During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.
Aging ; Arthritis, Rheumatoid ; Blood Proteins ; Cardiomyopathies ; Cataract ; Cell Membrane ; Collagen ; Diabetes Complications* ; Diabetes Mellitus ; Fibrinogen ; Free Radicals ; Gene Expression ; Globulins ; Glucose ; Glycosylation End Products, Advanced* ; Inflammation ; Molecular Conformation ; Nucleic Acids ; Osteoporosis ; Oxidative Stress

Objective: To investigate the molecular epidemiology and antimicrobial resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) among healthcare workers and patients. Methods: MRSA isolates were recovered from nasal swabs collected at a tertiary care hospital of Nepal and confirmed on the basis of Gram staining, conventional biochemical tests, and PCR amplification of mecA gene. PCRs were also used for detection of the different resistance genes and staphylococcal cassette chromosome (SCC) mec types. Antibiotic susceptibility patterns of isolates were assessed by disc diffusion method and minimum inhibitory concentrations were determined by E-test. Results: A total of 29 MRSA were isolated from 536 nasal swabs (5.4%) of health care workers and patients at a tertiary care hospital in Nepal. All isolates were susceptible to amikacin, gentamicin, vancomycin (minimal inhibitory concentrations<2μg/mL), tigecy-cline, tetracycline, nitrofurantoin, rifampicin, quinupristin-dalfopristin, and linezolid. Among the 29 MRSA isolates, resistance to erythromycin (72%), ciprofloxacin (75%), co-trimoxazole (62%), clindamycin (10%), and chloramphenicol (10%) was found, and fifteen isolates (51%) exhibited high-level mupirocin resistance (minimal inhibitory concentrations>1024μg/mL). Fourteen isolates were found harboring the mupA gene and one isolate was found carrying the novel mupB gene. High prevalence (68%) of SCCmec I type was found, followed by SCCmec V (13%) and SCCmec III (3%) among all the MRSA isolates. Conclusions: We found the emergence of SCCmec type Ⅰ with high-level mupirocin resistance among MRSA in Nepal. Data also suggest that MRSA SCCmec type V strain has spread from the community to the hospital.

Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, Wnt/β-catenin and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.
Adenosine Triphosphatases ; Chronic Pain ; Cyclic Nucleotide-Gated Cation Channels ; Drug Discovery ; Endoplasmic Reticulum Stress ; Ephrins ; Histone Deacetylases ; Humans ; Models, Animal ; Nervous System ; Neuralgia* ; Oxidoreductases ; Receptors, Eph Family ; Receptors, sigma

Prolyl 4 hydroxylases (P4H) are iron- and 2-oxoglutamate-dependent dioxygenase enzymes and hypoxia-inducible transcription factor (HIF)-P4Hs play a critical role in the regulating oxygen homeostasis in the local tissues as well in the systemic circulation. Over a period of time, a number of prolyl hydroxylase inhibitors and activators have been developed. By employing the pharmacological tools and transgenic knock out animals, the critical role of these enzymes has been established in the pathophysiology of number of diseases including myocardial infarction, congestive heart failure, stroke, neurodegeneration, inflammatory disease, respiratory diseases, retinopathy and others. The present review discusses the different aspects of these enzymes including their pathophysiological role in disease development.
Animals ; Heart Failure ; Homeostasis ; Inflammation ; Ischemia ; Mixed Function Oxygenases ; Myocardial Infarction ; Oxygen ; Procollagen-Proline Dioxygenase ; Stroke ; Transcription Factors

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine-mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of Na⁺ and K⁺, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioning-induced cardioprotection along with the possible mechanisms.
Adenosine ; Aging* ; Animals ; Catalase ; Heart ; Metabolism ; Myocardium ; Negotiating ; Oxidative Stress ; Phosphorylation ; Phosphotransferases ; PPAR gamma ; Protein Kinases ; Rats ; Receptors, Purinergic P1 ; Reperfusion Injury

Objective To investigate the molecular epidemiology and antimicrobial resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) among healthcare workers and patients. Methods MRSA isolates were recovered from nasal swabs collected at a tertiary care hospital of Nepal and confirmed on the basis of Gram staining, conventional biochemical tests, and PCR amplification of mecA gene. PCRs were also used for detection of the different resistance genes and staphylococcal cassette chromosome (SCC) mec types. Antibiotic susceptibility patterns of isolates were assessed by disc diffusion method and minimum inhibitory concentrations were determined by E-test. Results A total of 29 MRSA were isolated from 536 nasal swabs (5.4%) of health care workers and patients at a tertiary care hospital in Nepal. All isolates were susceptible to amikacin, gentamicin, vancomycin (minimal inhibitory concentrations < 2 μg/mL), tigecycline, tetracycline, nitrofurantoin, rifampicin, quinupristin-dalfopristin, and linezolid. Among the 29 MRSA isolates, resistance to erythromycin (72%), ciprofloxacin (75%), co-trimoxazole (62%), clindamycin (10%), and chloramphenicol (10%) was found, and fifteen isolates (51%) exhibited high-level mupirocin resistance (minimal inhibitory concentrations > 1 024 μg/mL). Fourteen isolates were found harboring the mupA gene and one isolate was found carrying the novel mupB gene. High prevalence (68%) of SCCmec I type was found, followed by SCCmec V (13%) and SCCmec III (3%) among all the MRSA isolates. Conclusions We found the emergence of SCCmec type I with high-level mupirocin resistance among MRSA in Nepal. Data also suggest that MRSA SCCmec type V strain has spread from the community to the hospital.