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In view of many complications of diabetes, kidney failure is considered as one of the main complications. The oxidative stress-induced due to persistent hyperglycemic conditions is the major cause of kidney disease. The present study was designed to explore the nephroprotective efficacy of polyherbal (PH) extract in a diabetic model induced by streptozotocin (STZ). STZ (55 mg/kg body weight, intraperitoneal) was injected in overnight fasting rats to develop the diabetic experimental model. Effect on kidney injury was evaluated by investigating biochemical and histological evidences in renal tissue after 56 days of treatment of PH extract. Results showed the high glucose level in STZ treated rats that suggested hyperglycemia persistence along with the successful establishment of nephropathy in diabetic rats with altered renal function, inflammatory cytokines level as well as oxidative and nitrosative stress. Administration of PH extract significantly improved the glycemic condition, glomerular function and proximal reabsorptive markers. Further, elevated pro-inflammatory cytokines levels and disturbed redox status were restored. Moreover, findings were fostered and substantiated by histopathological examinations. Our work strongly proposes that the nephroprotective effect of the PH extract on renal damage could be attributed due to its anti-inflammatory and antioxidant properties. Thus, PH extract could have potential as a pharmaceutical drug for diabetes mellitus (DM). Additional long-term study or clinical trial is required for further investigations.
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Diabetes Mellitus Experimental , Insuficiência Renal , Animais , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Rim/metabolismo , Modelos Teóricos , Estresse Oxidativo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Insuficiência Renal/complicações , Estreptozocina/farmacologiaRESUMO
Leishmania is a protozoan parasite that resides and replicates in macrophages and causes leishmaniasis. The parasite alters the signaling cascade in host macrophages and evades the host machinery. Small G-proteins are GTPases, grouped in 5 different families that play a crucial role in the regulation of cell proliferation, cell survival, apoptosis, intracellular trafficking, and transport. In particular, the Ras family of small G-proteins has been identified to play a significant role in the cellular functions mentioned before. Here, we studied the differential expression of the most important small G-proteins during Leishmania infection. We found major changes in the expression of different isoforms of Ras, mainly in N-Ras. We observed that Leishmania donovani infection led to enhanced N-Ras expression, whereas it inhibited K-Ras and H-Ras expression. Furthermore, an active N-Ras pull-down assay showed enhanced N-Ras activity. L donovani infection also increased extracellular signal-regulated kinase 1/2 phosphorylation and simultaneously decreased p38 phosphorylation. In contrast, pharmacological inhibition of Ras led to reduction in the phosphorylation of extracellular signal-regulated kinase 1/2 and enhanced the phosphorylation of p38 in Leishmania-infected cells, which could lead to increased interleukin-12 expression and decreased interleukin-10 expression. Indeed, farnesylthiosalicyclic acid (a Ras inhibitor), when used at the effective level in L donovani-infected macrophages, reduced amastigotes in the host macrophages. Thus, upregulated N-Ras expression during L donovani infection could be a novel immune evasion strategy of Leishmania and would be a potential target for antileishmanial immunotherapy.
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Leishmania donovani/patogenicidade , Leishmaniose Visceral/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosforilação , Células THP-1 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
According to the facts and figures 2023stated that 6.7 million Americans over the age of 65 have Alzheimer's disease (AD). The scenario of AD has reached up to the maximum, of 4.1 million individuals, 2/3rd are female patients, and approximately 1 in 9 adults over the age of 65 have dementia with AD dementia. The fact that there are now no viable treatments for AD indicates that the underlying disease mechanisms are not fully understood. The progressive neurodegenerative disease, AD is characterized by amyloid plaques and neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau protein and senile plaques (SPs), which are brought on by the buildup of amyloid beta (Aß). Numerous attempts have been made to produce compounds that interfere with these characteristics because of significant research efforts into the primary pathogenic hallmark of this disorder. Here, we summarize several research that highlights interesting therapy strategies and the neuroprotective effects of GLP-1, Sigma, and, AGE-RAGE receptors in pre-clinical and clinical AD models.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Feminino , Masculino , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas tau/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/metabolismoRESUMO
Parkinson's disease is a neurodegenerative illness linked to ageing, marked by the gradual decline of dopaminergic neurons in the midbrain. The exact aetiology of Parkinson's disease (PD) remains uncertain, with genetic predisposition and environmental variables playing significant roles in the disease's frequency. Epidemiological data indicates a possible connection between pesticide exposure and brain degeneration. Specific pesticides have been associated with important characteristics of Parkinson's disease, such as mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation, which are crucial for the advancement of the disease. Recently, many animal models have been developed for Parkinson's disease study. Although these models do not perfectly replicate the disease's pathology, they provide valuable insights that improve our understanding of the condition and the limitations of current treatment methods. Drosophila, in particular, has been useful in studying Parkinson's disease induced by toxins or genetic factors. The review thoroughly analyses many animal models utilised in Parkinson's research, with an emphasis on issues including pesticides, genetic and epigenetic changes, proteasome failure, oxidative damage, α-synuclein inoculation, and mitochondrial dysfunction. The text highlights the important impact of pesticides on the onset of Parkinson's disease (PD) and stresses the need for more research on genetic and mechanistic alterations linked to the condition.
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Modelos Animais de Doenças , Doença de Parkinson , Praguicidas , Animais , Praguicidas/toxicidade , Praguicidas/efeitos adversos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/etiologia , Humanos , Drosophila , Estresse Oxidativo/efeitos dos fármacos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , RoedoresRESUMO
Cerebral stroke is a pressing global health concern, ranking as the second leading cause of mortality and resulting in persistent neurobehavioral impairments. Cerebral strokes, triggered by various embolic events, initiate complex signaling pathways involving neuroexcitotoxicity, ionic imbalances, inflammation, oxidative stress, acidosis, and mitochondrial dysfunction, leading to programmed cell death. Currently, the FDA has approved tissue plasminogen activator as a relatively benign intervention for cerebral stroke, leaving a significant treatment gap. However, a promising avenue has emerged from Earth's toxic creatures. Animal venoms harbor bioactive molecules, particularly neuropeptides, with potential in innovative healthcare applications. These venomous components, affecting ion channels, receptors, and transporters, encompass neurochemicals, amino acids, and peptides, making them prime candidates for treating cerebral ischemia and neurological disorders. This review explores the composition, applications, and significance of toxin-derived peptides as viable therapeutic agents. It also investigates diverse toxins from select venomous creatures, with the primary objective of shedding light on current stroke treatments and paving the way for pioneering therapeutic strategies capable of addressing neurobehavioral deficits.
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Peptídeos , Acidente Vascular Cerebral , Humanos , Animais , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Toxinas Biológicas , Peçonhas/uso terapêutico , Peçonhas/farmacologiaRESUMO
AT1 receptor blockers (ARBs) are commonly used drugs to treat cardiovascular disease and hypertension, but research on their impact on brain disorders is unattainable. Valsartan (VAL) is a drug that specifically blocks AT1 receptor. Despite the previous evidence for VAL to provide neuroprotection in case of ischemic reperfusion injury, evaluation of their potential in mitigating mitochondrial dysfunction that causes neuronal cell death and neurobehavioral impairment remains unknown. The aim of this study was to evaluate the therapeutic effect of repurposed drug VAL against ischemic reperfusion injury-induced neuronal alternation. tMCAO surgery was performed to induce focal cerebral ischemic reperfusion injury. Following ischemic reperfusion injury, we analyzed the therapeutic efficacy of VAL by measuring the infarct volume, brain water content, mitochondrial oxidative stress, mitochondrial membrane potential, histopathological architecture, and apoptotic marker protein. Our results showed that VAL administrations (5 and 10 mg/kg b.wt.) mitigated the brain damage, enhanced neurobehavioral outcomes, and alleviated mitochondrial-mediated oxidative damage. In addition to this, our findings demonstrated that VAL administration inhibits neuronal apoptosis by restoring the mitochondrial membrane potential. A follow-up investigation demonstrated that VAL induces BDNF expression and promoted ischemic tolerance via modulating the Akt/p-Creb signaling pathway. In summary, our results suggested that VAL administration provided neuroprotection, ameliorated mitochondrial dysfunction, preserved the integrity of neurons, and lead to functional improvement after ischemic reperfusion injury.
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Four new hybrid compounds (H1-H4) bearing pyrazole (S1 and S2) and chalcone (P1 and P2) fragments were synthesized and characterized. Compounds were assayed for their ability to inhibit the proliferation of human lung (A549) and colon (Caco-2) cancer cell lines. Besides, toxicity against normal cells was determined using the human umbilical vein endothelial cells (HUVEC). In silico molecular docking, molecular dynamics (MD) simulation and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were carried out to predict the binding modes, protein stability, drug-likeness and toxicity of the reported compounds. The in vitro anticancer activity of the tested compounds revealed dose-dependent cell-specific cytotoxicity. In silico studies revealed that the compounds have a good binding affinity, possess appropriate drug-likeness properties and have low toxicity profiles.Communicated by Ramaswamy H. Sarma.
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Antineoplásicos , Chalcona , Chalconas , Humanos , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Chalconas/farmacologia , Linhagem Celular Tumoral , Chalcona/farmacologia , Células CACO-2 , Células Endoteliais , Antineoplásicos/química , Desenho de Fármacos , Proliferação de Células , Pirazóis/farmacologia , Pirazóis/químicaRESUMO
Respiratory allergies have become a major public health concern and affect one-third of the world's population. Several factors like environmental changes, industrialization, and immunologic interactions are reported to contribute to allergic respiratory diseases. Immunological reactions because of mosquito bite (allergic proteins) have been reported to have a high contribution to IgE-mediated allergic airway disease but they are largely ignored. In this study, we aim to predict the potential allergens (proteins) from Aedes aegypti that might play a role in the reactions of IgE-mediated allergic airway diseases. The allergens are identified from an extensive literature search and the 3D structures were prepared using the SwissDock server. Computational studies were performed to identify the potential allergens that might be responsible for IgE-mediated allergies. Our docking and molecular dynamics (MD) simulation results suggest that ADE-3, an allergen from Aedes aegypti, has the highest docking score and is predicted to be responsible for IgE-mediated allergic reaction(s). Overall, this study highlights the importance of immunoinformatics, and the obtained information can be used for designing prophylactic peptide vaccine candidates and inhibitors for controlling IgE-mediated inflammations.Communicated by Ramaswamy H. Sarma.
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Aedes , Hipersensibilidade , Mordeduras e Picadas de Insetos , Animais , Humanos , Alérgenos/química , Aedes/metabolismo , Imunoglobulina E/metabolismoRESUMO
Mesenchymal stem cells (MSCs) originating from the umbilical cord (UC) or Wharton's jelly (WJ) have attracted substantial interest due to their potential to augment therapeutic approaches for a wide range of disorders. These cells demonstrate a wide range of capabilities in the process of differentiating into a multitude of cell types. Additionally, they possess a significant capacity for proliferation and are conveniently accessible. Furthermore, they possess a status of being immune-privileged, exhibit minimal tumorigenic characteristics, and raise minimal ethical concerns. Consequently, they are well-suited candidates for tissue regeneration and the treatment of diseases. Additionally, UC-derived MSCs offer a substantial yield compared to other sources. The therapeutic effects of these MSCs are closely associated with the release of nanosized extracellular vesicles (EVs), including exosomes and microvesicles (MVs), containing lipids, microRNAs, and proteins that facilitate intercellular communication. Due to their reduced tumorigenic and immunogenic characteristics, in addition to their convenient manipulability, EVs have arisen as a viable alternative for the management of disorders. The favorable characteristics of UC-MSCs or WJ-MSCs and their EVs have generated significant attention in clinical investigations encompassing diverse pathologies. Therefore, we present a review encompassing current preclinical and clinical investigations, examining the implications of UC-MSCs in diverse diseases, including those affecting bone, cartilage, skin, liver, kidney, neural, lung, cardiovascular, muscle, and retinal tissues, as well as conditions like cancer, diabetes, sepsis, and others.
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Vesículas Extracelulares , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Cordão Umbilical , Geleia de Wharton , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Geleia de Wharton/citologia , Vesículas Extracelulares/metabolismo , AnimaisRESUMO
Mesenchymal stem/stromal cells (MSCs) are acknowledged for their remarkable ability to undergo differentiation into various cell types. In addition, they exhibit anti-tumor characteristics, prompting endeavors to modify MSCs for employment in cancer therapies. On the contrary, it is imperative to recognize that MSCs have been extensively linked to pathways that facilitate the advancement of tumors. Numerous research studies have sought to modify MSCs for clinical application; however, the outcomes have been ambiguous, potentially due to the heterogeneity of MSC populations. Furthermore, the conflicting roles of MSCs in suppressing and promoting tumor growth present a challenge to the appropriateness of their use in anti-cancer therapies. Currently, there exists a lack of comprehensive comprehension concerning the anti-tumor and pro-tumor characteristics of MSCs for gastric cancer (GC). This article discusses the influence of MSCs on GC, the underlying mechanisms, the origins of MSCs, and their effects. This review article also elucidates how MSCs exhibit dual characteristics of promoting and inhibiting tumor growth. Hence, it is of utmost importance that clinical inquiries aimed at utilizing MSCs as a therapeutic intervention for cancer consider the potentiality of MSCs to accelerate the progression of GC. It is crucial to exercise caution throughout the process of developing MSC-based cellular therapies to enhance their anti-cancer attributes while simultaneously eliminating their tumor-promoting impacts.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Diferenciação Celular , Microambiente TumoralRESUMO
Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
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Doença de Alzheimer , Doença de Huntington , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Humanos , Doenças Neurodegenerativas/genética , Caenorhabditis elegans/metabolismo , Doença de Alzheimer/genética , Doença de Huntington/genéticaRESUMO
Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or facilitated by a condition such as hypoxia or ischemia, or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Increasing evidence suggests that hypoxia may affect many pathological aspects of AD, including oxidative stress, mitochondrial dysfunction, ER stress, amyloidogenic processing of APP, and Aß accumulation, which may collectively result in neurodegeneration. Further investigation into the relationship between hypoxia and AD may provide an avenue for the effective preservation and pharmacological treatment of this neurodegenerative disease. This review summarizes the effects of normoxia and hypoxia on AD pathogenesis and discusses the underlying mechanisms. Regulation of HIF-1α and the role of its key players, including P53, VEGF, and GLUT1, are also discussed.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Hipóxia/complicações , Hipóxia/metabolismo , Hipóxia/patologia , Encéfalo/metabolismo , Estresse OxidativoRESUMO
AIM: Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. MATERIALS AND METHODS: Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 µM) and Mel (100 µM) at 25 °C for 1 h was given prior to TNPs (50 µg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. KEY FINDINGS: QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. SIGNIFICANCE: Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure.
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Melatonina , Nanopartículas , Ratos , Animais , Masculino , Melatonina/farmacologia , Melatonina/metabolismo , Quercetina/farmacologia , Quercetina/metabolismo , Ratos Wistar , Mitocôndrias/metabolismo , Nanopartículas/toxicidade , Estresse OxidativoRESUMO
Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aß accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aß induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/metabolismo , Estresse Oxidativo/fisiologia , Antioxidantes/metabolismo , Plasticidade Neuronal , Biomarcadores/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
This study effectively reports the influence of experimental incubation period on the sol-gel production of husk-like zinc oxide nanoparticles (ZNPs) and their anti-cancerous abilities. The surface morphology of ZNPs was studied with the help of SEM. With the use of TEM, the diameter range of the ZNPs was estimated to be ~86 and ~231 nm for ZNPA and ZNPB, prepared by incubating zinc oxide for 2 and 10 weeks, respectively. The X-ray diffraction (XRD) investigation showed that ZNPs had a pure wurtzite crystal structure. On prolonging the experimental incubation, a relative drop in aspect ratio was observed, displaying a distinct blue-shift in the UV-visible spectrum. Furthermore, RBC lysis assay results concluded that ZNPA and ZNPB both demonstrated innoxious nature. As indicated by MTT assay, reactive oxygen species (ROS) release, and chromatin condensation investigations against the human epidermoid carcinoma (HEC) A431 cells, ZNPB demonstrated viable relevance to chemotherapy. Compared to ZNPB, ZNPA had a slightly lower IC50 against A431 cells due to its small size. This study conclusively describes a simple, affordable method to produce ZNP nano-formulations that display significant cytotoxicity against the skin cancer cell line A431, suggesting that ZNPs may be useful in the treatment of cancer.
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ABSTRACT Objective: To compare the clinical parameters of 4th and 5th COVID waves in Karachi, Pakistan. STUDY DESIGN: Descriptive study. Place and Duration of the Study: PNS Shifa Hospital, Karachi, from July 2021 to February 2022. METHODOLOGY: All patients with COVID-19 in PNS Shifa Hospital were included in the study. The patients were divided into two groups, those who had COVID-19 during the 4th wave, and others who had it during the 5th wave. The patients' demographic details, comorbidities, vaccination status, initial presentation, the severity of disease, clinical progress, and final disposal from the hospital were noted. A comparison of severity, length of hospital stays, and mortality was made between the groups. RESULTS: There were 747 patients admitted during the Delta variant-dominated 4th wave of COVID-19, and 490 patients during the 5th wave, dominated by the Omicron variant. A vast majority of fifth-wave patients had the mild disease (87.35% vs. 49.39%), with significantly lower critical patients (2.04% vs. 7.09%). Vaccination was effective against both the Delta and the Omicron variant of the SARS-CoV-2 virus. The mean length of stay in the hospital for patients was significantly lesser (p < 0.001) during the 5th wave as compared to the 4th wave (6.43 ± 3.37 vs. 9.56 ± 5.45 days). The mortality rate was 7.09% among patients admitted in the 4th wave and 2.04% in the 5th wave. This difference was statistically significant (p < 0.001). CONCLUSION: The severity of disease, length of hospital stays, and mortality were higher in the Delta variant-dominated 4th wave of COVID-19 as compared to the Omicron variant-dominated 5th wave in Pakistan. The vaccination was effective against both the Delta and the Omicron variant of COVID 19, as the mortality rate among the vaccinated patients during the two waves was not significantly different. KEY WORDS: COVID 19, Vaccination, Disease outcome, Mortality.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Paquistão/epidemiologia , Centros de Atenção TerciáriaRESUMO
AIMS: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. MATERIALS AND METHODS: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. KEY FINDINGS: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. SIGNIFICANCE: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.
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Neoplasias Ósseas , Dor do Câncer , MicroRNAs , Osteossarcoma , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Dor do Câncer/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos C3H , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Doenças Neuroinflamatórias , NF-kappa B/metabolismo , Osteossarcoma/genética , Qualidade de VidaRESUMO
Oligospermia and asthenozoospermia, both frequent, can lead to male infertility. Oligospermia might be viewed as a milder form of azoospermia because the same mutations that produce azoospermia in some individuals also create oligospermia in other individuals. In this, we looked at different characteristics of oligospermia men, counting the level of apoptosis and a few related apoptotic and oxidative stress components, and compared them to solid controls. In this study, semen samples from healthy fertile men (n = 35) and oligospermia (n = 35) were collected, and sperm death rates in both groups were examined using flow cytometry. Also, gene expression of apoptotic and anti-apoptotic markers and miR-221 were investigated (Real-Time PCR). Moreover, for the evaluation of catalase and SOD activity and anti-inflammatory cytokines, including IL-10 and TGF-ß, the specific ELISA kits and procedures were applied. As a result, higher gene and protein expression levels of PTEN, P27, and P57 were observed in patients with oligospermia. In contrast, lower mRNA expression of AKT and miR-221 was detected in this group. In addition, IL-10, TGF-ß, and catalase activity were suppressed in the oligospermia group compared with healthy men samples. Moreover, the frequency of apoptosis of sperm cells is induced in patients. In conclusion, apoptosis-related markers, PTEN, and the measurement of significant and efficient oxidative stress markers like SOD and catalase in semen plasma could be considered as the critical diagnostic markers for oligospermia. Future studies will be better able to treat oligospermia by showing whether these indicators are rising or falling.
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Azoospermia , MicroRNAs , Oligospermia , Humanos , Masculino , Oligospermia/genética , Azoospermia/genética , Azoospermia/diagnóstico , Azoospermia/metabolismo , Catalase/genética , Catalase/metabolismo , Interleucina-10/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Background: The severity of the articular lesion is the single most essential element in investigating the extent of flexion that is required for activities. However, a prior study found no differences in muscle strength gains of quadriceps muscles at different knee angles in people with patellofemoral pain syndrome (PFPS). Objective: The effects of patellar taping and electromyographic biofeedback (EMG-BF)-guided isometric quadriceps strengthening at different knee angles (e.g., 30°, 60°, and 90° of knee flexion) on quadriceps strength and functional performance in people with PFPS were compared in this single-blind randomized controlled parallel trial. Methods: Sixty adult male athletes with PFPS (age: 26.9 ± 1.4 years) were randomly divided into two groups. The experimental group (n = 30) received patellar taping and EMG-BF-guided isometric contraction exercise at 30°, 60°, and 90° angles, and the control group (n = 30) received sham patellar taping without EMG-BF-guided exercises for six weeks. Pain intensity, knee function, muscle strength, and the single-leg triple hop (SLTH) test were assessed. Results: The pain intensity and SLTH scores between the groups were significantly different at the end of the trial (p ≤ 0.001). The EMG-BF and control groups had mean pain scores of 1.3 (0.8) and 4.5 (0.8), respectively. The EMG-BF and control groups had mean functional scores of 80.4 (5.1) and 69.1 (6.1), respectively. The mean SLTH score for the EMG-BF group was 540.7 (51.2) and for the control group it was 509.4 (49.8) after the trial. Quadriceps muscle strength was significantly higher in those who performed quadriceps strength training at 60° of knee flexion after six weeks than in those who performed strength training at 30° or 90° of knee flexion. Conclusion: The findings indicated that individuals who trained their quadriceps at a 60° knee angle had significantly stronger quadriceps muscles than individuals who trained at 30° or 90° of knee flexion. Trial Registration. This trial is registered at Clinical Trials.gov under the identifier NCT05055284.
Assuntos
Síndrome da Dor Patelofemoral , Adulto , Atletas , Biorretroalimentação Psicológica , Eletromiografia , Humanos , Masculino , Força Muscular/fisiologia , Síndrome da Dor Patelofemoral/terapia , Desempenho Físico Funcional , Músculo Quadríceps/fisiologia , Método Simples-Cego , Adulto JovemRESUMO
Background: The study's objective was to analyze the influence of an 8-week neuromuscular electrical stimulation (NMES) with a plyometric (PT) and strength training (ST) program on muscular, sprint, and functional performances in collegiate male football players. Methods: Sixty collegiate male football players participated in this randomized controlled trial single-blind study. All the participants were randomly divided into two groups: (1) NMES group (Experimental, n = 30) who received NMES assisted ST and (2) sham NMES group (Control, n = 30) who received sham NMES assisted ST. In addition, participants from both groups received a PT program; both groups received intervention on three days a week for 8-weeks. The study's outcomes, such as muscular, sprint, and functional performances, were assessed using a strength test (STN) for quadriceps muscle, sprint test (ST), and single-leg triple hop test (SLTHT), respectively, at baseline pre-intervention and 8-week post-intervention. The interaction between group and time was identified using a mixed design (2 × 2) ANOVA. Results: Significant difference found across the two time points for the scores of STN: F (1.58) = 5,479.70, p < 0.05; SLTHT: F (1.58) = 118.17, p < 0.05; and ST: F (1.58) = 201.63, p < 0.05. Similarly, the significant differences were found between groups averaged across time for the scores of STN: F (1.58) = 759.62, p < 0.05 and ST: F (1.58) = 10.08, p < 0.05. In addition, after 8-week of training, Cohen's d observed between two groups a large to medium treatment's effect size for the outcome STN (d = 10.84) and ST (d = 1.31). However, a small effect size was observed only for the SLTHT (d = 0.613). Conclusions: Findings suggest that the effect of PT and ST with either NMES or sham NMES are equally capable of enhancing muscular, sprint, and functional performances in collegiate male football players. However, PT and ST with NMES have shown an advantage over PT and ST with sham NMES in improving muscular performance and sprint performance among the same participants.