Exploring various novel diagnostic and therapeutic approaches in treating diabetic retinopathy.

Diabetic retinopathy is regarded as a common manifestation of diabetes mellitus, being a prominent cause of visual impairment and blindness. This microvascular complication is marked by the appearance of microaneurysms, elevated vascular permeability, capillary blockage, and proliferation of neovasculature. The etiology behind retinopathy is ambiguous and the efficacy of current treatment strategies is minimal. Early diagnosis of this complication using a biomarker with high sensitivity and specificity is very essential for providing better therapeutic strategies. The current available therapeutic options are limited with various adverse effects. Laser treatment is not beneficial in all the situations, economic constraints being the major challenge. Surgical interventions are employed when pharmacotherapy and laser treatment fail. New pharmacological treatments are becoming a necessity for treating the condition. This review highlights the use of various diagnostic tools, emerging biomarkers for early detection of diabetic retinopathy, pathological mechanisms associated with the disease, current therapeutic approaches used and future strategies for more enhanced treatment options and more potent pharmacological actions.

Elevated serum PAR-1 levels as an emerging biomarker of inflammation to predict the dengue infection severity.

The present study was designed to check the serum levels of protease-activated receptor (PAR-1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR-1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto-analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and PAR-1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF-α, IL-6, and IL-17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR-1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR-1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR-1 levels can be used as a diagnostic marker for assessing dengue severity.

Serum protease-activated receptor (PAR-1) levels as a potential biomarker for diagnosis of inflammation in type 2 diabetic patients.

BACKGROUND: Inflammation is a prominent clinical manifestation in type 2 diabetes mellitus (T2DM) patients, often associated with insulin resistance, metabolic dysregulation, and other complications. AIM OF THE STUDY: The present study has been designed to check the serum levels of PAR-1 and correlate with various clinical manifestations and inflammatory cytokines levels in type 2 diabetic subjects. MATERIAL AND METHODS: The study population was divided into two groups, healthy volunteers (n = 15): normal glycated hemoglobin (HbA1c) (4.26 ± 0.55) and type 2 diabetic subjects (n = 30): HbA1c levels (7.80 ± 2.41). The serum levels of PAR-1 (ELISA method) were studied in both groups and correlated with demographic parameters age, weight, body mass index (BMI), and conventional inflammation biomarkers like C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumour necrosis factor-alpha (TNF-α). RESULTS: The demographic variables including the body weight (77.38 ± 10.00 vs. controls 55.26 ± 6.99), BMI (29.39 ± 3.61 vs. controls 25.25 ± 4.01), glycemic index HbA1c (7.80 ± 2.41 vs. controls 4.26 ± 0.55) were found to be statistically increased in T2DM subjects than the healthy control group. The levels of various inflammatory biomarkers and PAR-1 were significantly elevated in T2DM groups in comparison to healthy volunteers. The univariate and multivariate regression analysis revealed that elevated PAR-1 levels positively correlated with increased body weight, BMI, HbA1c, and inflammatory cytokines. CONCLUSION: Our findings indicate that the elevated serum PAR-1 levels serve as an independent predictor of inflammation in T2DM subjects and might have prognostic value for determining T2DM progression.

Pathological role of the calcium-sensing receptor in sepsis-induced hypotensive shock: Therapeutic possibilities and unanswered questions.

Sepsis is a life-threatening disease involving multiorgan dysfunction, prompted by an unregulated host response to infection. Shock is a complication of sepsis in which the circulatory and cellular metabolism anomalies are significant enough to raise the risk of death. Calcium dyshomeostasis occurs during sepsis condition due to imbalance between calcium uptake and excessive release induced by inflammatory cytokines. This calcium imbalance can cause activation of calcium-sensing receptors (CaSRs) located on the surface of T cells and thereby promote release of reactive oxygen species (ROS). The elevated ROS and inflammatory cytokines during sepsis condition have been reported to directly damage the endothelial cells, disrupt the barrier functions that might result in leakage of fluids, and inflammatory cells in tissues Moreover, several evidence have revealed that the calcium mediated activation of CaSR could produce systemic vasodilatory response by stimulating the nitric oxide production and opening of calcium-activated potassium channels, while infusion of its antagonist elevated the blood pressure. These evidence indicate that activation of CaSR during sepsis conditions results in release of ROS and inflammatory cytokines, which could produce an endothelial barrier damage, cardiomyocyte apoptosis. These pathological events could produce loss of fluid in tissues and cardiac dysfunction. Further the direct vasodilatory effects of CaSR activation might add to the shock-like condition. Thus, we hereby propose that inhibition of CaSR could suppress the release of ROS, inflammatory mediators, and thereby prevent the endothelial damage, cardiac dysfunction, and maintain systemic vascular tone.

Emergence of nutriments as a nascent complementary therapy against antimicrobial resistance.

With these growing and evolving years, antimicrobial resistance has become a great subject of interest. The idea of using natural productive ways can be an effective measure against antimicrobial resistance. The growing prevalence of antimicrobial resistance indicates that advanced natural approaches are a topic of concern for fighting the resistance. Many natural products including essential oils, flavonoids, alkaloids and botanicals have been demonstrated as effective bactericidal agents. In this review, we will discuss in detail about the relevance of such natural products to tackle the problem of antimicrobial resistance, antibiotic adjuvants that aim towards non-essential bacterial targets to reduce the prevalence of resistant bacterial infections, latest bioinformatics approach towards antibacterial drug discovery along with an understanding of biogenic nanoparticles in antimicrobial activity.

Histopathological and molecular links of COVID-19 with novel clinical manifestations for the management of coronavirus-like complications.

Coronavirus disease 2019 (COVID-19) causes transmissible viral illness of the respiratory tract prompted by the SARS-CoV-2 virus. COVID-19 is one of the worst global pandemics affecting a large population worldwide and causing catastrophic loss of life. Patients having pre-existing chronic disorders are more susceptible to contracting this viral infection. This pandemic virus is known to cause notable respiratory pathology. Besides, it can also cause extra-pulmonary manifestations. Multiple extra-pulmonary tissues express the SARS-CoV-2 entry receptor, hence causing direct viral tissue damage. This insightful review gives a brief description of the impact of coronavirus on the pulmonary system, extra-pulmonary systems, histopathology, multiorgan consequences, the possible mechanisms associated with the disease, and various potential therapeutic approaches to tackle the manifestations.

Natural Products as Sources of Multitarget Compounds: Advances in the Development of Ferulic Acid as Multitarget Therapeutic.

Nature has provided therapeutic substances for millennia, with many valuable medications derived from plant sources. Multitarget drugs become essential in the management of various disorders, including hepatic disorders, neurological disorders, diabetes, and carcinomas. Ferulic acid is a significant potential therapeutic agent, which is easily available at low cost, possesses a low toxicity profile, and has minimum side effects. Ferulic acid exhibits various therapeutic actions by modulation of various signal transduction pathways such as Nrf2, p38, and mTOR. The actions exhibited by ferulic acid include anti-apoptosis, antioxidant, anti-inflammatory, antidiabetic, anticarcinogenic, hepatoprotection, cardioprotection, activation of transcriptional factors, expression of genes, regulation of enzyme activity, and neuroprotection, which further help in treating various pathophysiological conditions such as cancer, skin diseases, brain disorders, diabetes, Parkinson's disease, Alzheimer's disease, hypoxia, hepatic disorders, H1N1 flu, and viral infections. The current review focuses on the significance of natural products as sources of multitarget compounds, and a primary focus has been made on ferulic acid and its mechanism, role, and protective action in various ailments.

Potential of flavonoids as anti-Alzheimer's agents: bench to bedside.

Developing therapies for neurodegenerative diseases are challenging because of the presence of blood-brain barrier and Alzheimer being one of the commonest and uprising neurodegenerative disorders possess the need for developing novel therapies. Alzheimer's is attributed to be the sixth leading cause of death in the USA and the number of cases is estimated to be increased from 58 million in 2021 to 88 million by 2050. Natural drugs have benefits of being cost-effective, widely available, fewer side effects, and immuno-booster can be useful in managing Alzheimer. Flavonoids can slow the neuronal degeneration as they have shown activity in central nervous system and are able to cross the blood-brain barrier. These can be easily extracted from fruits, vegetable, and plants. In Alzheimer disease, flavonoids scavenges the reactive oxygen species and reduces the production of amyloid beta protein. Agents from sub-classes of flavonoids such as flavanones, flavanols, flavones, flavonols, anthocyanins, and isoflavones having pharmacological action in treating Alzheimer disease are discussed in this review.

Implication of Covid-19 on Neurological Complications with Specific Emphasis on Alzheimer's and Parkinson's Disease.

It is noticeable how the novel coronavirus has spread from the Wuhan region of China to the whole world, devastating the lives of people worldwide. All the data related to the precautionary measures, diagnosis, treatment, and even the epidemiological data are being made freely accessible and reachable in a very little time as well as being rapidly published to save humankind from this pandemic. There might be neurological complications of COVID-19 and patients suffering from neurodegenerative conditions like Alzheimer's disease and Parkinson's disease might have repercussions as a result of the pandemic. In this review article, we have discussed the effect of SARS-CoV-2 viral infection on the people affected with neurodegenerative disorders such as Parkinson's and Alzheimer's. It primarily emphasizes two issues, i.e., vulnerability to infection and modifications of course of the disease concerning the clinical neurological manifestations, the advancement of the disease and novel approaches to support health care professionals in disease management, the susceptibility to these diseases, and impact on the severity of disease and management.

Pertinence of nutriments for a stalwart body.

Nutrition plays a significant role in the prevention and treatment of common diseases. Some superb dietary choices such as functional foods and nutriments can surely help fight against certain diseases and provide various advantages to an individual's health. Plants have been regarded as a primary source of highly effective conventional drugs leading to the development of potential novel agents, which may boost the treatment. Growing demand for functional foods acts as an aid for the producers to expand in agriculture and pave the way for innovation and research by the nutraceutical industry. The given review highlights how various functional foods such as tomatoes, chocolates, garlic and flaxseed are currently being defined, their sources, benefit in treating various ailments and the challenges with their use.

Relevance of Aromatase Inhibitors in Breast Cancer Treatment.

Efficacious treatment for breast cancer is still a challenge despite the presence of various treatment options. Aromatase enzyme present in the breast tissue is responsible for estrogen formation from androgens. Aromatase inhibitors manifest remarkably ameliorated therapeutic efficacy as compared to the current therapeutic options available and exhibit a better safety profile as compared to the other drugs. Clinical resistance to aromatase inhibitors is perceived as a lack of growth inhibition by aromatase inhibitors treatment and cancer therapy becomes ineffective in causing a decrease in the size of the tumor. Naturally extracted aromatase inhibitors have a huge positive impact on vitality and living standards. This review article highlights the particulars of the currently approved steroidal and non-steroidal aromatase inhibitors for clinical use, adverse effects associated with their use and approach to tackling the problem, various strategies to overcome aromatase inhibitors resistance, information on the synthesis of various peculiar aromatase inhibitors which can prove as highly efficient and potent drugs in the near future and the drugs of natural and semi-synthetic origin which can demonstrate to be more efficient, potent and less-toxic than conventional therapy.

Prospecting the Intricate Role of Novel and Potent Biomarkers in Schizophrenia.

Schizophrenia is a serious psychiatric disorder leading to cognitive impairment and has higher rates of morbidity and mortality. There is a need to understand the mechanisms underlying the onset and progression of the disease as the clinical presentation may vary in patients and inadequate knowledge of neurochemical alterations can lead to decreased efficacy in treatment which makes it necessary to identify new potent biomarkers. Identification of biomarkers in schizophrenia offers significant benefits to the well-being of patients, including better prognosis, diagnosis, detection, screening, enhancement in treatment efficacy, prevention of relapse, and better clinical results. Incorporation of advanced technological techniques is necessary to provide an approach for the diagnosis and treatment of psychiatric disorders and to permit specific therapeutic interventions. This review highlights the particulars about the current use and application of various biomarkers such as proteomics, miRNAs, language techniques, antibodies, blood biomarkers, gut microbiota, such as analysis, neuroimaging techniques, and inflammatory biomarkers in effective prognosis, detection, and treatment of schizophrenia and which would contribute as an additional tool for a psychiatrist in cases where an appropriate diagnosis is lacking clarity.

Focus on the Multimodal Role of Biomarkers in Breast Cancer.

Breast cancer is the most common type of malignancy affecting women worldwide and also stands being the most diagnosed one. Mammography is considered as the golden standard for diagnosis but there are high chances that it can give false- negative as well as false-positive test results. Finding cost-effective, readily available diagnosis along with increased sensitivity as well as specificity is the need right now to decrease the mortality as well as the morbidity rate. The application of biomarkers to clinical use has paved the way for a better prognosis, diagnosis, detection, screening and better clinical results. The efficacy of the treatment is enhanced. Biomarkers are known to cause an advancement in breast cancer study and are expected to improve the quality of life in patients. Not only tissue biomarkers but serum and circulating biomarkers are also of significance in patients. This review highlights the particulars about the current use and application of biomarkers in an effective prognosis, detection, treatment of the breast cancer and also the ones which are currently being studied under clinical trials and have the potential to be advantageous and more specific in the future.

Flavonoids as Potential Therapeutic Agents for the Management of Diabetic Neuropathy.

Flavonoids are secondary metabolites that are widely distributed in plants. These phenolic compounds are classified into various subgroups based on their structures: flavones, flavonols, isoflavones, flavanones, and anthocyanins. They are known to perform various pharmacological actions like antioxidant, anti-inflammatory, anticancer, antimicrobial, antidiabetic and antiallergic, etc. Diabetes is a chronic progressive metabolic disorder that affects several biochemical pathways and leads to secondary complications such as neuropathy, retinopathy, nephropathy, and cardiomyopathy. Among them, the management of diabetic neuropathy is one of the major challenges for physicians as well as the pharmaceutical industries. Naturally occurring flavonoids are extensively used for the treatment of diabetes and its related complications due to their antioxidant properties. Moreover, flavonoids inhibit various pathways that are involved in the progression of diabetic neuropathy like the reduction of oxidative stress, decrease in glycogenolysis, increase glucose utilization, decrease in the formation of advanced glycation end products, and inhibition of the α-glucosidase enzyme. This review entails current updates on the therapeutic perspectives of flavonoids in the treatment of neuropathic pain. This manuscript explains the pathological aspects of neuropathic pain, the chemistry of flavonoids, and their application in amelioration of neuropathic pain through preclinical studies either alone or in combination with other therapeutic agents.

Impact of ganga canal on thermal comfort in the city of Roorkee, India.

The rise in urban air temperature has forced the researchers to look for nature-based solutions to resolve the problem sustainably. Urban waterbody plays a multidimensional role in the well-being of the city by catering to its economical, ecological, and socio-cultural needs. It can offer a potential solution for urban heat attenuation, but its effect on outdoor thermal comfort is contentious in humid subtropical climate. This study investigates the thermal impact of waterbody on its surroundings in humid subtropical climate by adopting a human centric approach. Waterbody impact on ambient air temperature, PET, and UTCI are evaluated and compared for a better understanding of its thermal impact on nearby surroundings. This study employs a CFD-based simulation model Envi-met for microclimate analysis. The results show that a dynamic waterbody lowers the ambient air temperature during daytime in summer of its nearby surroundings in humid subtropical climate. Maximum cooling is observed in open mid-rise LCZ where the cooling impact range is 140 m with the amplitude of 2.59 °C and compact low-rise LCZ exhibits minimum cooling of the identified LCZs with the cooling impact ending 24 m from waterbody edge with amplitude being 0.131 °C in the study area. Air temperature, UTCI, and PET do reflect the same trend when moving away from the waterbody in large low-rise LCZ, but it decreases drastically in open mid-rise LCZ and is non-existent in compact low-rise. This result provides an insight on the impact of waterbody on thermal comfort in its surroundings in humid subtropical climate, thus assisting urban planners and designers in making context-specific holistic decision.

Complements Spurned: Our Experience with Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder resulting from a dysregulated activation of the alternative pathway of the complement system. It results in significant morbidity and mortality if not diagnosed and treated promptly. It lends itself to myriad renal and extrarenal manifestations, all potentially disabling. Eculizumab, a monoclonal antibody to complement C5 is now the widely accepted norm for treatment. However, in resource-limited settings, plasma exchange if instituted early may be as beneficial. We report a case of aHUS treated with extended plasma exchange with excellent results. Critical care monitoring is essential for the management of the disease in view of a tendency to develop multiple complications. Long-term immunosuppression may be successful in maintaining remission.

High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asian Indian Rheumatoid Arthritis Patients-A Preliminary Study.

BACKGROUND: It is unclear whether erythrocyte methotrexate polyglutamate levels (MTX-glun) are associated with response or adverse effects to methotrexate in rheumatoid arthritis. This preliminary study evaluated their utility in Asian Indian patients over 24 weeks. METHODS: Rheumatoid arthritis patients were started on oral methotrexate at a dose of 15 mg/wk, which was escalated to 25 mg by 12 weeks and continued till 24 weeks. Erythrocyte (RBC) MTX-glu1 to MTX-glu5 levels (nmol/L RBC) were determined at 4, 8, 16, and 24 weeks by using reverse-phase high-performance liquid chromatography. Area under the concentration curve (AUC) of MTX-glu1-5, MTX-glu3-5, and MTX-glu3 levels was compared between groups with regards to response and adverse effects. RESULTS: This study included 117 patients with mean (SD) age of 42.7 (±11.9) years and disease duration of 2.0 (1.7) years. Mean (SD) RBC MTX-glu1-5 levels at 4, 8, 16, and 24 weeks were 93 (±29), 129 (±46), 143 (±49), and 159 (±65) nmol/L RBC; the highest individual polyglutamate was MTX-glu3 (40%). There was significant correlation between MTX-glu1-5 (r = 0.38, P < 0.001) and MTX-glu3 (r = 0.49, P < 0.001) with methotrexate dose. There was no significant difference of AUC MTX-glun between responders and nonresponders. However, AUC MTX-glu3 was significantly (P = 0.03) higher in patients with adverse effects. On logistic regression, AUC of MTX-glu3 [odds ratio = 1.004 (95% confidence interval 1.002-1.007)] and methotrexate dose at 24 weeks were independent predictors of adverse effects. CONCLUSIONS: In this preliminary study, higher levels of RBC MTX-glu3 were found to be the independent predictors for adverse effects in rheumatoid arthritis patients.

Clinically HIV but negative serology: Think of idiopathic CD4(+) lymphocytopenia.

idiopathic CD4(+) lymphocytopenia (ICL) is a rare disorder characterized by the presence of depleted CD4 cell line without the presence of HIV infection. Slight male preponderance is noticed and is usually seen in the middle age group. Opportunistic infections are the reason for their discovery and here we describe a case where a man was diagnosed as having Pneumocystis jiroveci pneumonia and oral candidiasis.

Comparison of two different folic acid doses with methotrexate--a randomized controlled trial (FOLVARI Study).

INTRODUCTION: There is reasonable evidence that folic acid 5-10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity. METHODS: This was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18-75 years of age, not be on MTX and have active disease as defined by 'Modified Disease Activity Score using three variables' (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed. RESULTS: Among 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4% (95% confidence interval -27.4 to 12.7%) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7%, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7%, p = 1.0) or cytopenias (4.3, 4.3%, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3%, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1 ± 1.0, -1.3 ± 1.0, p = 0.2) and 'European League Against Rheumatism' good or moderate response occurred in 56.9 and 67.4% (p = 0.3). CONCLUSIONS: Even with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week). TRIAL REGISTRATION: Clinicaltrials.gov NCT01583959 Registered 15 March 2012.