10 research outputs found
Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels
Sigma1 receptor protein (Sigmar1) is a small, multifunctional molecular chaperone protein ubiquitously expressed in almost all body tissues. This protein has previously shown its cardioprotective roles in rodent models of cardiac hypertrophy, heart failure, and ischemia-reperfusion injury. Extensive literature also suggested its protective functions in several central nervous system disorders. Sigmar1’s molecular functions in the pulmonary system remained unknown. Therefore, we aimed to determine the expression of Sigmar1 in the lungs. We also examined whether Sigmar1 ablation results in histological, ultrastructural, and biochemical changes associated with lung pathology over aging in mice. In the current study, we first confirmed the presence of Sigmar1 protein in human and mouse lungs using immunohistochemistry and immunostaining. We used the Sigmar1 global knockout mouse (Sigmar1−/−) to determine the pathophysiological role of Sigmar1 in lungs over aging. The histological staining of lung sections showed altered alveolar structures, higher immune cells infiltration, and upregulation of inflammatory markers (such as pNFκB) in Sigmar1−/− mice compared to wildtype (Wt) littermate control mice (Wt). This indicates higher pulmonary inflammation resulting from Sigmar1 deficiency in mice, which was associated with increased pulmonary fibrosis. The protein levels of some fibrotic markers, fibronectin, and pSMAD2 Ser 245/250/255 and Ser 465/467, were also elevated in mice lungs in the absence of Sigmar1 compared to Wt. The ultrastructural analysis of lungs in Wt mice showed numerous multilamellar bodies of different sizes with densely packed lipid lamellae and mitochondria with a dark matrix and dense cristae. In contrast, the Sigmar1−/− mice lung tissues showed altered multilamellar body structures in alveolar epithelial type-II pneumocytes with partial loss of lipid lamellae structures in the lamellar bodies. This was further associated with higher protein levels of all four surfactant proteins, SFTP-A, SFTP-B, SFTP-C, and SFTP-D, in the Sigmar1−/− mice lungs. This is the first study showing Sigmar1’s expression pattern in human and mouse lungs and its association with lung pathophysiology. Our findings suggest that Sigmar1 deficiency leads to increased pulmonary inflammation, higher pulmonary fibrosis, alterations of the multilamellar body stuructures, and elevated levels of lung surfactant proteins
Detection and Prevalence of Inducible Clindamycin Resistance in Clinical Isolates of Staphylococcus aureus: Experience from Tertiary Care Hospital in Jaipur
Background: Staphylococcus aureus is a frequent cause of bacterial infections in both developed and developing countries. Emerging resistance to methicillin in this organism has left us with very few therapeutic alternatives to treat the infections caused by them. Objective: We aimed to determine the prevalence of inducible clindamycin resistance in clinical isolates of S. aureus and antimicrobial susceptibility pattern of S. aureus isolates due to the increasing prevalence of resistance to most antimicrobial agents in staphylococci signifies the need for new effective agents to treat staphylococcal infections. Methods: The study was carried out in the Department of Microbiology at Mahatma Gandhi Hospital, Sitapura, Jaipur, Rajasthan. All S. aureus isolates (non-repetitive) from different clinical samples received in clinical microbiology laboratory from in and outpatients in Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan, were included in the study. Results: Out of 157 erythromycin-resistant S. aureus, 74 (47.133%) show MS phenotype, 48 (30.57%) show inducible clindamycin resistance, and 35 (22.29%) show constitutive resistance. All 48 S. aureus isolates which showed inducible clindamycin resistances (D-test positive) were further subjected to antimicrobial susceptibility testing.In the present study, 100% sensitivity was observed by vancomycin, linezolid and tigecycline, followed by tetracycline, 89.58% and gentamicin, 83.33% while 100% resistivity were observed by levofloxacin. Conclusion: We can conclude that there is high percentage of inducible clindamycin resistance among Staphylococcus isolates. If D-test would not have been performed, many inducible clindamycin-resistant S. aureus could have been easily misidentified as clindamycin susceptible, leading to therapeutic failure. Thus, simple and reliable D-test can be incorporated into routine in clinical microbiology laboratory
Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice
Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression
Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer
MMP10, which is upregulated in 86% of primary tongue tumors with lymph node metastases, is negatively regulated by miR-944 and promotes nodal metastasis in an orthotopic tongue cancer mouse model through the AXL signaling pathway
Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats
The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96Â h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24Â h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction
Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function
Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of binge and crash methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of binge and crash methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to binge and crash methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy
Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes
Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic
Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality