microRNAs may be used directly to target tumor cells, and also to enhance other therapies, for example, they
may have a potential use in reducing the drug resistance of tumors as has been shown by the chemo-resistant
properties of miR-100 in small cell lung cancer and the epigenetic silencing of miR-199b- 5p in chemoresistant
ovarian cancer. The most advanced microRNA trial involves use of anti-miR-122 (Miravirsen) for hepatitis C
therapy, which shows reduction in viral RNA with no evidence of resis-tance. Miravirsen is complementary in
sequence to miR- 122 but also has a modified locked-nucleic acid structure, which provides resistance to
degradation and increased affinity for its target. More recent studies have shown that although the intended
target of Miravirsen is mature miR- 122, it also has affinity for pri- and pre-miR-122 leading to reduced
processing and enhancement of its therapeu-tic effect. The first microRNA-based therapy specifically for can-
cer is MRX34: a synthetic miR-34a mimic loaded in lipo-somal nanoparticles. miR-34a is a tumor suppressor
microRNA downstream of p53. Its replacement in cancer cells antagonizes key hallmarks including self-
renewal, migratory potential, and chemo-resistance. MRX34 is in a phase I clinical trial for primary liver cancer
and liver metastases and should complete by the end of 2014. MRX34 nanoparticles readily accumulate in the
liver, and quantification of MRX34 in non-human primates has established a satisfactory 7.7 h half-life in whole
blood. Lipid-based local and systemic delivery of miR-34a in animal studies has also shown positive results for
lung cancer. For microRNA-based therapeutics, resistance may be-come a factor, which may be overcome by
using combina-torial microRNA-based therapies. With similar effect, certain anti-microRNA therapies have the
potential to target whole families of microRNAs, reducing the likelihood of resistance. The study of microRNA-
based therapies is still in its infancy, and side effects of these therapies need to be evaluated. MicroRNAs have
been shown to be exported from cells in exosomes and therefore have the potential for systemic effects which
might only become apparent in clinical trials. Also, the processing of other microRNAs is likely to be dampened
by overloading the microRNA processing machinery with replacement microRNAs, and the effects of this are
uncertain [9].