Septic cardiomyopathy (SCM) is featured by
severe myocardial dysfunction and remains one of the lethal complications in clinical sepsis. Toll-like receptor 4 (TLR4) signaling
is known as a classical innate pathway in heart diseases, whereas
the precise underlying mechanism of TLR4 in SCM remains elusive. This study was designed to examine the specific role of TLR4
in SCM with a focus on inflammation and apoptosis.
This document summarizes research on the effects of exercise on gene expression of inflammatory markers in human peripheral blood cells. It reviews 37 studies that examined gene expression in white blood cells like lymphocytes and monocytes after acute and long-term exercise. The studies found that an acute bout of exercise can upregulate expression of some pro-inflammatory genes like IL-1β, IL-8 and CXCL16 in peripheral blood mononuclear cells. However, long-term regular exercise is associated with attenuated inflammatory response and upregulation of anti-inflammatory genes like IL-10 and IL-13. Gene expression changes depend on exercise duration and intensity. The immune system and inflammatory response play a role in diseases like cardiovascular disease and cancer, so understanding
Toll-like receptors (TLRs) play a key role in the innate immune system and recognize distinct pathogen molecules. TLRs signal through either a MyD88-dependent or TRIF-dependent pathway to activate pro-inflammatory genes. Dysregulation of TLR signaling contributes to inflammatory diseases like sepsis, atherosclerosis, and systemic lupus erythematosus. Inhibiting TLRs through small molecule inhibitors, antibodies, oligonucleotides, or lipid A analogs may help treat these diseases. However, few TLR antagonists have been approved for clinical use.
This document discusses regulatory T cells (Tregs) as potential therapeutic targets for rheumatoid arthritis (RA). It begins with an introduction to RA, describing its causes, symptoms, risk factors, and current diagnostic tools and drug treatments. It then discusses Tregs, which suppress immune responses and help maintain tolerance. Several drugs are proposed that could promote Treg function or numbers to restore normal immune regulation in RA, including TNF inhibitors, T cell costimulatory blocking agents, TLR antagonists, HDAC inhibitors, and interleukin-2. The document concludes that controlling regulatory immune mechanisms through targeting Tregs may provide novel therapeutic approaches for treating autoimmune diseases like RA.
This document provides an overview of sepsis-induced cardiac dysfunction, specifically intrinsic myocardial depression. It discusses several key points:
1) Myocardial depression occurs in 40-50% of patients with septic shock and is associated with worse outcomes. Survivors have lower ejection fractions and higher end-diastolic volumes compared to non-survivors.
2) Biomarkers like troponins and BNP are often elevated in sepsis patients and correlated with severity of illness.
3) Mechanisms contributing to cardiac dysfunction include circulatory changes, autonomic dysregulation, metabolic and mitochondrial dysfunction, inflammation, and calcium trafficking issues.
4) Cytokines and nitric oxide are thought to
A seminar on Molecular mechanisms of drug induced cardio toxicityAkshata Nadgowda
This document summarizes the molecular mechanisms of drug-induced cardiotoxicity. It discusses how drugs can cause cardiotoxicity through several mechanisms, including disrupting ion homeostasis, impairing energy metabolism, and inducing apoptosis and necrosis in heart cells. It describes signaling pathways like mitochondrial permeability transition, Bcl-2 family proteins, caspases, cytokines and p38 MAPK that mediate cell death. Gene regulation pathways like AP-1, TEF-1, SRF and NFATs that are involved in cardiac hypertrophy are also summarized. Specific mechanisms of doxorubicin-induced cardiotoxicity involving oxidative stress, myofibrillar deterioration and calcium dysregulation are also outlined.
1) The study examined how an initial trauma-hemorrhage event (the first hit) modulated the response of plasminogen activator inhibitor 1 (PAI-1) in a subsequent polymicrobial sepsis infection (the second hit).
2) PAI-1 levels were measured in the blood, tissues, and organs. An initial rise in circulating PAI-1 levels was seen after trauma-hemorrhage, followed by a delayed decrease in PAI-1 mRNA levels in organs.
3) After sepsis infection, circulating PAI-1 profiles were similar between mice that experienced trauma-hemorrhage and those that did not. However, PAI-1 mRNA declined more in
This document discusses breaking immune tolerance to cancer (melanoma) by targeting regulatory T cells (Tregs). It suggests that Tregs suppress anti-tumor immune responses by secreting cytokines like TGF-β and IL-10. Depleting Tregs using cyclophosphamide or blocking CTLA-4 with ipilimumab can help activate the immune system. However, some tumors lack "danger signals" like inflammatory cytokines needed to recruit T cells. Stimulating toll-like receptor 4 on macrophages may induce cytokines like IL-6, IL-1β, and TNFα that create an inflammatory microenvironment and promote anti-tumor immunity.
Inflammation and immunity play major roles in coronary heart disease and stroke. Measures that induce regulatory T cells, shifting the immune response away from Th1, show promise for treating atherosclerosis. Considering individual immune response diversity could further improve current cardiovascular risk factor treatments.
This document summarizes research on the effects of exercise on gene expression of inflammatory markers in human peripheral blood cells. It reviews 37 studies that examined gene expression in white blood cells like lymphocytes and monocytes after acute and long-term exercise. The studies found that an acute bout of exercise can upregulate expression of some pro-inflammatory genes like IL-1β, IL-8 and CXCL16 in peripheral blood mononuclear cells. However, long-term regular exercise is associated with attenuated inflammatory response and upregulation of anti-inflammatory genes like IL-10 and IL-13. Gene expression changes depend on exercise duration and intensity. The immune system and inflammatory response play a role in diseases like cardiovascular disease and cancer, so understanding
Toll-like receptors (TLRs) play a key role in the innate immune system and recognize distinct pathogen molecules. TLRs signal through either a MyD88-dependent or TRIF-dependent pathway to activate pro-inflammatory genes. Dysregulation of TLR signaling contributes to inflammatory diseases like sepsis, atherosclerosis, and systemic lupus erythematosus. Inhibiting TLRs through small molecule inhibitors, antibodies, oligonucleotides, or lipid A analogs may help treat these diseases. However, few TLR antagonists have been approved for clinical use.
This document discusses regulatory T cells (Tregs) as potential therapeutic targets for rheumatoid arthritis (RA). It begins with an introduction to RA, describing its causes, symptoms, risk factors, and current diagnostic tools and drug treatments. It then discusses Tregs, which suppress immune responses and help maintain tolerance. Several drugs are proposed that could promote Treg function or numbers to restore normal immune regulation in RA, including TNF inhibitors, T cell costimulatory blocking agents, TLR antagonists, HDAC inhibitors, and interleukin-2. The document concludes that controlling regulatory immune mechanisms through targeting Tregs may provide novel therapeutic approaches for treating autoimmune diseases like RA.
This document provides an overview of sepsis-induced cardiac dysfunction, specifically intrinsic myocardial depression. It discusses several key points:
1) Myocardial depression occurs in 40-50% of patients with septic shock and is associated with worse outcomes. Survivors have lower ejection fractions and higher end-diastolic volumes compared to non-survivors.
2) Biomarkers like troponins and BNP are often elevated in sepsis patients and correlated with severity of illness.
3) Mechanisms contributing to cardiac dysfunction include circulatory changes, autonomic dysregulation, metabolic and mitochondrial dysfunction, inflammation, and calcium trafficking issues.
4) Cytokines and nitric oxide are thought to
A seminar on Molecular mechanisms of drug induced cardio toxicityAkshata Nadgowda
This document summarizes the molecular mechanisms of drug-induced cardiotoxicity. It discusses how drugs can cause cardiotoxicity through several mechanisms, including disrupting ion homeostasis, impairing energy metabolism, and inducing apoptosis and necrosis in heart cells. It describes signaling pathways like mitochondrial permeability transition, Bcl-2 family proteins, caspases, cytokines and p38 MAPK that mediate cell death. Gene regulation pathways like AP-1, TEF-1, SRF and NFATs that are involved in cardiac hypertrophy are also summarized. Specific mechanisms of doxorubicin-induced cardiotoxicity involving oxidative stress, myofibrillar deterioration and calcium dysregulation are also outlined.
1) The study examined how an initial trauma-hemorrhage event (the first hit) modulated the response of plasminogen activator inhibitor 1 (PAI-1) in a subsequent polymicrobial sepsis infection (the second hit).
2) PAI-1 levels were measured in the blood, tissues, and organs. An initial rise in circulating PAI-1 levels was seen after trauma-hemorrhage, followed by a delayed decrease in PAI-1 mRNA levels in organs.
3) After sepsis infection, circulating PAI-1 profiles were similar between mice that experienced trauma-hemorrhage and those that did not. However, PAI-1 mRNA declined more in
This document discusses breaking immune tolerance to cancer (melanoma) by targeting regulatory T cells (Tregs). It suggests that Tregs suppress anti-tumor immune responses by secreting cytokines like TGF-β and IL-10. Depleting Tregs using cyclophosphamide or blocking CTLA-4 with ipilimumab can help activate the immune system. However, some tumors lack "danger signals" like inflammatory cytokines needed to recruit T cells. Stimulating toll-like receptor 4 on macrophages may induce cytokines like IL-6, IL-1β, and TNFα that create an inflammatory microenvironment and promote anti-tumor immunity.
Inflammation and immunity play major roles in coronary heart disease and stroke. Measures that induce regulatory T cells, shifting the immune response away from Th1, show promise for treating atherosclerosis. Considering individual immune response diversity could further improve current cardiovascular risk factor treatments.
Toll-like receptor 9 (TLR9) agonists show potential for cancer treatment. TLR9 agonists activate dendritic cells and enhance B cell antibody production. This can induce antitumor immune responses. Preclinical studies show TLR9 agonists have activity against cancer as monotherapy and in combination with other therapies. Early clinical trials indicate TLR9 agonists have antitumor activity as single agents and enhance antitumor T cell responses when used as vaccine adjuvants. Several TLR9 agonists are being studied in clinical trials for various cancer types.
This document discusses the role of dendritic cells (DCs) in autoimmune diseases. It begins by introducing DCs as professional antigen presenting cells that are involved in both inducing immune responses and maintaining peripheral tolerance. The review then examines the different DC subsets and their potential roles in tolerance induction. It discusses factors that influence the generation of tolerogenic DCs, including their maturation status, intrinsic characteristics, interactions with other immune cells, and the tissue microenvironment. The review challenges the traditional view that immature DCs induce tolerance, presenting evidence that both immature and mature DCs can induce tolerance depending on other factors. It highlights the need to better define the features of DC subsets that induce tolerance.
This study compared the effects of levosimendan, dobutamine, and vasodilator therapy on ongoing myocardial injury in patients with acute decompensated heart failure. The study found that while all treatments were associated with decreases in cardiac troponin I levels and improvements in hemodynamic and functional indicators, levosimendan treatment showed the most pronounced improvements, especially in left ventricular ejection fraction and systolic pulmonary artery pressure. However, none of the treatments significantly reduced cardiac troponin I levels compared to each other. The study demonstrated beneficial effects of short-term use of levosimendan, dobutamine, and nitroglycerin on ongoing myocardial injury in acute decompensated heart failure.
This document describes an experiment investigating the effects of fenugreek extract on macrophage polarization using a THP-1 cell model. THP-1 macrophages were treated with two concentrations of fenugreek extract and the M1 marker CD86 and M2 marker CD163 were measured using flow cytometry. Preliminary experiments determined that EDTA was the optimal method for detaching adherent THP-1 macrophages without reducing cell viability. The results found that fenugreek upregulated CD86 but downregulated CD163 expression. This suggests fenugreek caused polarization of macrophages toward an M1 phenotype, though further shifted this to an M4 phenotype. The effect on CD163 was possibly due to multiple M2 subclasses making expression harder to measure
The Role of Nrf2 in the Attenuation of Cardiovascular DiseaseLifeVantage
This document discusses the role of the transcription factor Nrf2 in attenuating cardiovascular disease through regulating antioxidant defenses. It begins by explaining how oxidative stress contributes to cardiovascular diseases and how early trials of antioxidant supplements were disappointing. It then describes how Nrf2 is the master regulator of cellular antioxidant defenses, regulating over 200 genes. Nrf2 is normally bound by Keap1 in the cytoplasm and targeted for degradation, but oxidative stress or phytochemicals can activate Nrf2 by modifying Keap1 or through kinase signaling. Activated Nrf2 upregulates antioxidant enzymes and other genes to maintain redox homeostasis and protect against disease. Exercise and certain phytochemicals are highlighted as potential ways to activate Nrf2 and attenu
Studies Of Molecular Mechanisms Of Action Of Tnf Antagonists In Rheumatoid Ar...guest11f502
This document summarizes a thesis investigating the molecular mechanisms of action of TNF antagonists in rheumatoid arthritis (RA). RA is a common chronic inflammatory disease characterized by progressive joint destruction. New TNF antagonist drugs have been introduced to treat RA, but their exact mechanisms are still poorly understood. The thesis aims to study the effects of TNF antagonists on synovial inflammation and bone destruction. It finds that TNF antagonists induce apoptosis of macrophages but not lymphocytes in RA joints. They also decrease serum levels of matrix metalloproteinases (MMPs) implicated in joint destruction. Additionally, treatment increases synovial expression of osteoprotegerin (OPG), which regulates bone remodeling. The thesis provides new insights into how TNF antagon
The approach to sepsis certainly needs to be based on organ involement. The mysteri of the role of the heart associated with myocardial dysfunction, becomes a growing scientific challenge
Sepsis-induced myocardial dysfunction involves complex interactions between pathogens and the host immune system. Early sepsis is characterized by circulatory abnormalities related to intravascular volume depletion and vasodilation. Despite increased cardiac output, myocardial dysfunction is significant in septic shock. Direct myocardial depression in sepsis is caused by down-regulation of beta-adrenergic receptors and the effects of cytokines like TNF-alpha and IL-1 beta. Management of myocardial dysfunction in septic shock involves prompt antibiotic therapy, early goal-directed fluid resuscitation and hemodynamic support with vasopressors and inotropes according to surviving sepsis campaign guidelines. Further research is still needed to better understand sepsis-induced myocardial dysfunction and identify more targeted treatments
T cell Immune Pathways Current and Future Implementation in Cancer Immunother...CrimsonpublishersCancer
T cells are central players in cancer immune response. The discovery of T cell immune pathways has revealed several inhibitory and stimulatory pathways that affect the differentiation and activation of T cell. Theses pathways represent ideal candidates that can be targeted to augment in-vivo. T cell immune response against tumors. In this mini review we will try to reveal some inhibitory and stimulatory T cell immune pathways to which efforts of those interested in cancer immunotherapy can be directed.
A 43-Year-Old Male with PCM1-JAK2 Gene Fusion Experienced T-Lymphoblastic Lym...daranisaha
Myeloid/lymphoid neoplasms associated with eosinophilia and PCM1-JAK2 is a provisional entity in WHO 2016. Prior case reports have shown quite a few clinical presentations in different patients with this chromosome translocation,characterized by eosinophilia in combination with myelodysplastic/ myeloproliferative neoplasms, acute myeloid leukemia(AML) and rarely,
A 43-Year-Old Male with PCM1-JAK2 Gene Fusion Experienced T-Lymphoblastic Lym...semualkaira
Myeloid/lymphoid neoplasms associated with eosinophilia and PCM1-JAK2 is a provisional entity in WHO 2016. Prior case reports have shown quite a few clinical presentations in different patients with this chromosome translocation,characterized by eosinophilia in combination with myelodysplastic/ myeloproliferative neoplasms, acute myeloid leukemia(AML) and rarely, T-lymphoblastic lymphoma(T-LBL) or B-acute...
A 43-Year-Old Male with PCM1-JAK2 Gene Fusion Experienced T-Lymphoblastic Lym...semualkaira
Myeloid/lymphoid neoplasms associated with eosinophilia and PCM1-JAK2 is a provisional entity in WHO 2016. Prior case reports have shown quite a few clinical presentations in different patients with this chromosome translocation,characterized by eosinophilia in combination with myelodysplastic/ myeloproliferative neoplasms, acute myeloid leukemia(AML) and rarely, T-lymphoblastic lymphoma(T-LBL) or B-acute...
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kd...Mark Lipstein
This document summarizes a study examining the combination of a novel PI3Kδ inhibitor, TGR-1202, with the proteasome inhibitor carfilzomib for treating hematological malignancies. The study found that TGR-1202 synergizes strongly with carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary cells by silencing c-Myc translation. This synergistic effect is driven by TGR-1202's unexpected additional activity of inhibiting CK1ε, which contributes to repressing phosphorylation of 4E-BP1 and lowering c-Myc protein levels. The results suggest that TGR-1202, as a dual PI3Kδ/CK1ε inhibitor, may have
This document summarizes research finding that elevated activity of the Akt protein protects prostate cancer LNCaP cells from apoptosis induced by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). The researchers found that LNCaP cells have high constitutive Akt activity due to lack of the PTEN lipid phosphatase. Inhibiting PI3-kinase, which activates Akt, sensitized LNCaP cells to TRAIL-induced apoptosis. TRAIL alone activated caspases 8 and XIAP in LNCaP cells but failed to induce full apoptosis. Combining TRAIL with Akt inhibitors allowed cleavage of BID and subsequent mitochondrial apoptosis steps. Akt inhibition of BID cleavage appears to mediate the protective effect
This document describes the discovery of potent and selective inhibitors of the enzyme MTH1 by researchers seeking to validate claims that MTH1 inhibition can selectively kill cancer cells. The researchers developed three structurally distinct series of MTH1 inhibitors with excellent potency and selectivity based on previous work identifying MTH1 as a target of TLR7 agonists. Crystal structures showed the inhibitors binding in a similar manner to the natural MTH1 substrate. However, testing of the inhibitors in cells did not elicit the cancer-specific lethal phenotype reported for other MTH1 inhibitors, questioning the proposed role of MTH1 in cancer cell survival.
2012-PLoS One-Viral cross class serpin inhibits T cell fatricidekasinath viswanathan
1) The study examines the ability of two viral serpins, Serp-2 and CrmA, to inhibit vascular inflammation and T lymphocyte apoptosis.
2) In rodent models, purified Serp-2 given systemically after arterial injury markedly reduced plaque growth locally and systemically, while CrmA had no effect.
3) In human cell lines in vitro, Serp-2 selectively inhibited T cell caspase activity and cytotoxic T cell killing of other T cells, reducing fratricide. Both Serp-2 and CrmA inhibited monocyte apoptosis.
4) Serp-2's inhibitory activity depended on granzyme B, as it was reduced in granzyme B-
Markers of Both Autoimmune and Apoptotic Processes in Initiation and Progress...semualkaira
Hashimoto’s thyroiditis (HT) is part of a spectrum of thyroid autoimmune conditions
and the most frequent cause of hypothyroidism. Despite considerable progress achieved in identifying
factors responsible for the development of HT, its pathogenesis remains unclear.
Challenges and Practices in Modern Hand Surgery Nursingsemualkaira
Purpose This study aims to explore the changes in the patient spectrum and the challenges and practices in nursing brought about by
the evolution of modern hand surgery patients and medical development. Methods A retrospective study was conducted on clinical
data from 21,512 hand surgery patients in our hospital over the
past 15 years. T
The Impact Visceral Abdominal Fat and Muscle Mass Using CT on Patients with S...semualkaira
The association between abdominal visceral
fatty area (VFA) and muscle mass and mortality is not fully understood despite the fact that being overweight is an established
risk factor for the onset and severity of acute pancreatitis (AP). We
assessed the effect of VFA on severe AP (SAP) mortality
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This document describes an experiment investigating the effects of fenugreek extract on macrophage polarization using a THP-1 cell model. THP-1 macrophages were treated with two concentrations of fenugreek extract and the M1 marker CD86 and M2 marker CD163 were measured using flow cytometry. Preliminary experiments determined that EDTA was the optimal method for detaching adherent THP-1 macrophages without reducing cell viability. The results found that fenugreek upregulated CD86 but downregulated CD163 expression. This suggests fenugreek caused polarization of macrophages toward an M1 phenotype, though further shifted this to an M4 phenotype. The effect on CD163 was possibly due to multiple M2 subclasses making expression harder to measure
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Studies Of Molecular Mechanisms Of Action Of Tnf Antagonists In Rheumatoid Ar...guest11f502
This document summarizes a thesis investigating the molecular mechanisms of action of TNF antagonists in rheumatoid arthritis (RA). RA is a common chronic inflammatory disease characterized by progressive joint destruction. New TNF antagonist drugs have been introduced to treat RA, but their exact mechanisms are still poorly understood. The thesis aims to study the effects of TNF antagonists on synovial inflammation and bone destruction. It finds that TNF antagonists induce apoptosis of macrophages but not lymphocytes in RA joints. They also decrease serum levels of matrix metalloproteinases (MMPs) implicated in joint destruction. Additionally, treatment increases synovial expression of osteoprotegerin (OPG), which regulates bone remodeling. The thesis provides new insights into how TNF antagon
The approach to sepsis certainly needs to be based on organ involement. The mysteri of the role of the heart associated with myocardial dysfunction, becomes a growing scientific challenge
Sepsis-induced myocardial dysfunction involves complex interactions between pathogens and the host immune system. Early sepsis is characterized by circulatory abnormalities related to intravascular volume depletion and vasodilation. Despite increased cardiac output, myocardial dysfunction is significant in septic shock. Direct myocardial depression in sepsis is caused by down-regulation of beta-adrenergic receptors and the effects of cytokines like TNF-alpha and IL-1 beta. Management of myocardial dysfunction in septic shock involves prompt antibiotic therapy, early goal-directed fluid resuscitation and hemodynamic support with vasopressors and inotropes according to surviving sepsis campaign guidelines. Further research is still needed to better understand sepsis-induced myocardial dysfunction and identify more targeted treatments
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Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
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2012-PLoS One-Viral cross class serpin inhibits T cell fatricidekasinath viswanathan
1) The study examines the ability of two viral serpins, Serp-2 and CrmA, to inhibit vascular inflammation and T lymphocyte apoptosis.
2) In rodent models, purified Serp-2 given systemically after arterial injury markedly reduced plaque growth locally and systemically, while CrmA had no effect.
3) In human cell lines in vitro, Serp-2 selectively inhibited T cell caspase activity and cytotoxic T cell killing of other T cells, reducing fratricide. Both Serp-2 and CrmA inhibited monocyte apoptosis.
4) Serp-2's inhibitory activity depended on granzyme B, as it was reduced in granzyme B-
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The association between abdominal visceral
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catastrophic clinical situation for patients undergoing surgery in
hospitals. If patients encounter this infection picture, especially
after severe operations such as heart surgery, the life-threatening
rates increase gradually.
Incisional Hernia Occurring after Ventriculoperitoneal Shunt Fixationsemualkaira
Ventriculo-peritoneal shunt is the procedure of choice for hydrocephalus. Various complications of ventriculoperitoneal shunts
were reported. Abdominal complications involving the distal tip
of the catheter make the majority of the complications. In this case
report we present a case of incisional hernia occurring in a patient
who underwent fixation of ventriculoperitoneal shunt followed by
revision of the shunt after a while.
Fatal Condition of Aortic Dissection Produces Symptoms of Sudden and Tearing ...semualkaira
Aortic dissection is a very difficult condition in which the inner
sheath of the aortic wall is torn without tearing the outer sheath.
This causes blood to enter the aortic wall through the tear, which
further splits the mediastinum and creates a new channel in the
aortic wall. The serious and often fatal condition of aortic dissection produces symptoms of sudden and tearing chest pain. Although aortic dissection mostly occurs in people around the age of
60, the peak incidence in people with Marfan syndrome is between
20 and 40 years of age.
Prospective Study of Acute Appendicitis with its Clinical, Radiological Profi...semualkaira
Acute appendicitis is the most common condition encountered in general surgical practice. Alvarado and Modified Alvarado Scores (MASS) are the commonly used scoring
systems for its diagnosis, but its performance has been found to
be poor in certain populations. Hence, we compared the RIPASA
score with MASS, to find out which is a better diagnostic tool for
acute appendicitis in the Indian population.
Surgery or Endovascular Treatment, which is the Better Way to Treat Acute and...semualkaira
To investigate the influence of surgical and endovascular treatment on the prognosis of acute and chronic mesenteric ischemia and to further evaluate whether endovascular
treatment can reduce postoperative complications by performing
a meta-analysis.
Rare Case Of Primary Pulmonary Dedifferentiated Liposarcomasemualkaira
Liposarcoma is a relatively common soft tissue sarcoma, but primary pulmonary liposarcomas are extremely rare, expecially for
dedifferentiated subtype. We report the case of a 44-year-old African woman, healed from SARS-Covid, who presented with a 8
cm right lung ilary mass and underwent to a right intrapericardial pneumonectomy with diaphragmatic and pleural resections.
Histological test confirmed diagnosis of dedifferentiated primary
pulmonary liposarcoma. The patient recovered well having an uncomplicated postoperative course and was discharged after 7 days.
On four months follow up the patient was still alive and without
evidence of disease. More studies have to be conducted because
very few cases are reported in literature.
Psychological Impact and Sexual Behavior in Patients with Genital and Anal Co...semualkaira
Genital warts are benign viral tumors of the skin or mucous membranes, due to human papillomaviruses. Rare are the authors who
insist on studying the psycho-affective and sexual impact of this
condition.
A Case Report of Hypothermia Rescued by Veno-Arterial Extracorporeal Membrane...semualkaira
Severe hypothermia is a life-threatening condition that often causes hemodynamic instability or cardiac arrest
and carries a high risk of mortality. The use of VA-ECMO in this
indication has greatly improved the prognosis of patients.
Can Traditional Chinese Medicine Treat Blocked Fallopian Tubes.pptxFFragrant
There are many traditional Chinese medicine therapies to treat blocked fallopian tubes. And herbal medicine Fuyan Pill is one of the more effective choices.
STUDIES IN SUPPORT OF SPECIAL POPULATIONS: GERIATRICS E7shruti jagirdar
Unit 4: MRA 103T Regulatory affairs
This guideline is directed principally toward new Molecular Entities that are
likely to have significant use in the elderly, either because the disease intended
to be treated is characteristically a disease of aging ( e.g., Alzheimer's disease) or
because the population to be treated is known to include substantial numbers of
geriatric patients (e.g., hypertension).
BBB and BCF
control the entry of compounds into the brain and
regulate brain homeostasis.
restricts access to brain cells of blood–borne compounds and
facilitates nutrients essential for normal metabolism to reach brain cells
Pictorial and detailed description of patellar instability with sign and symptoms and how to diagnose , what investigations you should go with and how to approach with treatment options . I have presented this slide in my 2nd year junior residency in orthopedics at LLRM medical college Meerut and got good reviews for it
After getting it read you will definitely understand the topic.
Congestive Heart failure is caused by low cardiac output and high sympathetic discharge. Diuretics reduce preload, ACE inhibitors lower afterload, beta blockers reduce sympathetic activity, and digitalis has inotropic effects. Newer medications target vasodilation and myosin activation to improve heart efficiency while lowering energy requirements. Combination therapy, following an assessment of cardiac function and volume status, is the most effective strategy to heart failure care.
Storyboard on Skin- Innovative Learning (M-pharm) 2nd sem. (Cosmetics)MuskanShingari
Skin is the largest organ of the human body, serving crucial functions that include protection, sensation, regulation, and synthesis. Structurally, it consists of three main layers: the epidermis, dermis, and hypodermis (subcutaneous layer).
1. **Epidermis**: The outermost layer primarily composed of epithelial cells called keratinocytes. It provides a protective barrier against environmental factors, pathogens, and UV radiation.
2. **Dermis**: Located beneath the epidermis, the dermis contains connective tissue, blood vessels, hair follicles, and sweat glands. It plays a vital role in supporting and nourishing the epidermis, regulating body temperature, and housing sensory receptors for touch, pressure, temperature, and pain.
3. **Hypodermis**: Also known as the subcutaneous layer, it consists of fat and connective tissue that anchors the skin to underlying structures like muscles and bones. It provides insulation, cushioning, and energy storage.
Skin performs essential functions such as regulating body temperature through sweat production and blood flow control, synthesizing vitamin D when exposed to sunlight, and serving as a sensory interface with the external environment.
Maintaining skin health is crucial for overall well-being, involving proper hygiene, hydration, protection from sun exposure, and avoiding harmful substances. Skin conditions and diseases range from minor irritations to chronic disorders, emphasizing the importance of regular care and medical attention when needed.
Osvaldo Bernardo Muchanga-GASTROINTESTINAL INFECTIONS AND GASTRITIS-2024.pdfOsvaldo Bernardo Muchanga
GASTROINTESTINAL INFECTIONS AND GASTRITIS
Osvaldo Bernardo Muchanga
Gastrointestinal Infections
GASTROINTESTINAL INFECTIONS result from the ingestion of pathogens that cause infections at the level of this tract, generally being transmitted by food, water and hands contaminated by microorganisms such as E. coli, Salmonella, Shigella, Vibrio cholerae, Campylobacter, Staphylococcus, Rotavirus among others that are generally contained in feces, thus configuring a FECAL-ORAL type of transmission.
Among the factors that lead to the occurrence of gastrointestinal infections are the hygienic and sanitary deficiencies that characterize our markets and other places where raw or cooked food is sold, poor environmental sanitation in communities, deficiencies in water treatment (or in the process of its plumbing), risky hygienic-sanitary habits (not washing hands after major and/or minor needs), among others.
These are generally consequences (signs and symptoms) resulting from gastrointestinal infections: diarrhea, vomiting, fever and malaise, among others.
The treatment consists of replacing lost liquids and electrolytes (drinking drinking water and other recommended liquids, including consumption of juicy fruits such as papayas, apples, pears, among others that contain water in their composition).
To prevent this, it is necessary to promote health education, improve the hygienic-sanitary conditions of markets and communities in general as a way of promoting, preserving and prolonging PUBLIC HEALTH.
Gastritis and Gastric Health
Gastric Health is one of the most relevant concerns in human health, with gastrointestinal infections being among the main illnesses that affect humans.
Among gastric problems, we have GASTRITIS AND GASTRIC ULCERS as the main public health problems. Gastritis and gastric ulcers normally result from inflammation and corrosion of the walls of the stomach (gastric mucosa) and are generally associated (caused) by the bacterium Helicobacter pylor, which, according to the literature, this bacterium settles on these walls (of the stomach) and starts to release urease that ends up altering the normal pH of the stomach (acid), which leads to inflammation and corrosion of the mucous membranes and consequent gastritis or ulcers, respectively.
In addition to bacterial infections, gastritis and gastric ulcers are associated with several factors, with emphasis on prolonged fasting, chemical substances including drugs, alcohol, foods with strong seasonings including chilli, which ends up causing inflammation of the stomach walls and/or corrosion. of the same, resulting in the appearance of wounds and consequent gastritis or ulcers, respectively.
Among patients with gastritis and/or ulcers, one of the dilemmas is associated with the foods to consume in order to minimize the sensation of pain and discomfort.
Allopurinol, a uric acid synthesis inhibitor acts by inhibiting Xanthine oxidase competitively as well as non- competitively, Whereas Oxypurinol is a non-competitive inhibitor of xanthine oxidase.
CLASSIFICATION OF H1 ANTIHISTAMINICS-
FIRST GENERATION ANTIHISTAMINICS-
1)HIGHLY SEDATIVE-DIPHENHYDRAMINE,DIMENHYDRINATE,PROMETHAZINE,HYDROXYZINE 2)MODERATELY SEDATIVE- PHENARIMINE,CYPROHEPTADINE, MECLIZINE,CINNARIZINE
3)MILD SEDATIVE-CHLORPHENIRAMINE,DEXCHLORPHENIRAMINE
TRIPROLIDINE,CLEMASTINE
SECOND GENERATION ANTIHISTAMINICS-FEXOFENADINE,
LORATADINE,DESLORATADINE,CETIRIZINE,LEVOCETIRIZINE,
AZELASTINE,MIZOLASTINE,EBASTINE,RUPATADINE. Mechanism of action of 2nd generation antihistaminics-
These drugs competitively antagonize actions of
histamine at the H1 receptors.
Pharmacological actions-
Antagonism of histamine-The H1 antagonists effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response especially wheal, flare and itch. Constriction of larger blood vessel by histamine is also antagonized.
2) Antiallergic actions-Many manifestations of immediate hypersensitivity (type I reactions)are suppressed. Urticaria, itching and angioedema are well controlled.3) CNS action-The older antihistamines produce variable degree of CNS depression.But in case of 2nd gen antihistaminics there is less CNS depressant property as these cross BBB to significantly lesser extent.
4) Anticholinergic action- many H1 blockers
in addition antagonize muscarinic actions of ACh. BUT IN 2ND gen histaminics there is Higher H1 selectivitiy : no anticholinergic side effects
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is expected to continuously rise given the aging world population
[8]. Notwithstanding sepsis has been intensively studied from all
aspects for decades, effective therapeutic approach remains chal-
lenging due to the extremely complicated molecular mechanisms
of sepsis, and current clinical managements are limited to be sup-
portive rather than curative [9]. Thus, it is imperative to explore
the pathophysiological mechanisms of sepsis to guide novel ther-
apeutic interventions.
As one of the lethal complications in clinical sepsis, septic cardi-
omyopathy (SCM) referring to myocardial dysfunction caused by
sepsis is associated with increased mortality and poor prognosis
[10, 11]. Although the large-scale studies and standard diagnostic
criteria were not established in the past decades, the incidence of
SCM in patients with sepsis was estimated from 13.8% to 40%
[12, 13]. Compared with patients without cardiovascular impair-
ment, the mortality would double or triple with up to 70%-90% in
septic patients encountering heart dysfunction [14]. From a symp-
tomatic perspective, SCM is acknowledged by decreased left ven-
tricular ejection fraction (LVEF) [15]. Nevertheless, more in-depth
studies unveiled various potential molecular mechanisms involved
in SCM including inflammation response, cytokine overproduc-
tion, apoptosis damage, downregulation of adrenergic signaling,
microvascular damage, oxidative and nitrosative stress, calcium
overloading, endothelial dysfunction, mitochondrial dysfunction,
autophagy [16-18]. As mentioned earlier, SCM is connected with
proinflammatory responses triggered by pattern-recognition recep-
tors (PRRs), such as Toll-like receptors (TLRs) [19]. Despite ex-
tensive efforts on SCM, there are still controversies regarding the
pathological alterations.
As a type I transmembrane proteins, toll-like receptors (TLRs) are
conserved PRR activated by diverse pathogen-associated molec-
ular patterns (PAMPs), launching innate immune responses and
inflammatory reactions [20]. The mammalian family of TLRs
contains 13 members, among which TLR4 was first characterized
in mammalians [21, 22]. Most importantly, level of TLR4 is the
highest compared with other TLRs in the heart. In addition, TLR4
plays a critical role in myocardial inflammation and is involved
in myocardial dysfunctions, such as myocarditis, myocardial in-
farction (MI), ischemia-reperfusion (I/R) injury, hypertension, and
heart failure [23-25].
Beutler and colleagues previously revealed activation of TLR4
by lipopolysaccharide (LPS, endotoxin) [26], a major component
of the outer membrane of Gram-negative bacteria, and one of the
main contributors to infection and systemic inflammatory condi-
tions in sepsis. TLR4 is activated by LPS in MyD88-dependent
manner to trigger nuclear factor-κB (NF-κB)-dependent expres-
sion of inflammatory mediators such as IL-1, IL-6, and TNF-α [27-
29]. TLR4 has been indicated to play a critical role in SCM to me-
diate the inflammatory response. Further evidence suggested that
TLR4 knockout improves survival and cardiac function in sepsis
[30-34]. Our previous studies found increased TLR4 level in sep-
tic mice, resulting in the release of proinflammatory factors, and
apoptosis, ultimately triggering SCM [35]. However, the precise
underlying mechanism remains unclear. Meanwhile, inhibition of
TLR4 using TAK-242 resulted in prominent downregulation of
TLR4 in rat myocardium with coronary microembolization, and
ameliorated myocardial injury [36, 37]. We hypothesize that host
innate immunity is tightly associated with inflammatory response
and apoptosis accompanying SCM. This study was designed to
examine the impact of TLR4 knockout on cardiac function, in-
flammation and apoptosis, as well as the role of the TLR4/MyD88/
NF-κB signaling pathway. Our findings provide novel insights into
the molecular mechanisms of SCM as well as cardiac dysfunction.
3. Results
3.1. TLR4 Deficiency Attenuates Sepsis-Induced Myocardial
Dysfunction in Mice
To observe the effects of TLR4 deletion on cardiac function and
myocardial injury in LPS-induced SCM, cardiomyocyte-specific
TLR4 knockout (TLR4-/-) and WT mice were used and echocar-
diograms and cardiac injury indicators were evaluated (Figure 1).
Echocardiography of cardiac function exhibited that LPS chal-
lenge overtly disturbed EF, FS, and LVEDS. Although TLR4 de-
ficiency did not affect cardiac function (p>0.05 vs. WT group),
it partially relieved LPS-induced cardiac injury (p<0.05 vs. LPS
group, Figure-1a-d). In addition, LPS significantly elevated car-
diac injury indicators such as CK-MB, and troponin T (p<0.01),
the effect of which was reconciled by TLR4 deficiency (p<0.05
vs. LPS group, Figure-1e-f), with little effect from TLR4 deficien-
cy itself. Meanwhile, oxidative damage and histological analysis
of cardiac tissues were assessed. (Figure-1G-I) showed that LPS
injection overtly increased levels of carbonyl protein, the effect of
which was alleviated by TLR4 deletion with little effect from TLR4
deletion itself (p<0.05, Figure-1g). Given that LPS administration
lasted for only 6 h, little difference was noted for H&E staining
and pathological scores of cardiac tissues among any groups tested
(p>0.05, Figure-1h-i). These data demonstrated that TLR4 defi-
ciency attenuates sepsis-induced myocardial dysfunction.
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Figure 1: TLR4 deficiency attenuates sepsis-induced myocardial dysfunction in mice. Mice were challenged with intraperitoneall (i.p.) injections of
either LPS (4 mg/kg) or vehicle PBS in shams. Blood and heart samples were harvested 6 h after LPS injection. a. Representative echocardiographic
images (M mode) of each group. b-d. Echocardiographic data showing EF (ejection fraction), FS (fractional shortening), and LVESD (left ventricular
end-systolic dimension) in each group. e-f. The concentration of CK-MB and TNNT2 in serum by ELISA analysis. g. The expression of oxidative
carbonyl proteins in different cardiac tissues. h. The cross-section area of H&E in cardiac tissues. i. Representative images of hematoxylin and eo-
sin‑stained sections of the cardiac tissues in mice (original magnification, ×200). Scale bar=100 μm. (*
denotes p< 0.05 versus WT, **
denotes p< 0.01
versus WT, #
denotes p< 0.05 versus LPS.)
3.2. TLR4 Deficiency Ameliorated Cardiac Inflammation in
Mice with Sepsis-Induced Cardiac Injury
To illustrate the impact on the levels of inflammation of TLR4 de-
ficiency in mice, ELISA and RT-qPCR assays were carried out to
measure the levels of pro-inflammatory cytokines in serum and
cardiac tissue, respectively. The results indicated that TLR4 de-
ficiency did not affect the levels of pro-inflammatory cytokines
including TNF-α, IL-1β, and IL-6 in serum and cardiac tissue
(Figure-2a-f). After LPS administration, the levels of inflammato-
ry factors like TNF-α, IL-1β, and IL-6 were significantly aggran-
dized in the serum and myocardium of mice in the LPS group com-
pared with the control group (p<0.01). Meanwhile, the levels of
pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 in
serum and cardiac tissue were reduced in the TLR4-/-+LPS group
compared with the WT group (p<0.05). Overall, TLR4 deficiency
ameliorated cardiac inflammation in mice with sepsis-induced car-
diac injury.
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3.3. Effects of TLR4 Deficiency on TLR4/MyD88/NF-κB Sig-
naling Pathway in Mice with Sepsis-Induced Cardiac Injury
To assess the effect of TLR4 deficiency on activation of TLR4 sig-
naling in mice in SCM, RT-qPCR assay and western blot were
performed to analyze whether TLR4 deficiency impacts the ex-
pression of TLR4, MyD88, NF-κB phosphorylation (p-NF-ΚB)
in myocardial tissues of septic mice. RT-qPCR results indicated
that relative mRNA expression levels of TLR4, MyD88, and NF-
κB in cardiac tissues were significantly increased in response to
LPS (p<0.01, Figure-3a-c). Moreover, protein levels of TLR4,
MyD88, and p-NF-κB were increased in myocardial tissues of
LPS-challenged mice compared with WT group. These findings
indicated that TLR4 deficiency contributed to prominent reduc-
tion of LPS-induced upregulation of TLR4, MyD88, and p-NF-κB
(Figure 3d).
Figure 2: TLR4 deficiency ameliorated cardiac inflammation in mice with sepsis-induced cardiac injury. a-c. Pro-inflammatory cytokines including
TNF-α, IL-1β, and IL-6 in serum were measured by ELISA assays. d-f. The mRNA expression of TNF-α, IL-1β, and IL-6 in myocardium tissue. (*
denotes p< 0.05 versus WT, ** denotes p< 0.01 versus WT, # denotes p< 0.05 versus LPS.)
Figure 3: Effects of TLR4 deficiency on TLR4/MyD88/NF-κB signaling pathway in mice with sepsis-induced cardiac injury. a-c. The relative mRNA
expression levels of TLR4, MyD88, and NF-κB in cardiac tissue were detected by RT-qPCR. d. Representative western blotting images of TLR4,
MyD88, and p-NF-kB in each group. (* denotes p< 0.05 versus WT, ** denotes p< 0.01 versus WT, # denotes p< 0.05 versus LPS.)
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3.4. TLR4 Deficiency Decreases Cardiac Apoptosis in Mice
with Sepsis-Induced Cardiac Injury
We next performed TUNEL staining, caspase 3 activity, and
Western blot to evaluate the impact of TLR4 deficiency on ap-
optosis in mice with LPS-induced sepsis. First, TUNEL staining
assay was used to analyze number of apoptotic cardiomyocytes
in LPS-treated mice. Results indicated that LPS led to increased
number of TUNEL positive myocardial cardiomyocytes, suggest-
ing antiapoptotic capacity of TLR4 deficiency in septic myocar-
dium (p<0.01, Figure-4a-b). Furthermore, evaluation of caspase
3 activity and levels of apoptotic-related proteins confirmed that
LPS evoked remarkable increase in caspase 3 activity and ex-
pression of pro-apoptotic protein Bax (p<0.01), accompanied by
decreased anti-apoptotic protein Bcl-2 (p<0.05). On the contrary,
TLR4 deficiency reversed effects mentioned earlier (p<0.05, Fig-
ure-4c-e). Moreover, TLR4 deficiency itself did not elicit any no-
table effect on TUNEL apoptosis, caspase 3 activity, and levels of
Bax and Bcl-2 (p>0.05). These data showed that TLR4 deficiency
decreased cardiomyocyte apoptosis in mice with sepsis-induced
cardiac injury.
Figure 4: TLR4 deficiency decreases cardiomyocyte apoptosis in mice with sepsis-induced cardiac injury. a. Representative images of TUNEL staining
of the cardiac tissues in mice (original magnification, ×400). b. The number of TUNEL positive cardiomyocytes. c. The activity of caspase 3. d. The
relative expression of pro-apoptotic protein Bax. e. The relative expression of anti-apoptotic protein Bcl-2. (* denotes p< 0.05 versus WT, ** denotes
p< 0.01 versus WT, # denotes p< 0.05 versus LPS.)
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3.5. The Inhibition of TLR4 Alleviates Inflammation in an in
Vitro Model of Sepsis-Induced Cardiac Injury
In vitro experiments were conducted to analyze the effect of TLR4
inhibition by evaluating H9c2 cardiomyocytes challenged with
LPS (1μg/ml) for 24 h. Firstly, a dose-response experiment was
carried out to explore the proper concentration of TAK-242 to re-
press the expression of TLR4 maximally in H9c2 cardiomyocytes
and revealed with the Cell Counting Kit-8 assay. Hence, the H9c2
cardiomyocytes were exposed to 10, 20, 30, and 40 μM TAK-
242 for 24 h, respectively. We found that the H9c2 cardiomyo-
cytes challenged with TAK-242 for 24 h didn’t have any obvious
change in cell viability until the concentration exceeded 30 μM
(p>0.05, Figure 5a). Therefore, otherwise mentioned, following
H9c2 cardiomyocytes were treated with 30 μM TAK-242 for 24
h to repress the expression of TLR4. Subsequently, the effect of
TLR4 inhibition on LPS-induced cell viability was evaluated by
the CCK-8 assay. The results indicated that the cell viability of
H9c2 cardiomyocytes decreased remarkably after the LPS chal-
lenge, and the situation was ameliorated due to the inhibition of
TLR4 (p<0.05, Figure 5b). The levels of cardiac injury biological
indicators and pro-inflammatory cytokines were recorded to fur-
ther explore the effect of TLR4 inhibition during sepsis-induced
cardiac injury in vitro (Figure 5c-g). These data showed that the
LPS group accelerated the expression of cardiac injury biological
indicators and pro-inflammatory cytokines (p<0.01). Simultane-
ously, the TAK-242+LPS group reversed the effects as previously
mentioned (p<0.05). In addition, there were no significant differ-
ences between the control group and the TAK-242 group (p>0.05).
Taken together, these results illustrated that the inhibition of TLR4
alleviated inflammation during sepsis-induced cardiac injury in
vitro.
Figure 5: The inhibition of TLR4 alleviates inflammation and apoptosis in vitro model of sepsis-induced cardiac injury.a. The cell viability of H9c2
cardiomyocytes in different concentrations of TAK-242. b. The cell viability of each group. c-d. The concentration of CK-MB and cTnT in the super-
natant of each group in H9c2 cardiomyocytes by ELISA analysis. e-g. The mRNA expression of TNF-α, IL-1β, and IL-6 of each group in H9c2 cardi-
omyocytes, respectively. (* denotes p< 0.05 versus Con, ** denotes p< 0.01 versus Con, # denotes p< 0.05 versus LPS.)
3.6. TLR4/MyD88/NF-κB signaling Pathway is Involved in
Vitro with Sepsis-Induced Cardiac Injury
To further explore whether TLR4/MyD88/NF-κB signaling path-
way participates in sepsis-induced cardiac injury of H9c2 car-
diomyocytes, RT-qPCR and Western blot were carried out and
shown in (Figure 6). The relative mRNA expressions of TLR4 and
MyD88 were efficaciously inhibited by TAK-242. Compared with
the Control group, the mRNA expressions of TLR4, MyD88, and
p-NF-κB in the LPS group boosted remarkably (p<0.01, Figure
6a-c). Moreover, the protein expressions of TLR4, MyD88, and
p-NF-κB in the LPS group increased with the protein expression
relative levels of TLR4, MyD88, and p-NF-κB were inhibited by
TAK-242 (p<0.05). However, the protein levels of TLR4, MyD88,
and p-NF-κB in the TAK-242+LPS group were decreased notably
compared with the LPS group (p<0.05). Meanwhile, compared to
NF-κB, LPS treatment markedly active the expression levels of
p-NF-κB (p<0.01, Figure 6d-h). The above data suggested that
TLR4/MyD88/NF-κB signaling pathway participated in sepsis-in-
duced cardiac injury in vitro.
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Figure 6: TLR4/MyD88/NF-κB signaling pathway is involved in sepsis-induced cardiac injury. a-c. The mRNA levels of TLR4, MyD88, and NF-κB
in H9c2 cardiomyocytes were detected by fluorescence quantitative PCR respectively. d-f. The protein expression relative levels of TLR4, MyD88,
and p-NF-κB in H9c2 cardiomyocytes were detected by Western blot. g. The protein expression relative level of p-NF-κB was compared with NF-κB.
h. Representative images of Western blot of TLR4, MyD88, p-NF-kB, and NF-κB in each group. (* denotes p<0.05 versus Con, ** denotes p<0.01
versus Con, # denotes p<0.05 versus LPS.)
3.7. The Inhibition of TLR4 Reduces Myocardial Apoptosis in
Vitro with Sepsis-Induced Cardiac Injury
Next, flow cytometry and Western blot were performed to deter-
mine the apoptosis level of H9c2 cardiomyocytes during sepsis.As
depicted in (Figure 7), LPS administration raised the total number
of apoptotic cardiomyocytes and the protein expression relative
level of pro-apoptosis Bax in H9c2 cardiomyocytes (p<0.01).
Meanwhile, the level of anti-apoptosis Bcl-2 in H9c2 cardiomyo-
cytes reduced during LPS administration (p<0.01). Nevertheless,
the inhibitory state of TLR4 by TAK-242 remarkably reversed
the apoptosis of H9c2 cardiomyocytes after the LPS challenge
(p<0.05).
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Figure 7: The inhibition of TLR4 reduces myocardial apoptosis in vitro with sepsis-induced cardiac injury. a. Representative images of flow cytometry.
b. The apoptosis ratio in H9c2 cardiomyocytes of each group. c. The expression relative level of Bax (pro-apoptosis). d. The expression relative level
of Bcl-2 (anti-apoptosis). (* denotes p< 0.05 versus Con, ** denotes p< 0.01 versus Con, # denotes p< 0.05 versus LPS)
4. Discussion
SCM is a lethal heart complication with high morbidity and mor-
tality in patients with sepsis [45]. Diverse mechanisms were spec-
ulated for SCM, including uncontrollable inflammatory response,
mitochondrial dysfunction, apoptosis, reactive oxygen species
(ROS) accumulation, calcium dysregulation, ATP shortage, com-
plement activation, metabolic reprogramming, ferroptosis, auto-
phagy, mitophagy, endoplasmic reticulum (ER) stress, and myo-
cardial edema [14, 46-50]. Little effective therapies or drugs are
readily available for the clinical management of SCM largely due
to the multifactorial characteristics of the disease along with the
ambiguous pathogenesis [51]. Therefore, in depth understanding
for the pathophysiology would benefit the diagnosis and treatment
of SCM and related syndrome. In present study, our results re-
vealed that TLR4 knockout ameliorated expression of proinflam-
matory cytokine and cardiomyocyte apoptosis in vivo in sepsis.
Further measurements noted that the inflammatory response and
cardiomyocyte apoptosis were closely related to activation of
TLR4/MyD88/NF-κB signaling in septic mice and LPS-chal-
lenged H9c2 cardiomyocytes mimicking septic cardiomyopathy in
the clinic reality. Furthermore, in vitro experiments indicated that
inhibition of TLR4 by TAK-242 exerted a protective effect against
LPS-challenged cardiomyocytes through refraining inflammation
response and apoptosis via TLR4/MyD88/NF-κB signaling. Tak-
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en together, these results revealed that TLR4 deficiency amelio-
rates septic cardiomyopathy by lessening activation of the TLR4/
MyD88/NF-κB signaling pathway and corresponding manipula-
tion of inflammatory responses and cardiomyocyte apoptosis.
As the dominating component of the outer membrane of Gram-neg-
ative bacteria, LPS is deemed a common molecular signature of
bacteria and can be responded by the human immune system, and
launches inflammatory responses and corresponding damage in
cardiomyocytes mainly via TLR4 receptor, followed by receptor
dimerization on the cytomembrane [28, 37, 52, 53]. TLR4 recruits
MyD88 to tun on NF-κB and successive translocation of the nucle-
us, prior to amplification of inflammatory signals to upregulate the
pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [54].
Furthermore, Tavener and associates first reported that TLR4 acted
as the primary mediator in LPS-induced cardiomyocyte dysfunc-
tion back in 2004, although its specific pathogenesis remains un-
clear [55-60]. In recent years, numerous studies have confirmed a
role for TLR4/MyD88/NF-κB signaling in various cardiovascular
pathologies including heart failure, coronary microembolization,
myocardial infarction, cardiac dysfunction in post-traumatic stress
disorder, inactivation staphylococcus epidermidis-induced cor-
nea inflammation, allergic asthma, streptococcus pneumonia, and
spontaneous intestinal tumorigenesis [56-60]. For instance, our
team previously reported that the TLR4/MyD88/NF-κB signaling
participated in sepsis-induced acute liver injury [43]. However,
little evidence has depicted a role for TLR4/MyD88/NF-κB signa-
ling cascade in the regulation of inflammatory cascade and cardio-
myocyte apoptosis under SCM. Therefore, this study revealed for
the first time a role of the TLR4/MyD88/NF-κB signaling in SCM
using TLR4 deficient murine model and H9c2 cardiomyocytes.
Our results implied activation of TLR4/MyD88/NF-κB signaling
in SCM, specifically in inflammatory responses of myocardium,
resulting in deterioration of cardiac function and abnormal aggre-
gation of protein carbonyl in mice. In addition, the TLR4 inhibitor
resatorvid (TAK-242) was applied subsequently in H9c2 cardio-
myocytes to verify the intravital results. The in vitro results also
found that TLR4/MyD88/NF-κB signaling pathway was activated
in H9c2 cardiomyocytes after LPS administration, resulting in not
only cell death but also upregulated pro-inflammatory cytokines
along with myocardial injury. Intriguingly, TLR4 deficiency or in-
hibition of TLR4 effectively reversed these pathological changes
and detrimental effects on cardiac function.
In the present study, we assessed the apoptosis levels in cardiomy-
ocytes of mice during sepsis by TUNEL assays, caspase 3 activity,
and Western blot.Also, it was found that in the mice model of SCM,
both TUNEL positive cells and caspase 3 activity were increased
with the ascending expression level of pro-apoptosis protein Bax
and the descending expression level of anti-apoptosis protein Bcl-
2. Consequently, TLR4 deficiency exhibited the reversed function
which embodied the abatement of TUNEL positive cells, caspase
3 activity, and expression of Bax, yet increased expression level
of Bcl-2. Meanwhile, our in vitro results showed that inhibition of
TLR4 reduced levels of apoptosis after LPS challenge in H9c2 car-
diomyocytes, consistent with the results in vivo. All results togeth-
er suggested that TLR4 deficiency protected the myocardium from
septic damage by restricting apoptosis during SCM. In summary,
our study demonstrates that the TLR4/MyD88/NF-κB signaling
cascade participates in the activation of inflammatory responses
and apoptosis in SCM. TLR4 deficiency or inhibition ameliorates
myocardial damage and improves cardiac function by inhibiting
the TLR4/MyD88/NF-κB signaling pathway and then reduces
pro-inflammatory cytokines and apoptosis after SCM. These find-
ings propose a relative solid mechanism underlying SCM and pave
a new route to the prevention and management of SCM.
5. Materials and Method
5.1. Animals and Experimental Protocol
Male adult C57BL/10J mice and TLR4−/− mice (8 weeks old and
weighing 20‑25g) were purchased from GemPharmatech Co, Ltd.
These mice were bred and maintained at the Animal Laboratory
Center of the Nanfang Hospital. In our study, mice were randomly
assigned to 4 groups wild type (WT) group (n=16), LPS group
(n=16), TLR4−/− group (n=16), and TLR4−/−+LPS group. Male
adult C57BL/10J mice and TLR4−/− mice were injected intra-
peritoneally with normal saline (NS) or lipopolysaccharide (LPS)
(4 mg/kg) for 6h as described to induce septic cardiomyopathy
[38]. After echocardiography assessment of left ventricular (LV)
function, mice were euthanized via pentobarbital, and heart tissues
were then harvested for subsequent experimentations.
5.2. Cell Culture and Treatment
H9c2 cardiomyocytes were purchased from the American Type
Culture Collection (ATCC, Manassas, VA, USA) and cultured in
a high-sugar DMEM (Gibco, Grand Island, NY, USA) contain-
ing penicillin/streptomycin (1%) with fetal bovine serum (10%)
at 37℃ in a humidified incubator at 5% CO2. Four groups were
included including control, LPS, TAK-242 group (or Resatorvid,
a selective TLR4 inhibitor, No: HY-11109) was purchased from
MedChemExpress (MCE, USA), and TAK-242+LPS group. When
cell density reached nearly 70%-80%, septic cardiomyopathy was
simulated in vitro by culturing H9c2 cardiomyocytes with 1µg/mL
LPS for 24 h as grouping [39, 40]. For inhibitor treatment, H9c2
cardiomyocytes were incubated with 30 µM TAK-242 for 24 h
prior to LPS stimulation [36, 41]. All experiments were repeated
at least three times.
5.3. Cell Viability Assay
To evaluate cell viability, H9c2 cardiomyocytes were seeded in
96 well plate with 5×104/mL for CCK-8 assay (No: CK04, Dojin-
do, Japan) at 37℃ in a humidified incubator containing 5% CO2.
Briefly, septic cardiomyopathy was simulated in cardiomyocytes,
followed with 10 µl CCK-8 solution and 90 µl DMEM to each
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Volume 10 Issue 7 -2023 Research Article
well. Following incubation at 37°C for 1 h in a dark chamber, OD
values were measured at 450 nm wavelength.
5.4. Echocardiography
Operators who were ignorant of the groups performed echocar-
diography on animals using an echocardiogram imaging system
(15 MHz, VisualSonics Vevo 2100). Two-dimensionally directed
M-mode images were obtained from long-axis views, collected
the principle cardiac function parameters, including fractional
shortening (FS), wall thickness estimated wall mass, volume, ejec-
tion fraction, heart rate, and cardiac output were collected, syn-
chronously. Meanwhile, the left ventricular end-diastolic volume
(LVEDV), the left ventricular end-diastolic dimension (LVEDD),
left ventricular end-systolic dimension (LVESD), left ventricular
ejection fraction (LVEF), and left ventricular fraction shortening
(LVFS) were calculated by the computer algorithms.
5.5. Histopathological Examination of Myocardial Tissues
The heart tissues were dissected and fixed within 4% paraformal-
dehyde for 24 h to stabilize samples and subsequently embedded
in paraffin as standard techniques. The tissue sections were stained
with hematoxylin and eosin (H&E) and then observed by a micro-
scope.
5.6. Terminal Deoxynucleotidyl Transferase DUTP Nick-End
Labeling (TUNEL) Staining
Myocardial apoptosis was evaluated using TUNEL staining ac-
cording to the instruction (Beyotime, China), and DAPI (blue)
was used for nuclear staining of cardiomyocytes. All sections were
sealed with fluorescence quenching sealing solution and ultimate-
ly observed under a fluorescence microscope [42]. The software
Image J was utilized to assess apoptosis level in cardiomyocytes
(quantitatively as percentage of TUNEL-positive cardiomyocytes).
5.7. Enzyme-Linked Immunosorbent Assay (ELISA)
The levels of TNF-α, IL-6, and IL-1β in serum were analyzed us-
ing ELISA kits (R&D Systems, Minneapolis, MN, USA) accord-
ing to the instructions of the manufacturer. In addition, the levels
of CK-MB (Cusabio Biotech CO., Ltd, Wuhan, China) and cTn
(Cusabio Biotech CO., Ltd) in serum and supernatant were also
measured by relevant ELISA kits according to the instructions.
5.8. Carbonyl Assay
To evaluate protein oxidative damage in the heart, carbonyl assay
was performed according to the instruction of the micro protein
carbonyl assay (Solarbio, China, BC1275). Briefly, heart tissues
were mixed with extracting solution by a homogenizer. The super-
natant was collected after centrifugation at 5000×g for 10 min at
4 °C. Next, secondary centrifugation was conducted at 12000×g
for 10 min to collect the new supernatant. After determining the
protein concentration by BCA detection kit (Thermo, USA), the
samples were added to 96 well plate and incubated at 37°C for 1h
away from light. After that, we collected the sediment centrifuged
to perform the subsequent process in proper order according to the
reagent instruction. Finally, the OD values at 370 nm wavelength
were assessed and the content of carboxide based on correspond-
ing calculation formulas was evaluated [43].
5.9. Cysteinyl Aspartate Specific Proteinase 3 (Caspase 3) As-
say
Enzymatic activity of apoptosis-induced caspase 3 was measured
with the corresponding kit (BestBio, Shanghai, China). Briefly,
myocardial tissue was minced to homogenate in cold lysis buffer
and then shook for 15 min on the ice. Next, the supernatant was
collected after centrifugation at 12000×g for 10 min at 4 °C. Pro-
tein contents were estimated by using the BCA method. Caspase 3
activity was measured in a 96-well plate, and each well contained
50 μL of lysate, 40 μL of assay buffer, and 10 μL of caspase 3
colorimetric substrate reagent. The plate was incubated away from
the light at 37 °C for 4 h. Finally, the OD values at 405 nm wave-
length were measured [44].
5.10. Reverse Transcription‑Quantitative PCR (RT‑qPCR)
Total RNA was extracted from each group of myocardial tissues or
H9c2 cardiomyocytes using the RNAiso Plus kit (Takara, Japan)
according to the reagent instruction. After that, the PrimeScript™
RT reagent kit (Takara, Japan) was employed to synthesize cDNA
by reverse transcription. Next, qPCR was conducted using an
SYBR Premix Ex Taq kit on a QuantStudio™ 5 system (Thermo,
USA). The amplification conditions included initial denaturation
at 95 °C for 10 s, followed by 40 cycles at 95 °C for 5 s and 60
°C for 20 s. GAPDH was used as an internal reference for target
genes. Ultimately, the relative expression levels of genes were cal-
culated by using the 2−ΔΔCt method. The primers used in animals
(mouse) and cells (rat) were respectively synthesized by Sangon
(Shanghai, China) and Thermo Fisher Scientific (Thermo, USA),
and the sequences are listed in (Table 1).
5.11. Western Blot Analysis
The whole proteins were extracted from the heart and H9c2 cell,
then quantitatively determined the protein concentration of the
BCA detection kit (Thermo, USA) to complete the preparatory
work for subsequent experiments. Sodium dodecyl sulfate-poly-
acrylamide gel electrophoresis (SDS-PAGE, 10%-12%) gels were
employed to separate the proteins. These separated proteins were
subsequently transferred onto undefiled polyvinylidene fluoride
(PVDF) membranes. The membranes were blocked with TBS con-
taining 5% bovine serum albumin (BSA) for 1h at room tempera-
ture and incubated overnight on a table concentrator with a prima-
ry antibody at 4℃. The membranes were washed three times (10
min) with tris-buffered saline (TBS) containing 0.1% tween-20,
then incubated with horseradish peroxidase (HRP) - conjugated
secondary antibodies (1:10000) for 1 h at room temperature. All
the antibodies were purchased from Cell Signaling Technology
(CST, Inc. MA, USA), the concentrations of antibodies were TLR4
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Volume 10 Issue 7 -2023 Research Article
(1:500), p-NF-κB p65 (1:1000), NF-κB p65 (1:1000), MyD88
(1:1000), Bax (1:1000), Bcl-2 (1:1000) and β-actin (1:1000). Af-
ter that, all protein bands were washed three times and visualized
through electrochemiluminescence with enhanced chemilumines-
cence reagent solution. GAPDH was used as the internal reference
for target proteins.
5.12. Statistical Analysis
The data analyzed by GraphPad 9.0.0 software are presented as the
mean ± SEM. Comparisons among multiple groups were analyzed
by one-way analysis of variance (ANOVA) followed by Tukey’s
post hoc test. p<0.05 was considered statistically significant.
6. Acknowledgement
This study was supported by the National Natural Science Foun-
dation of China (Nos. 81571895 and 81372055) and the Nat-
ural Science Foundation of Guangdong Province, China (No.
2019A1515010944).
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