Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Buckwheat tartary regulates the Gsk-3ß/ß-catenin pathway to prevent neurobehavioral impairments in a rat model of surgical menopause.

Menopause is a natural aging process characterized by decreased levels of sex hormones in females. Deprivation of estrogen following menopause results in alterations of dendritic arborization of the neuron that leads to neurobehavioral complications. Hormone replacement therapy is in practice to manage postmenopausal conditions but is associated with a lot of adverse effects. In the present study, the efficacy of buckwheat tartary (Fagopyrum tataricum) whole seed extract was investigated against the neurobehavioral complication in middle-aged ovariectomized rats, which mimic the clinical postmenopausal condition. Hydroalcoholic extraction (80% ethanol) was done, and quantification of major marker compounds in the extract was performed using HPLC. Oral treatment of the extract following the critical window period rescued the reconsolidation process of spatial and recognition memory, as well as depression-like behavior. Gene expression analysis disclosed elevated oxidative stress and neuroinflammation that largely disturb the integrity of the blood-brain barrier in ovariectomized rats. Gfap and Pparγ expression also showed reactive astrogliosis in the rats subjected to ovariectomy. The extract treatment reverted the elevated oxidative stress, neuroinflammation and expression of the studied genes. Furthermore, protein expression analysis revealed that Gsk-3ß was activated differentially in the brain, as suggested by ß-catenin protein expression, which was normalized following the treatment with extract and rescued the altered neurobehavioral process. The results of the current study concluded that Fagopyrum tataricum seed extract is better option to overcome the neurobehavioral complications associated with the menopause.

Deciphering key regulators involved in epilepsy-induced cardiac damage through whole transcriptome and proteome analysis in a rat model.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy. METHODS: A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies. RESULTS: Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor ß (TGF-ß) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures. SIGNIFICANCE: The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan.

Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.

Design, microwave-mediated synthesis and biological evaluation of novel 4-aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl)amino-3-nitroquinolines as anticancer agents.

Design, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a-1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a-2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure-activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR.

ß-Hydroxybutyrate Improves the Redox Status, Cytokine Production and Phagocytic Potency of Glucose-Deprived HMC3 Human Microglia-like Cells.

Brain glucose deprivation is a component of the pathophysiology of ischemia, glucose transporter1 (GLUT1) deficiency, neurological disorders and occurs transiently in diabetes. Microglia, the neuroimmune cells must function effectively to offer immune defence and debris removal in low-energy settings. Brain glucose deprivation may compromise microglial functions further escalating the disease pathology and deteriorating the overall mental health. In the current study, HMC3 human microglia-like cells were cultured in vitro and exposed to glucose deprivation to investigate the effects of glucose deprivation on phenotypic state, redox status, secretion of cytokines and phagocytic capabilities of HMC3 cells. However, HMC3 cells were able to proliferate in the absence of glucose but showed signs of redox imbalance and mitochondrial dysfunction, as demonstrated by decreased MTT reduction and Mito Tracker™ staining of cells, along with a concomitant reduction in NOX2 protein, superoxide, and nitrite levels. Reduced levels of secreted TNF and IL-1ß were the signs of compromised cytokine secretion by glucose-deprived HMC3 microglia-like cells. Moreover, glucose-deprived HMC3 cells also showed reduced phagocytic activity as assessed by fluorescently labelled latex beads-based functional phagocytosis assay. ß-hydroxybutyrate (BHB) supplementation restored the redox status, mitochondrial health, cytokine secretion, and phagocytic activity of glucose-deprived HMC3 microglia-like cells. Overall, impaired brain glucose metabolism may hinder microglia's capacity to release diffusible immune factors and perform phagocytosis. This could escalate the mental health issues in neurological diseases where brain glucose metabolism is compromised. Moreover, nutritional ketosis or exogenous ketone supplementation such as BHB may be utilized as a potential metabolic therapies for these conditions.

Resectable Distal Duodenal Gastrointestinal Stromal Tumour Presenting with Features of Anaemia.

Although gastrointestinal stromal tumours (GISTs) are encountered all along the gastrointestinal tract, duodenal GISTs are uncommon and account for <5% of the cases. A 45-year-old woman presented chiefly with anaemia and associated symptoms, whom on further evaluation was found to have a non-metastatic GIST in the distal duodenum sparing the pancreas and major vasculature. Patient was undertaken for segmental duodenectomy with the help of advanced bipolar energy device (tumour occupying D3-D4 with 1 cm proximal margin and 15 cm jejunum) preserving the pancreas and ampulla with end-to-end duodenojejunostomy with an uneventful postoperative course and clear margins on histopathology. Thus, the patient underwent a less morbid procedure with satisfactory oncological outcome and early resumption of activity. This highlights the need to conduct more trials to gather high level evidence in favour of conservative resection and its oncological adequacy and impact on overall survival and recurrence.

Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.

Protective effect of Nardostachys jatamansi extract against lithium-pilocarpine-induced spontaneous recurrent seizures and associated cardiac irregularities in a rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Nardostachys jatamansi (D.Don) DC. is a perennial herbaceous medicinal plant widely used for the ethnomedical treatment of various ailments. The underground parts of the plants are used in traditional medicine to manage epilepsy and other cardiovascular conditions. AIM OF THE STUDY: The present study was undertaken to investigate the efficacy of a characterized hydroalcoholic extract (NJET) of Nardostachys jatamansi in the lithium-pilocarpine rat model of spontaneous recurrent seizures (SRS) and associated cardiac irregularities. MATERIALS AND METHODS: NJET was prepared by percolation using 80% ethanol. The dried NEJT was subjected to UHPLC-qTOF-MS/MS for chemical characterization. Molecular docking studies were performed using the characterized compounds to understand mTOR interactions. The animals showing SRS following lithium-pilocarpine administration were treated with NJET for 6 weeks. Afterward, seizure severity, cardiac parameters, serum biochemistry, and histopathological parameters were studied. The cardiac tissue was processed for specific protein and gene expression studies. RESULTS: The UHPLC-qTOF-MS/MS characterized 13 compounds in NJET. The identified compounds subjected to molecular docking showed promising binding affinities toward mTOR. There was a dose-dependent decrease in the severity of SRS following the extract administration. A reduction in mean arterial pressure and serum biochemical markers (lactate dehydrogenase and creatine kinase) was also observed following NJET treatment in epileptic animals. Histopathological investigations revealed reduced degenerative changes and decreased fibrosis following the extract treatment. The cardiac mRNA level of Mtor, Rps6, Hif1a, and Tgfb3 was reduced in the extract-treated groups. Further, a similar reduction in the protein expression of p-mTOR and HIF-1α was also observed following NJET treatment in the cardiac tissue. CONCLUSIONS: The results concluded that NJET treatment reduces lithium-pilocarpine-induced recurrent seizures and associated cardiac irregularities via downregulation of the mTOR signalling pathway.

Lithium co-administration with rutin improves post-stroke neurological outcomes via suppressing Gsk-3ß activity in a rat model.

Cerebral ischemic stroke is one of the leading causes of adult disability worldwide. Reperfusion is the only therapeutic option with a lot of side effects. In the current study, we investigated the efficacy of rutin and lithium co-treatment in improving post-stroke neurological outcomes in a transient global cerebral ischemia-reperfusion injury rat model. Middle-aged male rats were subjected to transient global cerebral ischemia-reperfusion. NORT and Y-maze were used to assess the cognitive processes. Lipid peroxidation, protein carbonylation, and nitric oxide assays were performed to study oxidative stress. The excitotoxicity index was calculated by HPLC. Real time-PCR and western blotting were performed to study gene and protein expressions. The co-administration of rutin and lithium improved the overall survival, recognition memory, spatial working memory, and neurological score following cerebral ischemia-reperfusion in rats. Further, a marked decrease in malonaldehyde, protein carbonyls, and nitric oxide levels was observed following combined treatment. The mRNA expression of antioxidant (Hmox1 and Nqo1) and pro-inflammatory (Il2, Il6, and Il1ß) markers were significantly attenuated in the rutin and lithium co-administrated group. The treatment inhibited the Gsk-3ß and maintained a normal pool of the downstream ß-catenin and Nrf2 proteins. The results revealed that co-administration of rutin and lithium had a neuroprotective potential, suggesting it to be a viable treatment to overcome post-stroke deaths and neurological complications.

Inhibition of Mammalian Target of Rapamycin Attenuates Recurrent Seizures Associated Cardiac Damage in a Zebrafish Kindling Model of Chronic Epilepsy.

Sudden Unexpected Death in Epilepsy (SUDEP) is primarily linked with the cardiac irregularities that occur due to recurrent seizures. Our previous studies found a role of mTOR pathway activation in seizures-linked cardiac damage in a rat model. In continuation to the earlier work, the present study was devised to explore the role of rapamycin (mTOR inhibitor and clinically used immunosuppressive agent) in a zebrafish kindling model and associated cardiac damage. Adult zebrafish were incubated with increasing concentrations of rapamycin (1, 2 and, 4 µM), followed by pentylenetetrazole (PTZ) exposure to record seizure latency and severity. In another experiment, zebrafish were subjected to a standardized PTZ kindling protocol. The kindled fish were treated daily with rapamycin for up to 25 days, along with PTZ to record seizure severity. At the end, zebrafish heart was excised for carbonylation assay, gene expression, and protein quantification studies. In the acute PTZ convulsion test, treatment with rapamycin showed a significant increase in seizure latency and decreased seizure severity without any change in seizure incidence. Treatment with rapamycin also reduced the severity of seizures in kindled fish. The cardiac expressions of gpx, nppb, kcnh2, scn5a, mapk8, stat3, rps6 and ddit were decreased, whereas the levels of trxr2 and beclin 1 were increased following rapamycin treatment in kindled fish. Furthermore, rapamycin treatment also decreased p-mTOR expression and protein carbonyls level in the fish cardiac tissue. The present study concluded that rapamycin reduces seizures and associated cardiac damage by inhibiting mTOR activation in the zebrafish kindling model.

Lithium therapy subdues neuroinflammation to maintain pyramidal cells arborization and rescues neurobehavioural impairments in ovariectomized rats.

Oestrogen deprivation as a consequence of menopause alters the brain neuronal circuit and results in the development of neurobehavioural symptoms later. Hormone replacement therapy to some extent helps to overcome these abnormalities but is associated with various adverse events. Lithium therapy is being used to manage multiple neuropsychiatric disorders and is reported to maintain structural synaptic plasticity, suppress neuroinflammation, and promote adult neurogenesis. The present study examined the effect of lithium treatment on the neurobehavioural impairments in ovariectomized rat model mimicking clinical postmenopausal condition. A protective effect of lithium treatment was observed on the reconsolidation of spatial and recognition memory along with depression-like behaviour in ovariectomized rats. The Golgi-Cox staining revealed increased dendritic length and spine density in the pyramidal neurons of the CA1 region of the hippocampus, layer V of the somatosensory cortex, and layer II/III of the prefrontal cortex in the treated group. A significant reduction in pro-inflammatory markers, Il2, II6, and Il1b, was observed in the hippocampus, somatosensory cortex, and prefrontal cortex following lithium treatment. mRNA expression studies of Gfap and Pparg, along with histopathological analysis, suggested reactive astrogliosis to be a major contributor of neuroinflammation in ovariectomized rats that was normalized following lithium treatment. Further, the treatment inhibited Gsk-3ß activity and maintained the normal level of ß-catenin, CREB, and BDNF. The results revealed a defensive role of lithium against ovariectomy-induced neurobehavioural impairments, thus suggesting it to be a potential therapeutic agent for managing postmenopausal neurological symptoms.

Rutin protects hemorrhagic stroke development via supressing oxidative stress and inflammatory events in a zebrafish model.

Intracerebral hemorrhagic (ICH) stroke is a major cause of death and disability globally, with no proper treatment available so far. Rutin, a dietary flavonoid, has shown protection against cerebral ischemic stroke due to its antioxidant and anti-inflammatory attributes. However, the efficacy of rutin against ICH stroke remained unexplored. Therefore, in the current study, we investigated the effect of rutin in an ICH stroke zebrafish larva model. The larvae were exposed to atorvastatin (1.25  µM) in system water for induction of experimental ICH. Rutin treatment reduced the hematoma size, ROS production and decreased apoptosis in the zebrafish larvae brains. Reduction in the malondialdehyde and protein carbonyl level in the rutin-treated larvae also indicated quenching of the free radicals. The treatment increased the expression of tight junction claud5a gene and decreased the mRNA level of matrix metalloproteases (mmp2 and mmp9). Furthermore, rutin treatment also attenuated the genomic expression of oxidative markers (nrf2, hmox1a, sod1, and gpx) and inflammatory genes (il6, tnfa, il10, and irf2a) related to ICH. The Gsk-3ß activity was also downregulated, and a normal pool of ß-catenin and Nrf2 was maintained in the larvae treated with rutin. The current study suggested that rutin protects ICH stroke via suppressing oxidative stress and inflammatory events in a zebrafish model.

Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis.

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases.

Protein aggregation is a hallmark of many neuronal disorders, including the polyglutamine disorder spinocerebellar ataxia 3 and peripheral neuropathies associated with the K141E and K141N mutations in the small heat shock protein HSPB8. In cells, HSPB8 cooperates with BAG3 to stimulate autophagy in an eIF2α-dependent manner and facilitates the clearance of aggregate-prone proteins (Carra, S., Seguin, S. J., Lambert, H., and Landry, J. (2008) J. Biol. Chem. 283, 1437-1444; Carra, S., Brunsting, J. F., Lambert, H., Landry, J., and Kampinga, H. H. (2009) J. Biol. Chem. 284, 5523-5532). Here, we first identified Drosophila melanogaster HSP67Bc (Dm-HSP67Bc) as the closest functional ortholog of human HSPB8 and demonstrated that, like human HSPB8, Dm-HSP67Bc induces autophagy via the eIF2α pathway. In vitro, both Dm-HSP67Bc and human HSPB8 protected against mutated ataxin-3-mediated toxicity and decreased the aggregation of a mutated form of HSPB1 (P182L-HSPB1) associated with peripheral neuropathy. Up-regulation of both Dm-HSP67Bc and human HSPB8 protected and down-regulation of endogenous Dm-HSP67Bc significantly worsened SCA3-mediated eye degeneration in flies. The K141E and K141N mutated forms of human HSPB8 that are associated with peripheral neuropathy were significantly less efficient than wild-type HSPB8 in decreasing the aggregation of both mutated ataxin 3 and P182L-HSPB1. Our current data further support the link between the HSPB8-BAG3 complex, autophagy, and folding diseases and demonstrate that impairment or loss of function of HSPB8 might accelerate the progression and/or severity of folding diseases.

Recognition of Acute Page Kidney following Renal Transplant: Varied Etiologies Requiring High Clinical Suspicion.

Oliguria in the early postoperative phase after renal transplantation has many causes with overlapping presentations. Page kidney refers to external compression of the kidney by a hematoma, urinoma or tumor, leading to parenchymal hypoperfusion, unexplained hypertension (HTN), or frank acute renal failure. About 100 cases of Page kidney are reported; mostly after kidney biopsy. After the analysis of records, we identified four cases of acute Page kidney posttransplant, akin to a compartment syndrome. All biochemical, laboratory, and clinical parameters were recorded. Cases occurred within two to three weeks of transplant, with different causes. Clinical presentation was sudden, with HTN, raised serum creatinine and perigraft swelling in all. Rejection co-existed Page kidney in two cases, while tacrolimus had to be potentiated with diltiazem in one case. Serial parameters such as increased resistive index (>0.7), perigraft collection, and absent diastolic flow with normal peak systolic velocity were consistent with diagnosis. Two were caused by lymphoceles, more than 3 L. Both were managed by laparoscopic fenestration surgery; probably the first such instance for Page kidney. Two patients had postoperative hematoma; in one case, it followed early percutaneous angiographic stenting and "leakage" from the transplant artery, only the second such report. A high index of suspicion required for diagnosis; after excluding rejection and pre/postrenal causes, aggressive early management is the key for graft salvage.

Can renal transplant improve the quality of life of caregiver donors? A prospective study from India.

Live-related renal transplantation in India by "caregiver donors" provides huge financial, emotional, and physical support. Their psychological and mental health has not been addressed. We performed a prospective study using the World Health Organization Quality of Life (WHOQoL) BREF Scores and the Hospital Anxiety and Depression Scales preoperatively, at two weeks and three months after transplant. We included 30 pairs; most donors were females (80%, 60% mothers, 28% wives). The mean age of donors was 43.77 ± 10.64 years (34.8 ± 9.01 for recipients). There was improvement in the WHOQoL BREF after two weeks and three months as follows: physical domain (74.30 ± 9.74 vs. 78.30 ± 8.20; P = 0.001), and (74.30 ± 9.74 vs. 86.23 ± 7.25; P <0.001); psychological (74.90 ± 8.44 vs. 82.07 ± 7.19; P <0.001) and (74.90 ± 8.44 vs. 88.07 ± 6.89; P <0.001); environmental (75.33 ± 8.09 vs. 79.57 ± 6.18; P <0.001), and, (75.33 ± 8.09 vs. 86.97 ± 3.8; P <0.001); social-relationships (77.73 ± 8.28 vs. 79.77 ± 7.99; P <0.001), and (77.73 ± 8.28 vs. 84.77 ± 7.45; P <0.001). The recipient scores were similar. Factors with significant Pearson's or standardized beta co-efficient were donor age <20 years, donor complications, donor anxiety, education (<12th standard), recipient hospital stay (>3 weeks), and, recipient complications (increased creatinine, hemodialysis, lymphocele, and graft dysfunction). The median anxiety scores of donors increased significantly two weeks after operation but later became normal. Caregiver donors have improved QoL scores, despite kidney donation; a larger study is needed.

Glycogen synthase kinase-3: A putative target to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

The coronavirus disease 19 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had turned out to be highly pathogenic and transmittable. Researchers throughout the globe are still struggling to understand this strain's aggressiveness in search of putative therapies for its control. Crosstalk between oxidative stress and systemic inflammation seems to support the progression of the infection. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Nucleocapsid protein of SARS-CoV-2 is an important structural protein responsible for viral replication and interferes with the host defence mechanism by the help of Gsk-3 protein. The viral infected cells show activated Gsk-3 protein that degrades the Nuclear factor erythroid 2-related factor (Nrf2) protein, resulting in excessive oxidative stress. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-​κB, and degrades ß-catenin, thus provokes systemic inflammation. Interaction between these two pathophysiological events, oxidative stress, and inflammation enhance mucous secretion, coagulation cascade, and hypoxia, which ultimately leads to multiple organs failure, resulting in the death of the infected patient. The present review aims to highlight the pathogenic role of Gsk-3 in viral replication, initiation of oxidative stress, and inflammation during SARS-CoV-2 infection. The review also summarizes the potential Gsk-3 pathway modulators as putative therapeutic interventions in combating the COVID-19 pandemic.

Predictors of Lymphatic Complications Following Renal Transplant: A Prospective Study Involving Predominantly Living Donor Transplants From India.

Introduction Lymphatic complications (LC) are common (up to 33%) and troublesome after renal transplantation. Different studies have established varying medical and surgical risk factors, mostly by retrospective analysis on deceased donor renal transplants (DDRTs). The end-point is mostly lymphocele, with few reports documenting the equally important lymphorrhea. Methods In our prospective analytical study done over three years, most were living donor renal transplant (LDRT) pairs by a single team. The primary outcome measure was lymphocele and/or prolonged drainage for more than 15 days, with a six-month follow-up. The variables recorded were age, gender, hemodialysis duration, etiology, relationship, human leucocyte antigen (HLA) mismatch, induction regimen, acute rejection, warm ischemia time (WIT), and delayed graft function (DGF). Univariate analysis was by chi-square and t-tests as applicable, while logistic regression (both simultaneous and forward stepwise) was used for risk factor prediction. Results Eligible cases were 150, with 145 (97%) LDRT pairs. Donors were mostly female (122/150; 81%) with mean age (~43 years) higher than recipient age (~33 years). The common etiologies were diabetes (31%), hypertension (23%), and IgA nephropathy (11%). Most donors were mothers (37%) and wives (31%), and 28% of LDRT pairs had HLA mismatch >3. Mean duration of hemodialysis was about 18 months, and mean WIT was 52 minutes. Both DGF (B coefficient= -1.69, p<0.000) and WIT (B=-0.038, p=0.024) were significant predictors of the primary outcome, while drain removal before 15 days predicted lymphocele significantly (B=-2.4, p<0.000).  Conclusions LDRT has specific risk factors for lymphatic complications, which may be related to extent of recipient vascular dissection, arterial anastomotic time, and early drain removal.