RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.

BACKGROUND: Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. METHODS: Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. RESULTS: Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. CONCLUSION: Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.

Diel variation of plankton in the highly impacted freshwater zone of Hooghly estuary in relation to ecological alteration.

Plankton are promising ecological monitoring tool that responds quickly to any sort of aquatic ecological alteration, of which many of them are much susceptible to ecological variations. Therefore, monitoring shifts in plankton composition can indicate changes in water quality and aid to identify potential pollution sources. In the present study, the variation in plankton dynamics in relation to ecological variables were monitored in the freshwater zone of the Hooghly estuary from May 2020 to April 2021. The study was conducted in the interval of every six hours. i.e., at 6 A.M., 12 P.M., 6 P.M., and 12 A.M. The present finding revealed the occurrence of 54 phytoplankton and 20 zooplankton taxa/species. Diel variation revealed that among different time intervals, the highest abundance of phytoplankton was recorded 28,307 cells l-1 at 12 P.M, while the lowest was recorded 10,632 cells l-1 at 6 A.M. However, the highest zooplankton abundance was observed 804 ind l-1 at 6 A.M., and the lowest was recorded 156 ind l-1 at 6 P.M. The ANOVA (p < 0.05) analysis indicated significant diel variation for many planktonic genera. The CCA exhibited that most of the phytoplankton were influenced by multiple water quality variables such as temperature, turbidity, calcium, pH, salinity, DO, and nutrients. However, the majority of the zooplankton were affected by turbidity, total phosphorus, sulphate, calcium and available nitrogen. Significant seasonal variation in plankton composition has also been observed. The present study will help to determine the varying diel pattern of planktons in retort to alterations in the water quality parameters and varying ecological niches.

Bioaccumulation of polystyrene microplastics and changes in antioxidant and AChE pattern in a freshwater snail (Filopaludina bengalensis) from river Ganga.

Microplastic pollution is a leading global problem affecting terrestrial and marine aquatic ecosystems. Due to the stagnant nature of microplastics, the toxic effect of microplastics is more pronounced to benthic organisms than the surface feeder. Hence, the present study effort was to study the microplastic bioaccumulation pattern and changes in the enzymatic and nonenzymatic antioxidant and AChE pattern of freshwater snail Filopaludina bengalensis, which were subjected to 0.5 ppm to 5 ppm levels of polystyrene microsphere (∼ 30 µm) for 27 days. The study showed that microplastics were easily accumulated in the test organism in a dose and time-dependent manner, amounting to 82 ± 6.02 particles /individuals at a 5 ppm dose on the 27th day. However, no mortality was observed at the test microplastic dosages. The enzymatic antioxidant profile (SOD and catalase) showed limited variability and remained stable with increased duration and microplastic dose. However, the nonenzymatic antioxidant profile showed distinct variability with the complete seizing of the DPPH activity on the 27th day at 5 ppm microplastic dose and a gradual decrease of ABTS and FRAP activity at all the dose ranges. Even the AChE activity decreased with higher exposure concentrations. The present study for the first time shows the direct impact of microplastics on a freshwater snail widely available in the Indian subcontinent, indicating the role of microplastic pollution will create havoc in the Ganga river eco-biosystem in the long run.

Altitudinal and seasonal distribution of benthic macroinvertebrates in River Tons - a tributary of Yamuna River, Uttarakhand, India.

The main tributary of the Yamuna, the Tons River, exhibits altitudinal changes in its macroinvertebrate community's diversity, abundance, and composition. Between May 2019 and April 2021, the study was conducted in the upper section of the river. A total of 48 numbers of taxa from 34 families and ten orders were recorded during the investigation. At this elevation of 1150 to 1287 m, the two most predominant orders are Ephemeroptera (32.9%) and Trichoptera (29.5%). During the premonsoon season, they had the lowest macroinvertebrate density (250-290 individuals/m2), and the post-monsoon season had the highest density (600-640 individuals/m2). During the post-monsoon season, the maximum larval forms (60%) of various insect orders were predominant. The findings indicated that lower altitudes (1150-1232 m) have higher macroinvertebrate abundance than higher ones. The diversity of dominance is shallow at site-I (0.0738) and strong at the site-IV during the premonsoon season (0.03837). Taxa richness, as measured by the Margalef index (D), peaked in the spring season (January to March) at 6.9 and reached its lowest point (5.74) in the premonsoon season (April to May). Only 16 taxa were discovered in site-I and site-II, but 39 taxa were discovered at low altitudes (site-IV, 1100 m) (1277-1287 m). The Tons River contains a total of 12 and 13 genera, respectively, that belong to the orders Ephemeroptera and Trichoptera, according to qualitative study of the macroinvertebrates. The current study supports the use of macroinvertebrates as bioindicator species for monitoring biodiversity and assessing the health of ecosystems.

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis.

Dose limiting cardiotoxicity remains a major limiting factor in the clinical use of several cancer chemotherapeutics including anthracyclines and the antimetabolite 5-fluorouracil (5-FU). Prior work has demonstrated that chemotherapeutics increase expression of R7 family regulator of G protein signaling (RGS) protein-binding partner Gß5, which drives myocyte cytotoxicity. However, though several R7 family members are expressed in heart, the exact role of each protein in chemotherapy driven heart damage remains unclear. Here, we demonstrate that RGS11, downregulated in the human heart following chemotherapy exposure, possesses potent anti-apoptotic actions, in direct opposition to the actions of fellow R7 family member RGS6. RGS11 forms a direct complex with the apoptotic kinase CaMKII and stress responsive transcription factor ATF3 and acts to counterbalance the ability of CaMKII and ATF3 to trigger oxidative stress, mitochondrial dysfunction, cell death, and release of the cardiokine neuregulin-1 (NRG1), which mediates pathological intercommunication between myocytes and endothelial cells. Doxorubicin triggers RGS11 depletion in the murine myocardium, and cardiac-specific OE of RGS11 decreases doxorubicin-induced fibrosis, myocyte hypertrophy, apoptosis, oxidative stress, and cell loss and aids in the maintenance of left ventricular function. Conversely, RGS11 knockdown in heart promotes cardiac fibrosis associated with CaMKII activation and ATF3/NRG1 induction. Indeed, inhibition of CaMKII largely prevents the fibrotic remodeling resulting from cardiac RGS11 depletion underscoring the functional importance of the RGS11-CaMKII interaction in the pathogenesis of cardiac fibrosis. These data describe an entirely new role for RGS11 in heart and identify RGS11 as a potential new target for amelioration of chemotherapy-induced cardiotoxicity.

Integration of pen aquaculture into ecosystem-based enhancement of small-scale fisheries in a macrophyte dominated floodplain wetland of India.

The rapid degradation, overexploitation, and encroachment of floodplain wetlands have led to considerable decline in fish diversity and production from these invaluable aquatic resources threatening livelihood of the dependent fishers. The climate change evident in the fast few decades has further aggravated the problem of eutrophication causing water stress and sedimentation leading to rampant macrophyte proliferation affecting ecological and economic functioning of these ecosystems. Macrophyte control and management needs serious attention for sustaining ecosystem services provided by these resources. In this direction, pen culture of grass carp Ctenopharyngodon idella as a biocontrol for macrophytes along with Indian major carps was implemented in a co-management mode in Beledanga, a typical floodplain wetland, a gradually shrinking, macrophyte dominated floodplain wetland in lower Ganga basin. Indian major carps Labeo catla (6.28±0.23g), Labeo rohita (5.1±0.12g), Cirrhinus mrigala (3.5±0.08g) were stocked in the ratio 4:3:3 at the rate of 20 Nos.m-2 in pens (0.1ha each) in triplicate. Grass carp (7.1±0.42g) was stocked in pen at the rate of 20Nos.m-2 in duplicate. The fishes were fed with pelleted feed twice a day at the rate of 2-3% of body weight. The seed was overwintered in pens for a period of 90 days from November 2019 to January 2020. Average weight recorded at the end of culture period was 25.13±1.70g, 18.11±0.63g, 14.53±0.87g, and 39.20±1.90g in L. catla, L. rohita, C. mrigala, and C. idella, respectively. The survival of fish ranged from 70 to 81%. Growth performance and feed utilization efficiency of grass carp were significantly higher (p<0.05) compared to other carp species. The pen culture was found to be economically viable with a benefit cost ratio of 1.53. The fishes produced were released back into the open wetland as an additional input for culture-based fisheries. The intervention along with niche-based enhanced stocking led to 24% increase in the fish production from the wetland with grass carp contributing 20-22% of the total catch with 32% increase in revenue generated by the sale of fish within a short span of 1 year. The study successfully demonstrated technological suitability and economic feasibility of pen culture in this wetland and role of grass carp as a potential biocontrol species for macrophyte management. Grass carp stocked in open wetland grew to 0.8 to 1kg within 6 months and 2-2.3kg within a year and could utilize 40-45% of the submerged and emergent macrophytes. Integration and optimization of grass carp will not only aid in habitat management of macrophyte-choked wetlands but will also boost their small-scale fisheries by converting standing macrophyte biomass into protein-rich fish biomass. The enhanced production will also cater to nutritional and livelihood security of the dependent fishers.