Dantrolene alleviates mitochondrial dysfunction and neuroinflammation in traumatic brain injury by modulating the NF-ĸß/Akt pathway.

Traumatic brain injury (TBI) triggers a bevy of changes including mitochondrial dysfunction, apoptosis, oxidative stress, neurobehavioural impairment, and neuroinflammation, among others. Dantrolene (DNT), a muscle relaxant which inhibits intracellular Ca2+ signaling from the ER, has been repurposed as a potential neuroprotective agent in various neurological diseases. However, there have been limited studies on whether it can mitigate TBI-induced deficits and restore impaired mitochondrial dynamics. This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary Acidic Protein (GFAP) and immunohistochemistry with NF-κß to investigate neuroinflammation. H&E staining was also performed post-TBI. Our findings revealed DNT administration inhibits mitochondria-mediated apoptotis and reduces heightened oxidative stress. DNT treatment was also found to reverse neurobehavioural impairments and offer neuroprotection by preserving neuronal architechture. We also demonstrated that DNT inhibits neuronal autophagy and alleviates neuroinflammation following TBI by modulating the NF-κß/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection.

Neurological Complications Caused by Human Immunodeficiency Virus (HIV) and Associated Opportunistic Co-infections: A Review on their Diagnosis and Therapeutic Insights.

Neurocognitive disorders associated with human immunodeficiency virus (HIV) infected individuals increase the risk of mortality and morbidity that remain a prevalent clinical complication even in the antiretroviral therapy era. It is estimated that a considerable number of people in the HIV community are developing neurological complications at their early stages of infection. The daily lives of people with chronic HIV infections are greatly affected by cognitive declines such as loss of attention, learning, and executive functions, and other adverse conditions like neuronal injury and dementia. It has been found that the entry of HIV into the brain and subsequently crossing the blood-brain barrier (BBB) causes brain cell damage, which is the prerequisite for the development of neurocognitive disorders. Besides the HIV replication in the central nervous system and the adverse effects of antiretroviral therapy on the BBB, a range of opportunistic infections, including viral, bacterial, and parasitic agents, augment the neurological complications in people living with HIV (PLHIV). Given the immuno-compromised state of PLHIV, these co-infections can present a wide range of clinical syndromes with atypical manifestations that pose challenges in diagnosis and clinical management, representing a substantial burden for the public health system. Therefore, the present review narrates the neurological complications triggered by HIV and their diagnosis and treatment options. Moreover, coinfections that are known to cause neurological disorders in HIV infected individuals are highlighted.

A review of venous thromboembolism in India.

Venous thromboembolism (VTE), which entails the formation of a thrombus (blood clot) in a vein, has a significant disease burden worldwide. While VTE has traditionally been considered to predominantly affect Caucasian populations, recent studies have indicated a gradual shift in the disease burden towards Asian populations, with added significance of it being a key driver of post-operative mortality. It is imperative to develop a sound understanding of the various factors that affect VTE in stratified local populations. However, there is a glaring paucity of quality data on VTE and its ramifications among Indians - both in terms of quality of life and cost of healthcare. This review aims to throw light on the disease burden, epidemiology, risk factors, environmental factors, food and nutrition that plays a key role in VTE. We also explored the association of VTE with coronavirus disease 2019 to grasp the interplay between the two most significant public health crises of our time. It is vital to place a special emphasis on future research on VTE in India to plug the gaps, which exist in our current knowledge of the disease, particularly with respect to Indian population.

NLRP3 inflammasome in traumatic brain injury: Its implication in the disease pathophysiology and potential as a therapeutic target.

Traumatic brain injury (TBI), an acquired brain injury imparted by a mechanical trauma to the head, has significant ramifications in terms of long-term disability and cost of healthcare. TBI is characterized by an initial phase of cell death owing to direct mechanical injury, followed by a secondary phase in which neuroinflammation plays a pivotal role. Activation of inflammasome complexes triggers a cascade that leads to activation of inflammatory mediators such as caspase-1, Interleukin (IL)-18, and IL-1ß, eventually causing pyroptosis. NLRP3 inflammasome, a component of the innate immune response, has been implicated in a number of neurodegenerative diseases, including TBI. Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation and improve cognition and motor function in TBI. The NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. Although several therapeutic agents have shown promising results in pre-clinical studies, none of them have been effective in human trials for TBI, to date. Thus, it is imperative that such promising therapeutic candidates are evaluated in clinical trials to assess their efficacy in alleviating neurological impairments in TBI. This review offers an insight into the pathophysiology of TBI, with an emphasis on neuroinflammation in the aftermath of TBI. We highlight the NLRP3 inflammasome and explore its role in the neuroinflammatory cascade in TBI. We also shed light on its potential as a prospective biomarker and therapeutic target for TBI management.

Modulatory Role of Quercetin in Mitochondrial Dysfunction in Titanium Dioxide Nanoparticle-Induced Hepatotoxicity.

Background : Titanium dioxide (TiO2) nanoparticles are among the largely manmade nanomaterials worldwide and are broadly used as both industrial and user products. The primary target site for several nanoparticles is the liver, including TiO2 nanoparticles (TNPs), exposed directly or indirectly through ingestion of contaminated water, food, or animals and elevated environmental contamination. Oxidative stress is a known facet of nanoparticle-induced toxicity, including TNPs. Mitochondria are potential targets for nanoparticles in several types of toxicity, such as hepatotoxicity. Nevertheless, its causal mechanism is still controversial due to scarcity of literature linking the role of mitochondria-mediated TNP-induced hepatotoxicity. Aim : The objective of the current study was to evaluate the relation of mitochondrial oxidative stress and respiratory chain mechanisms with TNP-induced mitochondrial dysfunction in vitro, and explore the hepatoprotective effect of quercetin (QR), which is a polyphenolic flavonoid abundant in fruits and vegetables with known antioxidant properties, on TNP-induced mitochondrial oxidative stress and disturbance in respiratory chain complex enzymes in the liver of rats. Results: Enzymatic and non-enzymatic antioxidant levels, oxidative stress markers, and mitochondrial complexes were assessed with regard to TNP-induced hepatotoxicity. The depleted lipid peroxidation levels and protein carbonyl content, in mitochondria, induced by TNPs were restored significantly by pretreatment with QR. QR modulated the altered non-enzymatic and enzymatic antioxidants and mitochondrial complex enzymes. Conclusion : Based on the findings, we conclude that QR, which mitigates oxidative stress caused by mitochondrial dysfunction, holds promising capability to potentially diminish TNP-induced adverse effects in the liver.

Doping- and Strain-Dependent Electrolyte-Gate-Induced Perovskite to Brownmillerite Transformation in Epitaxial La1-xSrxCoO3-δ Films.

Much recent attention has focused on the voltage-driven reversible topotactic transformation between the ferromagnetic metallic perovskite (P) SrCoO3-δ and oxygen-vacancy-ordered antiferromagnetic insulating brownmillerite (BM) SrCoO2.5. This is emerging as a paradigmatic example of the power of electrochemical gating (using, e.g., ionic liquids/gels), the wide modulation of electronic, magnetic, and optical properties generating clear application potential. SrCoO3 films are challenging with respect to stability, however, and there has been little exploration of alternate compositions. Here, we present the first study of ion-gel-gating-induced P → BM transformations across almost the entire La1-xSrxCoO3 phase diagram (0 ≤ x ≤ 0.70), under both tensile and compressive epitaxial strain. Electronic transport, magnetometry, and operando synchrotron X-ray diffraction establish that voltage-induced P → BM transformations are possible at essentially all x, including x ≤ 0.50, where both P and BM phases are highly stable. Under small compressive strain, the transformation threshold voltage decreases from approximately +2.7 V at x = 0 to negligible at x = 0.70. Both larger compressive strain and tensile strain induce further threshold voltage lowering, particularly at low x. The P → BM threshold voltage is thus tunable, via both composition and strain. At x = 0.50, voltage-controlled ferromagnetism, transport, and optical transmittance are then demonstrated, achieving Curie temperature and resistivity modulations of ∼220 K and at least 5 orders of magnitude, respectively, and enabling estimation of the voltage-dependent Co valence. The results are analyzed in the context of doping- and strain-dependent oxygen vacancy formation energies and diffusion coefficients, establishing that it is thermodynamic factors, not kinetics, that underpin the decrease in the threshold voltage with x, that is, with increasing formal Co valence. These findings substantially advance the practical and mechanistic understanding of this voltage-driven transformation, with fundamental and technological implications.

Elevated urinary IL-36α and IL-18 levels are associated with diabetic nephropathy in patients with type 2 diabetes mellitus.

BACKGROUND: Inflammatory cytokines have been reported to be pathogenic factors for the development and progression of diabetic nephropathy (DN). Interleukin (IL)-36α is a newly discovered member of the IL-1 cytokine family that has been implicated in animal models of renal impairment. However, little is known about the role of IL-36α in DN in humans. The purpose of the present study was to assess the levels of IL-36α and IL-18 in type 2 diabetic patients (T2DM) patients with and without DN. METHODS: Subjects were divided into 3 groups: Control (N.=20), T2DM without DN (N.=30), and T2DM with DN (N.=30). Urinary IL-36α and IL-18 levels were assessed using ELISA. Correlation analysis was performed to determine the association of the IL levels with clinical markers of T2DM and DN. RESULTS: IL-36α and IL-18 levels were significantly elevated in T2DM patients with DN, when compared to T2DM patients without DN (P<0.0001, P=0.0025, respectively) and controls (P<0.0001, for both). IL-36α levels showed a positive correlation with urinary albumin excretion (r=0.754, P<0.0001), HbA1c (r=0.433, P=0.0168), fasting plasma glucose (r=0.433, P=0.0168) and negative correlation with glomerular filtration rate (r=-0.852 P<0.0001). CONCLUSIONS: The results highlighted the association of IL-36α with DN. However, further extensive studies are suggested for evaluating the association.

COVID-19: An overview of the current pharmacological interventions, vaccines, and clinical trials.

COVID-19, the greatest public health emergency of the 21st century, has affected 215 countries and territories around the world resulting in 15,151,738 confirmed cases and 621,121 deaths. The outbreak has continued at breakneck pace despite stringent public health measures, ravaging the global economy and causing profound human casualties. Vaccination is currently the best bet for the prevention of COVID-19. Still, in its absence, there has been considerable interest in repurposing existing therapeutic agents to reduce the severity of the illness and ease the burden on the already strained healthcare systems. This review outlines the current evidence regarding proposed treatments- experimental or repurposed, for COVID-19, and gives an insight into the clinical trial landscape for drugs as well as vaccines.

Anomalous Self-Assembly and Ion Transport in Nanostructured Organic-Inorganic Solid Electrolytes.

Nanostructured solid electrolytes containing ion-conducting domains and rigid nonconducting domains are obtained by block copolymer self-assembly. Here, we report on the synthesis and characteristics of mixtures of a hybrid diblock copolymer with an organic and inorganic block: poly(ethylene oxide)-b-poly(acryloisobutyl polyhedral oligomeric silsesquioxane) (PEO-POSS) and a lithium salt. In the neat state, PEO-POSS exhibits a classical order-to-disorder transition upon heating. Dilute electrolytes exhibit a dramatic reversal; a disorder-to-order transition upon heating is obtained, indicating that the addition of salt fundamentally changes interactions between the organic and inorganic chains. At higher salt concentrations, the electrolytes primarily form a lamellar phase. Coexisting lamellae and cylinders are found at intermediate salt concentrations and high temperatures. The conductivity and shear modulus of PEO-POSS are significantly higher than that of an all-organic block copolymer electrolyte with similar molecular weight and morphology, demonstrating that organic-inorganic block copolymers provide a promising route for developing the next generation of solid electrolytes for lithium batteries.