Interplay of mitochondria-associated membrane proteins and autophagy: Implications in neurodegeneration.

Since the discovery of membrane contact sites between ER and mitochondria called mitochondria-associated membranes (MAMs), several pieces of evidence identified their role in the regulation of different cellular processes such as Ca2+ signalling, mitochondrial transport, and dynamics, ER stress, inflammation, glucose homeostasis, and autophagy. The integrity of these membranes was found to be essential for the maintenance of these cellular functions. Accumulating pieces of evidence suggest that MAMs serve as a platform for autophagosome formation. However, the alteration within MAMs structure is associated with the progression of neurodegenerative diseases. Dysregulated autophagy is a hallmark of neurodegeneration. Here, in this review, we highlight the present knowledge on MAMs, their structural composition, and their roles in different cellular functions. We also discuss the association of MAMs proteins with impaired autophagy and their involvement in the progression of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Riverine connectivity influences the phytoplankton ecology in the open floodplain wetland of the lower river Ganga.

The river Ganga has several floodplain wetlands that support its ecology and ecosystem. Phytoplankton is an important component of the aquatic ecosystem, which plays an important role as a bioindicator for the assessment of aquatic health. The present study was conducted between 2018 and 2019 to understand the seasonal variation in the phytoplankton diversity of the Charaganga wetland and, parallelly, in the river Ganga in Nabadweep, India. The study explains how riverine connectivity affects the structure of the algal community in the wetland ecosystem. In the study, it has been observed that in the wetland, maximum mean phytoplankton density was noticed during pre-monsoon, i.e., 4079 unit l-1 followed by post-monsoon 3812 unit l-1 and monsoon 550 unit l-1, respectively. In the river system, the phytoplankton density varied from 78 unit l-1 to 653 unit l-1 seasonally, i.e., highest during monsoon and lowest during pre-monsoon. In both the ecosystems, i.e., wetland and river, the supreme influential group was Cyanophyceae followed by diatoms. One-way ANOVA showed a significant variation (p > 0.05) of three algal groups of phytoplankton (Bacillariophyceae, Coscinodiscophyceae, Chlorophyceae) in the river, while in the wetland, no significant variation (p > 0.05) was found among the other algal groups. The observed higher Shannon and Margalef's species richness value in the wetland was observed than in the river defines the significance and importance of the wetland ecosystem, which may support the growth and conservation of various aquatic organisms as well. The study highlighted that the influencing abiotic factors like water temperature, dissolved oxygen, pH, and nutrients have affected the phytoplankton community in both the water bodies, i.e., wetland and river. We concluded that river connectivity is required to restore the biotic flora of the wetland ecosystem.

Association of Higher Intake of Plant-Based Foods and Protein With Slower Kidney Function Decline in Women With HIV.

BACKGROUND: We investigated whether there exists an association between dietary acid load and kidney function decline in women living with HIV (WLWH) receiving antiretroviral therapy (ART). SETTING: One thousand six hundred eight WLWH receiving ART in the WIHS cohort with available diet data and a baseline estimated glomerular filtration rate (eGFR) ≥15 mL/minute/1.73 m2. METHODS: A brief dietary instrument conducted from 2013 to 2016 under the Food Insecurity Sub-Study was used for assessing fruits and vegetables (FV) and protein intake. A mixed-effects model with random intercept and slope was used to estimate subjects' annual decline rate in eGFR and the association between FV intake and eGFR decline, adjusting for sociodemographics, serum albumin, comorbidities, time on ART, ART drugs, HIV markers, and baseline eGFR. We evaluated whether markers of inflammation mediated the effect of FV intake on decline in eGFR, using causal mediation analysis. RESULTS: We found a dose-response relationship for the association of FV intake and eGFR decline, with lesser annual decline in eGFR in the middle and highest tertiles of FV intake. An increase of 5 servings of FV intake per day was associated with a lower annual eGFR decline (-1.18 [-1.43, -0.94]). On average, 39% of the association between higher FV intake and slower eGFR decline was explained by decreased levels of inflammation. CONCLUSIONS: Plant-rich diet was associated with slower decline in kidney function. Inflammation is a potential path through which diet may affect kidney function. The findings support an emerging body of literature on the potential benefits of plant-rich diets for prevention of chronic kidney disease.

Ameliorative effect of natural floating island as fish aggregating devices on heavy metals distribution in a freshwater wetland.

Growing human population and climate change are leading reasons for water quality deterioration globally; and ecologically important waterbodies including freshwater wetlands are in a vulnerable state due to increasing concentrations of pollutants like heavy metals. Given the declining health of these valuable resources, the present study was conducted to evaluate the effect of natural floating island in the form of fish aggregating devices (FADs) made of native weed mass on the distribution of heavy metals in the abiotic and bio compartments of a freshwater wetland. Lower concentrations of surface water heavy metals were observed inside the FADs with a reduction of 73.91%, 65.22% and 40.57-49.16% for Cd, Pb and other metals (viz. Co, Cr, Cu, Ni and Zn), respectively as compared to outside FAD. These led to 14.72-55.39% reduction in the heavy metal pollution indices inside the FAD surface water. The fish species inside the FADs were also found less contaminated (24.07-25.07% reduction) with lower health risk indices. The study signifies the valuable contribution of natural floating island as FADs in ameliorating the effect of heavy metals pollution emphasizing the tremendous role of the natural floating islands in sustainable maintenance of freshwater wetlands for better human health and livelihood.

DNA Methylation-Mediated Mfn2 Gene Regulation in the Brain: A Role in Brain Trauma-Induced Mitochondrial Dysfunction and Memory Deficits.

Repeated mild traumatic brain injuries (rMTBI) affect mitochondrial homeostasis in the brain. However, mechanisms of long-lasting neurobehavioral effects of rMTBI are largely unknown. Mitofusin 2 (Mfn2) is a critical component of tethering complexes in mitochondria-associated membranes (MAMs) and thereby plays a pivotal role in mitochondrial functions. Herein, we investigated the implications of DNA methylation in the Mfn2 gene regulation, and its consequences on mitochondrial dysfunction in the hippocampus after rMTBI. rMTBI dramatically reduced the mitochondrial mass, which was concomitant with decrease in Mfn2 mRNA and protein levels. DNA hypermethylation at the Mfn2 gene promoter was observed post 30 days of rMTBI. The treatment of 5-Azacytidine, a pan DNA methyltransferase inhibitor, normalized DNA methylation levels at Mfn2 promoter, which further resulted into restoration of Mfn2 function. The normalization of Mfn2 function was well correlated with recovery in memory deficits in rMTBI-exposed rats. Since, glutamate excitotoxicity serves as a primary insult after TBI, we employed in vitro model of glutamate excitotoxicity in human neuronal cell line SH-SY5Y to investigate the causal epigenetic mechanisms of Mfn2 gene regulation. The glutamate excitotoxicity reduced Mfn2 levels via DNA hypermethylation at Mfn2 promoter. Loss of Mfn2 caused significant surge in cellular and mitochondrial ROS levels with lowered mitochondrial membrane potential in cultured SH-SY5Y cells. Like rMTBI, these consequences of glutamate excitotoxicity were also prevented by 5-AzaC pre-treatment. Therefore, DNA methylation serves as a vital epigenetic mechanism involved in Mfn2 expression in the brain; and this Mfn2 gene regulation may play a pivotal role in rMTBI-induced persistent cognitive deficits. Closed head weight drop injury method was employed to induce repeated mild traumatic brain (rMTBI) in jury in adult, male Wistar rats. rMTBI causes hyper DNA methylation at the Mfn2 promoter and lowers the Mfn2 expression triggering mitochondrial dysfunction. However, the treatment of 5-azacytidine normalizes DNA methylation at the Mfn2 promoter and restores mitochondrial function.

Mechanistic Insight into the role of Vitamin D and Zinc in Modulating Immunity Against COVID-19: A View from an Immunological Standpoint.

The pathophysiology of coronavirus disease-19 (COVID-19) is characterized by worsened inflammation because of weakened immunity, causing the infiltration of immune cells, followed by necrosis. Consequently, these pathophysiological changes may lead to a life-threatening decline in perfusion due to hyperplasia of the lungs, instigating severe pneumonia, and causing fatalities. Additionally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause mortality due to viral septic shock, resulting from unrestrained and backfiring immune reactions to the pathogen. Sepsis can cause premature organ failure in COVID-19 patients, as well. Notably, vitamin D and its derivatives and minerals, such as zinc and magnesium, have been reported to improve the immune system against respiratory illnesses. This comprehensive review aims to provide updated mechanistic details of vitamin D and zinc as immunomodulators. Additionally, this review also focuses on their role in respiratory illnesses, while specifically delineating the plausibility of employing them as a preventive and therapeutic agent against current and future pandemics from an immunological perspective. Furthermore, this comprehensive review will attract the attention of health professionals, nutritionists, pharmaceuticals, and scientific communities, as it encourages the use of such micronutrients for therapeutic purposes, as well as promoting their health benefits for a healthy lifestyle and wellbeing.

Association of Diet-dependent Systemic Acid Load, Renal Function, and Serum Albumin Concentration.

OBJECTIVE: Inflammation may be present with chronic kidney disease CKD and diet composition high in protein intake and fats may affect inflammation thereby impacting kidney health. We investigated whether acid load estimated from urine measures is associated with kidney function decline and whether the effect of acid load on an inflammatory marker, serum albumin, is a pathway to this association. METHODS: We studied 188 postmenopausal women in a randomized clinical trial of potassium bicarbonate treatment for up to 36 months. Twenty-four-hour urine and arterialized blood collections were done at baseline and at subsequent follow-up visits at 3 months interval. Acid load was estimated from potential renal acid load calculated using urinary measures of chloride, phosphate, sodium, potassium, calcium, and magnesium (UPRAL). Mixed effects model with random-intercept and slope was used to estimate subjects' annual decline rate in creatinine clearance (CrCl), and the association between (i) UPRAL and serum albumin and (ii) serum albumin and CrCl, adjusting for age, body mass index, systolic BP, and glucose. A Cox proportional regression model was used to study the relative hazard (RH) for rapid progression of kidney function decline (defined as loss of ≥5 mL/min CrCl/yr based on the last CrCl in the rolling window) with UPRAL, adjusting for the potential covariates and baseline CrCl. RESULTS: A 25 mEq/day increase in UPRAL was inversely associated with serum albumin (Adjusted ß[95% CI]: -0.02[-0.09;-0.001). During a mean follow-up of 28 months, 19 women (10%) had a rapid decline in kidney function. For each 25 mEq/day increase in UPRAL, the risk of a rapid decline in CrCl increased by 17% (95% CI: 1.06-1.28). On adjustment for potential confounders, the risk attenuated to 5% (1.02-1.14). Mediation analysis indicated that of the total effect of the association between UPRAL and CrCl, the proportion mediated by serum albumin increased to 0.346 (i.e. 34.6%). CONCLUSION: Higher UPRAL was associated with lower serum albumin as well as greater kidney function decline in postmenopausal women. Our findings suggest inflammatory response may exert a modulatory effect on the association of UPRAL and kidney function and might be a potential pathway explaining the effects of systemic acid load on progression of kidney failure.

Mitofusin-2: Functional switch between mitochondrial function and neurodegeneration.

Mitochondria are highly dynamic organelles known to play role in the regulation of several cellular biological processes. However, their dynamics such as number, shape, and biological functions are regulated by mitochondrial fusion and fission process. The balance between the fusion and fission process is most important for the maintenance of mitochondrial structure as well as cellular functions. The alterations within mitochondrial dynamic processes were found to be associated with the progression of neurodegenerative diseases. In recent years, mitofusin-2 (Mfn2), a GTPase has emerged as a multifunctional protein which not only is found to regulate the mitochondrial fusion-fission process but also known to regulate several cellular functions such as mitochondrial metabolism, cellular biogenesis, signalling, and apoptosis via maintaining the ER-mitochondria contact sites. In this review, we summarize the current knowledge of the structural and functional properties of the Mfn2, its transcriptional regulation and their roles in several cellular functions with a focus on current advances in the pathogenesis of neurodegenerative diseases.

Proinflammatory Diets and Risk of ESKD in US Adults with CKD.

Background: Inflammation may affect long-term kidney function. Diet may play a role in chronic inflammation. We hypothesized that proinflammatory diets increase the risk of progression to kidney failure with replacement therapy (KFRT), and systemic inflammation is a mediator of the effect of diet on progression to KFRT. Methods: In the 1988-1994 National Health and Nutrition Examination Survey linked to the national ESKD registry, in adults with CKD (eGFR 15-59 ml/min per 1.73 m2), aged ≥20 years, we calculated the Adapted Dietary Inflammatory Index (ADII) at baseline from a 24-hour dietary recall and an inflammation score (IS) using average of z scores of four inflammation biomarkers. We explored the association of the ADII and IS with risk of incident KFRT using Cox proportional model, adjusting for sociodemographics, physical activity, Framingham risk score, eGFR, and urinary ACR. We evaluated whether, and to what extent, IS mediated the effect of the ADII on KFRT incidence, using causal mediation analysis. Results: Of 1084 adults with CKD, 109 (10%) developed KFRT. The ADII was associated with increased risk of KFRT (relative hazard [RH] per SD increase (2.56): 1.4 [1.04-1.78]). IS was also associated with KFRT (RH: 1.12; 95% CI, 1.02 to 1.25). Approximately 36% of the association between the ADII and KFRT was explained by IS. Conclusions: Among adults with CKD, a proinflammatory diet was associated with risk of KFRT, and that association was partially explained by an increase in inflammatory markers. Dietary interventions that reduce inflammation may offer an approach for preventing KFRT.

Dietary Contributions to Metabolic Acidosis.

Eating a net acid-producing diet can produce an "acid stress" of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.