ABSTRACT
The increasing global incidence of multidrug-resistant (MDR) bacterial infections threatens public health and compromises various aspects of modern medicine. Recognising the urgency of this issue, the World Health Organisation has prioritised the development of novel antimicrobials to combat ESKAPEE pathogens. Comprising Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli, such pathogens represent a spectrum of high to critical drug resistance, accounting for a significant proportion of hospital-acquired infections worldwide. In response to the waning efficacy of antibiotics against these resilient pathogens, phage therapy (PT) has emerged as a promising therapeutic strategy. This review provides a comprehensive summary of clinical research on PT and explores the translational journey of phages from laboratory settings to clinical applications. It examines recent advancements in pre-clinical and clinical developments, highlighting the potential of phages and their proteins, alone or in combination with antibiotics. Furthermore, this review underlines the importance of establishing safe and approved routes of phage administration to patients. In conclusion, the evolving landscape of phage therapy offers a beacon of hope in the fight against MDR bacterial infections, emphasising the imperative for continued research, innovation and regulatory diligence to realise its full potential in clinical practice.
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BACKGROUND: Succinylcholine is the most used short-acting depolarizing muscle relaxant for rapid sequence induction. However, its use is associated with adverse effects, like fasciculations and myalgia. Thus, many pretreatment modalities were used to minimize or prevent these adverse effects. Our aim for this study was to compare the efficacy of propofol and thiopentone in preventing succinylcholine-induced fasciculation and myalgia in gabapentin-premedicated patients. Methods: Eighty patients with American Society of Anesthesiologists (ASA) physical status I/II, either male or female, in the aged group of 18-60 years, and scheduled to undergo elective abdominal surgery under general anesthesia were randomly allocated into either the propofol (P) or thiopentone (T) group. Anesthesia was induced with IV fentanyl 2 µg/kg, IV succinylcholine 2 mg/kg, and either IV propofol (2 mg/kg) in group P or IV thiopentone (5 mg/kg) in group T. In both groups, oral gabapentin 600 mg was given two hours before the surgery. All patients were observed and graded for intraoperative fasciculations and myalgia during 24 postoperative hours by a blinded observer. Fasciculation grade, myalgia grade, total tramadol consumption, and demographic data were compared using a test of proportion and chi-squared test. RESULTS: Study results demonstrated that the use of propofol significantly decreases the severity of fasciculation at one, two, and three minutes (P < 0.001) and myalgia at two, six, and 12 hours (P < 0.001) more than thiopentone in gabapentin-premedicated patients. Tramadol consumption in both groups was insignificant (P = 0.658). CONCLUSIONS: Propofol (2 mg/kg) is more effective than thiopentone (5 mg/kg) in decreasing the severity of fasciculation and myalgia following succinylcholine administration in gabapentin-premedicated patients.
ABSTRACT
The complex and multidimensional landscape of type 2 diabetes mellitus (T2D) is a major global concern. Despite several years of extensive research, the precise underlying causes of T2D remain elusive, but evidence suggests that it is influenced by a myriad of interconnected risk factors such as epigenetics, genetics, gut microbiome, environmental factors, organelle stress, and dietary habits. The number of factors influencing the pathogenesis is increasing day by day which worsens the scenario; meanwhile, the interconnections shoot up the frame. By gaining deeper insights into the contributing factors, we may pave the way for the development of personalized medicine, which could unlock more precise and impactful treatment pathways for individuals with T2D. This review summarizes the state of knowledge about T2D pathogenesis, focusing on the interplay between various risk factors and their implications for future therapeutic strategies. Understanding these factors could lead to tailored treatments targeting specific risk factors and inform prevention efforts on a population level, ultimately improving outcomes for individuals with T2D and reducing its burden globally.
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These diverse outcomes of Covid-19 are influenced by various factors including age, gender, underlying health conditions, immune responses, viral variants, external factors, and overall quality of life. Demographic analysis of patients aged 0-18 years experienced mild to moderate cases, above 55 years with co-morbidities, were more severely affected.COVID-19 incidence was higher in males (58 %) & (42 %) in females. The reduced expression of Toll-like receptors (TLR) in severe and critical patients is a crucial determinant. This reduced TLR expression is primarily attributed to the dominance of the PLpro viral protein of COVID-19. Disease enrichment analysis highlights the long-term impact of COVID-19, which can lead to post-recovery complications such as hypertension, diabetes, cardiac diseases, and brain ischemia in Covid-19 patients. In conclusion, a comprehensive strategy targeting key factors like PLpro, TLR, and inflammatory cytokines such as IL-1 and IL-6 could offer an effective approach to mitigate the devastating effects of COVID-19.
Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Young Adult , COVID-19/immunology , Cytokines/immunology , Cytokines/blood , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Retrospective StudiesABSTRACT
BACKGROUND: Invasive ductal carcinoma (IDC) is the most common form of breast cancer which accounts for 85% of all breast cancer diagnoses. Non-invasive and early stages have a better prognosis than late-stage invasive cancer that has spread to lymph nodes. The involvement of microRNAs (miRNAs) in the initiation and progression of breast cancer holds great promise for the development of molecular tools for early diagnosis and prognosis. Therefore, developing a cost effective, quick and robust early detection protocol using miRNAs for breast cancer diagnosis is an imminent need that could strengthen the health care system to tackle this disease around the world. METHODS: We have analyzed putative miRNAs signatures in 100 breast cancer samples using two independent high fidelity array systems. Unique and common miRNA signatures from both array systems were validated using stringent double-blind individual TaqMan assays and their expression pattern was confirmed with tissue microarrays and northern analysis. In silico analysis were carried out to find miRNA targets and were validated with q-PCR and immunoblotting. In addition, functional validation using antibody arrays was also carried out to confirm the oncotargets and their networking in different pathways. Similar profiling was carried out in Brca2/p53 double knock out mice models using rodent miRNA microarrays that revealed common signatures with human arrays which could be used for future in vivo functional validation. RESULTS: Expression profile revealed 85% downregulated and 15% upregulated microRNAs in the patient samples of IDC. Among them, 439 miRNAs were associated with breast cancer, out of which 107 miRNAs qualified to be potential biomarkers for the stratification of different types, grades and stages of IDC after stringent validation. Functional validation of their putative targets revealed extensive miRNA network in different oncogenic pathways thus contributing to epithelial-mesenchymal transition (EMT) and cellular plasticity. CONCLUSION: This study revealed potential biomarkers for the robust classification as well as rapid, cost effective and early detection of IDC of breast cancer. It not only confirmed the role of these miRNAs in cancer development but also revealed the oncogenic pathways involved in different progressive grades and stages thus suggesting a role in EMT and cellular plasticity during breast tumorigenesis per se and IDC in particular. Thus, our findings have provided newer insights into the miRNA signatures for the classification and early detection of IDC.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal , MicroRNAs , Animals , Female , Mice , Biomarkers , Biomarkers, Tumor/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Signal TransductionABSTRACT
The presence of highly toxic dioxins, specifically polychlorinated dibenzo-p-dioxins (PCDDs), in drinking water is a matter of great concern due to their long-lasting nature and harmful effects. In this study, we detected three out of the five dioxin congeners: 2, 3, 7, 8-tetrachlorodibenzodioxin (TCDD), 1, 2, 3, 7, 8-pentachlorodibenzo-p-dioxin (PeCDD), and octachlorodibenzo-p-dioxin (OCDD). The investigation revealed that three dioxins were present in water samples of winter season, while TCDD and OCDD were found in the summer season. The geometric mean concentrations of PCDDs were 229.9 ng/L (winter) and 108.4 ng/L (summer), exceeded the maximum contaminant level of 30 pg/L set by the USEPA in surface water. The estimated daily intake of PCDDs for residents through drinking water was 273.97 ng-WHO2005-TEQ/kg/days during winter and 78.875 ng-WHO2005-TEQ/kg/days during summer. Our study emphasizes the urgent need for further research on persistent organic pollutants in drinking water to safeguard public health and community well-being.
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Capra hircus (goat) induced pluripotent stem cells (giPSCs) harbor enormous scientific value and contribute to cellular agriculture, animal cloning, etc. Conventional approaches to giPSC generation suffer from complexity and low preparation efficiency. In the present study, we introduced the episomal vectors carrying the human pluripotent genes in goat somatic cells to generate the giPSC-like colonies. Initially, a simple non-enzymatic method was used to isolate the goat dermal fibroblast cells and, further, a cell line was established. Later, goat fibroblast cells were transfected with commercially available episomal vectors carrying the human pluripotent genes and successfully generated the iPSC-like colonies which exhibited the expression of goat endogenous pluripotent genes and positive staining with alkaline phosphatase. Moreover, giPS-like cells formed embryoid bodies (EBs)-like aggregates and weekly expressed the marker genes of two germ layers. Reprogramming of goat fibroblast using episomal vectors carrying human pluripotent genes could lead to the development of an efficient and time- and cost-effective approach to giPSC generation.
Subject(s)
Induced Pluripotent Stem Cells , Pluripotent Stem Cells , Humans , Animals , Cellular Reprogramming/genetics , Pluripotent Stem Cells/metabolism , Fibroblasts , Goats , Cell Differentiation/geneticsABSTRACT
Introduction: Dengue fever is hyperendemic in several Southeast and South Asian countries, including India, with all four serotypes (DENV 1-4) circulating at different periods and in different locations. Sustainable and improved virological and entomological surveillance is the only tool to prevent dengue and other vector-borne diseases. Objectives: The present study has been carried out to detect and characterize the circulating dengue virus (DENV) in field-collected Aedes mosquitoes in Bhopal, Central India. Methods: Aedes mosquitoes were collected from 29 localities within Bhopal city during October 2020 to September 2022. DENV infection was assessed in the individual head and thorax regions of Aedes mosquitoes using reverse transcriptase PCR. Positive samples were sequenced, and the circulating serotypes and genotypes were determined using phylogenetic analysis. Results: DENV RNA was detected in 7 Aedes aegypti and 1 Aedes albopictus, with infection rates of 0.59 and 0.14%, respectively. Phylogenetic analysis revealed all the isolates belonged to DENV serotype 2 and distinctly clustered with the non-Indian lineage (cosmopolitan genotype 4a), which was not recorded from the study area earlier. The time to most common recent ancestor (TMRCA) of these sequences was 7.4 years old, with the highest posterior density (HPD) of 3.5-12.2 years, indicating that this new lineage emerged during the year 2014. This is the first report on the DENV incrimination in both Ae. aegypti and Ae. albopictus mosquitoes collected from Bhopal, Central India. Conclusion: The observed emergence of the non-Indian lineage of DENV-2 in Bhopal, which again is a first report from the area, coincides with the gradual increase in DENV cases in Bhopal since 2014. This study emphasizes the importance of DENV surveillance and risk assessment in this strategically important part of the country to decipher its outbreak and severe disease-causing potential.
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Metabolic disorders are increasingly prevalent worldwide, leading to high rates of morbidity and mortality. The variety of metabolic illnesses can be addressed through personalized medicine. The goal of personalized medicine is to give doctors the ability to anticipate the best course of treatment for patients with metabolic problems. By analyzing a patient's metabolomic, proteomic, genetic profile, and clinical data, physicians can identify relevant diagnostic, and predictive biomarkers and develop treatment plans and therapy for acute and chronic metabolic diseases. To achieve this goal, real-time modeling of clinical data and multiple omics is essential to pinpoint underlying biological mechanisms, risk factors, and possibly useful data to promote early diagnosis and prevention of complex diseases. Incorporating cutting-edge technologies like artificial intelligence and machine learning is crucial for consolidating diverse forms of data, examining multiple variables, establishing databases of clinical indicators to aid decision-making, and formulating ethical protocols to address concerns. This review article aims to explore the potential of personalized medicine utilizing omics approaches for the treatment of metabolic disorders. It focuses on the recent advancements in genomics, epigenomics, proteomics, metabolomics, and nutrigenomics, emphasizing their role in revolutionizing personalized medicine.
Subject(s)
Metabolic Diseases , Proteomics , Humans , Proteomics/methods , Artificial Intelligence , Genomics/methods , Precision Medicine/methods , Metabolomics/methods , Metabolic Diseases/genetics , Metabolic Diseases/therapyABSTRACT
The skeletal system is an extraordinary structure that serves multiple purposes within the body, including providing support, facilitating movement, and safeguarding vital organs. Moreover, it acts as a reservoir for essential minerals crucial for overall bodily function. The intricate interplay of bone cells plays a critical role in maintaining bone homeostasis, ensuring a delicate balance. However, various factors, both intrinsic and extrinsic, can disrupt this vital physiological process. These factors encompass genetics, aging, dietary and lifestyle choices, the gut microbiome, environmental toxins, and more. They can interfere with bone health through several mechanisms, such as hormonal imbalances, disruptions in bone turnover, direct toxicity to osteoblasts, increased osteoclast activity, immune system aging, impaired inflammatory responses, and disturbances in the gut-bone axis. As a consequence, these disturbances can give rise to a range of bone disorders. The regulation of bone's physiological functions involves an intricate network of continuous processes known as bone remodeling, which is influenced by various intrinsic and extrinsic factors within the organism. However, our understanding of the precise cellular and molecular mechanisms governing the complex interactions between environmental factors and the host elements that affect bone health is still in its nascent stages. In light of this, this comprehensive review aims to explore emerging evidence surrounding bone homeostasis, potential risk factors influencing it, and prospective therapeutic interventions for future management of bone-related disorders.
Subject(s)
Bone Density , Gastrointestinal Microbiome , Humans , Osteoclasts , Aging , HomeostasisABSTRACT
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic ß-cells, leading to insulin deficiency. Insulin replacement therapy is the current standard of care for T1D, but it has significant limitations. However, stem cell-based replacement therapy has the potential to restore ß-cell function and achieve glycaemic control eradicating the necessity for drugs or injecting insulin externally. While significant progress has been made in preclinical studies, the clinical translation of stem cell therapy for T1D is still in its early stages. In continuation, further research is essentially required to determine the safety and efficacy of stem cell therapies and to develop strategies to prevent immune rejection of stem cell-derived ß-cells. The current review highlights the current state of cellular therapies for T1D including, different types of stem cell therapies, gene therapy, immunotherapy, artificial pancreas, and cell encapsulation being investigated, and their potential for clinical translation.
Subject(s)
Diabetes Mellitus, Type 1 , Insulin-Secreting Cells , Humans , Diabetes Mellitus, Type 1/therapy , Diabetes Mellitus, Type 1/metabolism , Immunotherapy , Insulin/metabolism , Cell- and Tissue-Based Therapy , Insulin-Secreting Cells/metabolismABSTRACT
COVID-19 has caused mayhem in the life of people. It has disrupted the social fabric of life. The children and adolescent population has been particularly affected by its direct and indirect effects. This systematic review aims to find the prevalence of depression and anxiety in children and adolescent age groups. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for finding the prevalence of depression and anxiety. We found the total number of participants to be 71,016. A random effect model was used for conducting meta-analysis. The prevalence of depression was mentioned in 17 studies of 23 and the pooled prevalence was 27% [95% confidence interval: 21%-36%] and heterogeneity (I2 statistics; P <.00001) was 100%. The prevalence of anxiety was found in 20 studies of 23 and the pooled anxiety prevalence was 25% (95% confidence interval: 16%-41%) and heterogeneity (I2 statistics; P < .00001) was found to be 100%. The summary of the findings has been provided. Due to high heterogeneity, moderator analysis was performed separately for depression and anxiety subgroups. The study design consisted of cross-sectional studies and some studies conducted through online surveys. The age range varied considerably from 1 year to 19 years; 5 studies had participants aged more than 19 years, but the mean age of the total sample was less than 18 years. We conclude that indeed there is a mental health epidemic among the child and adolescent population. We recommend early intervention and tailored made strategies should for management. As the pandemic is enduring, rigorous monitoring should be done. This age group is under extra pressure owing to a large uncertainty about their studies as well their future.
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Mitochondrial function is essential for maintaining neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is proinflammatory and triggers the cGAS-STING pathway that aids AD pathology. In this review, we critically discuss the factors that affect mitochondrial impairment and different mitophagy processes in AD. Furthermore, we discuss the molecules used in mouse studies as well as clinical trials that could result in potential therapeutics in the future.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Mice , Animals , Alzheimer Disease/metabolism , Mitochondria/metabolism , Autophagy/physiology , Mitophagy/genetics , Neurodegenerative Diseases/metabolismABSTRACT
The complexity and variety of gut microbiomes within and among individuals have been extensively studied in recent years in connection to human health and diseases. Our growing understanding of the bidirectional communication between metabolic diseases and the gut microbiome has also highlighted the significance of gut microbiome dysbiosis in the genesis and development of obesity-related cancers. Therefore, it is crucial to comprehend the possible role of the gut microbiota in the crosstalk between obesity and colorectal cancer (CRC). Through the induction of gut microbial dysbiosis, gut epithelial barrier impairment, metabolomic dysregulation, chronic inflammation, or dysregulation in energy harvesting, obesity may promote the development of colorectal tumors. It is well known that strategies for cancer prevention and treatment are most effective when combined with a healthy diet, physical activity, and active lifestyle choices. Recent studies also suggest that an improved understanding of the complex linkages between the gut microbiome and various cancers as well as metabolic diseases can potentially improve cancer treatments and overall outcomes. In this context, we herein review and summarize the clinical and experimental evidence supporting the functional role of the gut microbiome in the pathogenesis and progression of CRC concerning obesity and its metabolic correlates, which may pave the way for the development of novel prognostic tools for CRC prevention. Therapeutic approaches for restoring the microbiome homeostasis in conjunction with cancer treatments are also discussed herein.
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Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.
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In vitro meat production via stem cell technology and tissue engineering provides hypothetically elevated resource efficiency which involves the differentiation of muscle cells from pluripotent stem cells. By applying the tissue engineering technique, muscle cells are cultivated and grown onto a scaffold, resulting in the development of muscle tissue. The studies related to in vitro meat production are advancing with a seamless pace, and scientists are trying to develop various approaches to mimic the natural meat. The formulation and fabrication of biodegradable and cost-effective edible scaffold is the key to the successful development of downstream culture and meat production. Non-mammalian biopolymers such as gelatin and alginate or plant-derived proteins namely soy protein and decellularized leaves have been suggested as potential scaffold materials for in vitro meat production. Thus, this article is aimed to furnish recent updates on bioengineered scaffolds, covering their formulation, fabrication, features, and the mode of utilization.
Subject(s)
Pluripotent Stem Cells , Tissue Scaffolds , Tissue Engineering/methods , Cell Differentiation , MeatABSTRACT
The selection of an appropriate scaffold is imperative for the successful development of alternative animal protein in the form of cultured meat or lab-grown meat. Decellularized tissues have been suggested as a potential scaffold for cultured meat production owing to their capacity to support an optimal environment and niche conducive to cell proliferation and growth. This approach facilitates the systematic development of 3D tissues in the laboratory. Decellularized scaffold biomaterials have characteristics of high biocompatibility, biodegradation, and various bioactivities, which could potentially address the limitations associated with synthetic bio-scaffold materials. The present study involved the derivation and characterization of a decellularized scaffold from mushroom tissue following subsequent assessment of the scaffold's capacity to support myogenic differentiation. Mushroom sections were soaked in nuclease and detergent solution for 4 days. Furthermore, decellularization was confirmed by histology and DAPI staining, which showed the removal of cellular components and nuclei. Myoblast cells were seeded onto decellularized tissue, which exhibited excellent cytocompatibility and promoted myogenic growth and differentiation. The study's findings can serve as a foreground for the generation of an edible and natural scaffold for producing a safe and disease-free source of alternative animal protein, potentially reducing the burden on the health sector caused by conventional animal protein production and consumption.
Subject(s)
Biocompatible Materials , Tissue Scaffolds , Animals , Cell Differentiation , Biocompatible Materials/pharmacology , Cell Proliferation , MyoblastsABSTRACT
Objective: The aim of this review is to speculate the pre-clinical and clinical evidences indicating the association between butyrate-synthesizing firmicutes and development and progression of type 2 diabetes mellitus. Methodology: Literature was searched using 'Google Scholar' and 'PubMed' to find out most relevant articles for the scope of this review. Information was also gathered from authentic sources such as the World Health Organisation and the International Diabetes Federation. Results: Evidences suggest that an abnormal perturbation in the gut microbiome characterized by subsided levels of butyrate-producing bacteria may gradually result in the progression of type-2 diabetes; however, the explicit mechanisms underlying and implicating the role of specific butyrate-producing microbes remain unclear. Conclusions: This review explicitly summarizes the role of butyrate-synthesizing firmicutes known to be reduced in the subjects with type-2 diabetes mellitus in host metabolic health and contemplates the putative and reported mechanisms underlying its implication in the pathophysiology of type-2 diabetes mellitus.
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In recent decades, dengue has been expanding rapidly in the tropical cities. Even though environmental factors and landscape features profoundly impact dengue vector abundance and disease epidemiology, significant gaps exist in understanding the role of local environmental heterogeneity on dengue epidemiology in India. In this study, we assessed the role of remotely sensed climatic factors (rainfall, temperature and humidity) and landscape variables (land use pattern, vegetation and built up density) on dengue incidence (2012-2019) in Bhopal city, Central India. Dengue hotspots in the city were assessed through geographical information system based spatial statistics. Dengue incidence increased from 0.59 cases in 2012 to 9.11 cases in 2019 per 10,000 inhabitants, and wards located in Southern Bhopal were found to be dengue hotspots. Distributed lag non-linear model combined with quasi Poisson regression was used to assess the exposure-response association, relative risk (RR), and delayed effects of environmental factors on dengue incidence. The analysis revealed a non-linear relationship between meteorological variables and dengue cases. The model shows that the risk of dengue cases increases with increasing mean temperature, rainfall and absolute humidity. The highest RR of dengue cases (~2.0) was observed for absolute humidity ≥60 g/m3 with a 5-15 week lag. Rapid urbanization assessed by an increase in the built-up area (a 9.1% increase in 2020 compared to 2014) could also be a key factor driving dengue incidence in Bhopal city. The study sheds important insight into the synergistic effects of both the landscape and climatic factors on the transmission dynamics of dengue. Furthermore, the study provides key baseline information on the climatic variables that can be used in the micro-level dengue prediction models in Bhopal and other cities with similar climatic conditions.
Subject(s)
Dengue , Humans , Humidity , India/epidemiology , Temperature , IncidenceABSTRACT
Calpain-1 is a ubiquitous calcium dependent cysteine protease and found in cytoplasm as well as mitochondria. We have earlier reported that active calpain-1 is translocated from cytosol to mitochondria and activates MMP9. Calpain-1 activation is detrimental to the heart in several different ways, but there is little evidence that it can degrade Purkinje cell protein (PCP-4) and impair contractility in diabetes. Our hypothesis is that in diabetes, PCP-4 is degraded by calpain-1, causing contractile dysfunction that can be mitigated by exercise. To test this hypothesis, we recruited four groups of mice, 1) db/+ control, 2) db/+ with exercise, 3) db/db, 4) db/db with exercise. The mice were exercised on treadmill for 8 weeks as per American Veterinary Research Guidelines. Adding calcium to isolated cardiomyocytes caused them to lose shape and die. Compared with live myocytes, we observed high calpain-1 levels as well as significantly lower levels of PCP-4 and increased levels of calmodulin and calmodulin kinase II (CaMKII) in dead myocytes. We used the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) plasmid to knock down calpain-1 in HL-1 myocytes which restored the levels of PCP-4 along with calmodulin and CaMKII. In vivo, we found upregulated levels of calpain-1 in db/db mice (diabetic) as compared to db/+ which were mitigated in the exercised mice. Conclusively our data strongly suggests that in diabetes there is high induction of calpain-1 with degrades PCP-4, a protein important for contractility and exercise can mitigate this.