Seema Singh

Introduction: Chronic alcohol consumption is common among people living with HIV (PLWH) and exacerbates HIV‐associated neurocognitive disorders (HAND). HIV‐1 transactivator of transcription (Tat) and ethanol synergistically promote neuroinflammation, but the underlying molecular mechanisms remain unclear. This study aimed to determine whether endoplasmic reticulum (ER) stress regulates astrocytic NLRP6 inflammasome activation in response to HIV Tat and ethanol coexposure. Methods: Mouse primary astrocytes were exposed to HIV Tat (50 ng/mL) and ethanol (50 mM), individually or in combination. Astrocyte activation, NLRP6 inflammasome signaling, proinflammatory cytokine production, and ER stress responses were assessed using western blotting, immunocytochemistry, qPCR, and ELISA. ER stress was inhibited using 4‐phenylbutyric acid (4‐PBA), and NLRP6 was silenced using siRNA to define pathway hierarchy. Results: Combined HIV Tat and ethanol exposure markedly increased astrocytic activation, NLRP6 expression, caspase‐1 cleavage, and IL‐1β and IL‐18 production compared with individual treatments. Coexposure also significantly induced ER stress markers BiP, ATF6, and phosphorylated eIF2α. Pharmacological inhibition of ER stress suppressed NLRP6 inflammasome activation and astrocytic reactivity, whereas NLRP6 knockdown attenuated inflammatory signaling without affecting ER stress markers, indicating ER stress acts upstream of NLRP6. Conclusion: These findings identify an ER stress–NLRP6 inflammasome axis as a potential mechanism underlying HIV Tat and ethanol‐induced astrocytic neuroinflammation, providing mechanistic insight into alcohol‐associated neuroinflammatory processes relevant to HAND.

Extracellular vesicles (EVs) serve as conduits for intercellular communication, under both physiological and pathological contexts. During disease pathogenesis, microglia‐derived EVs (MEVs) play a key role in transferring pathological cargo to the recipient cells, thereby modulating their phenotype and function. The current study was aimed to explore how HIV Transactivator of transcription (Tat) protein‐mediated dysregulated autophagy/ferritinophagy contributes to the expression and release of ferroptotic mediators in Tat‐activated MEVs. Exposure of microglial BV2 cells to HIV Tat for 48 h resulted in significantly increased expression of the ferroptosis mediators—FTH1 and ACSL4 in Tat‐MEVs. Reciprocally, pretreatment of microglia with the ferroptosis inhibitors abrogated the expression and release of these mediators in both microglial cells as well as in Tat‐MEVs, without affecting the overall MEV release. Furthermore, inhibition of autophagic flux with bafilomycin A1 resulted in potentiation of HIV Tat‐mediated expression and release of ferroptosis mediators in Tat‐MEVs. In contrast, treatment of cells with the autophagy inducer‐ rapamycin, attenuated these effects. Exposure of BV2 cells to HIV Tat also resulted in increased expression of the ferritinophagy adaptor protein NCOA4, an effect mitigated by both ferroptosis inhibitors and rapamycin. These findings were also validated in brain lysates as well as brain‐derived MEVs isolated from HIV Transgenic rats. Collectively, this study highlights the role of dysregulated autophagy in modulating both HIV Tat‐induced ferroptosis and the release of ferroptosis cargo in MEVs. These findings advance our understanding of the molecular mechanism(s) driving HIV‐associated neuropathology.

Extracellular vesicles (EVs) constitute a heterogeneous group of membrane-derived particles generated through distinct biogenesis pathways, each regulated by precise molecular mechanisms. They carry a diverse array of cargo that reflects the physiological or pathological state of their parent cells. Their classification continues to evolve, as advances in isolation and characterization techniques have revealed novel vesicle subpopulations beyond the traditional categories of microvesicles, and apoptotic bodies, further highlighting the complexity of the EV landscape. Within the central nervous system (CNS), neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells actively release EVs that contribute to intercellular communication. Growing evidence demonstrates that these vesicles play critical roles in neuroinflammation and neurodegeneration by transporting bioactive molecules that influence disease pathways. Their ability to cross the blood–brain barrier allows CNS-derived EVs to be detected in peripheral fluids, making them promising candidates for noninvasive biomarkers. Moreover, EVs are increasingly being explored as therapeutic tools due to their stability, biocompatibility, and capacity to deliver targeted molecular cargo. In this review, we provide a comprehensive overview of EV biogenesis and release mechanisms in CNS cell types, discuss their emerging functions in neuroinflammatory and neurodegenerative disorders, and summarize current advances in EV-based diagnostics and therapeutic approaches, including ongoing clinical trials.

NeuroHIV affects approximately 30–60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities.

HIV-1 infection in the era of combined antiretroviral therapy has been associated with premature aging. Among the various features of HIV-1 associated neurocognitive disorders, astrocyte senescence has been surmised as a potential cause contributing to HIV-1-induced brain aging and neurocognitive impairments. Recently, lncRNAs have also been implicated to play essential roles in the onset of cellular senescence. Herein, using human primary astrocytes (HPAs), we investigated the role of lncRNA TUG1 in HIV-1 Tat-mediated onset of astrocyte senescence. We found that HPAs exposed to HIV-1 Tat resulted in significant upregulation of lncRNA TUG1 expression that was accompanied by elevated expression of p16 and p21, respectively. Additionally, HIV-1 Tat-exposed HPAs demonstrated increased expression of senescence-associated (SA) markers—SA-β-galactosidase (SA-β-gal) activity and SA-heterochromatin foci—cell-cycle arrest, and increased production of reactive oxygen species and proinflammatory cytokines. Intriguingly, gene silencing of lncRNA TUG1 in HPAs also reversed HIV-1 Tat-induced upregulation of p21, p16, SA-β gal activity, cellular activation, and proinflammatory cytokines. Furthermore, increased expression of astrocytic p16 and p21, lncRNA TUG1, and proinflammatory cytokines were observed in the prefrontal cortices of HIV-1 transgenic rats, thereby suggesting the occurrence of senescence activation in vivo. Overall, our data indicate that HIV-1 Tat-induced astrocyte senescence involves the lncRNA TUG1 and could serve as a potential therapeutic target for dampening accelerated aging associated with HIV-1/HIV-1 proteins.

Diabetes mellitus (DM) is a metabolic disorder in which the ability to produce insulin is defective or there is resistance to the action of insulin at the cellular level culminating in raised levels of glucose in the blood. The option to look for alternative antidiabetics from plant origin arose as the conventional antidiabetic drugs were expensive and tagged with a variety of associated side effects. The potential of antidiabetic plants was explored and their active principles isolated which generally contained alkaloids, flavonoids, steroids, and organic acids. The antidiabetic plants not only delayed the diabetic complications but also proved to be rich sources of antioxidants which already had an established role to play in delaying the onset of this disease. Latest molecular techniques like omics help in providing in-depth knowledge about the active constituents of the medicinal plants, their characterization, pharmacokinetics, toxicological studies, and most importantly the standardization and quality control of the antidiabetic plant derivatives. Recent molecular techniques like DNA sequencing, DNA fingerprinting, and DNA microarrays help us in the identification of the biomedical resources 126and extend their help in differentiating simultaneous molecular effects of mixtures on various chemical agents. Thus, omics technology helps in the standardization and modernization of antidiabetic medicinal plants.

Despite the effectiveness of combined antiretroviral therapy (cART) in suppressing virus replication, chronic inflammation remains one of the cardinal features intersecting HIV-1, cART, drug abuse, and likely contributes to the accelerated neurocognitive decline and aging in people living with HIV-1 (PLWH) that abuse drugs. It is also estimated that ~30–60% of PLWH on cART develop cognitive deficits associated with HIV-1-associated neurocognitive disorders (HAND), with symptomatology ranging from asymptomatic to mild, neurocognitive impairments. Adding further complexity to HAND is the comorbidity of drug abuse in PLWH involving activated immune responses and the release of neurotoxins, which, in turn, mediate neuroinflammation. Premature or accelerated aging is another feature of drug abusing PLWH on cART regimes. Emerging studies implicate the role of HIV-1/HIV-1 proteins, cART, and abused drugs in altering the inflammasome signaling in the central nervous system (CNS) cells. It is thus likely that exposure of these cells to HIV-1/HIV-1 proteins, cART, and/or abused drugs could have synergistic/additive effects on the activation of inflammasomes, in turn, leading to exacerbated neuroinflammation, ultimately resulting in premature aging referred to as “inflammaging” In this review, we summarize the current knowledge of inflammasome activation, neuroinflammation, and aging in central nervous system (CNS) cells such as microglia, astrocytes, and neurons in the context of HIV-1 and drug abuse.

Heracleum candicans belongs to the family Apiaceae, and is categorized as a vulnerable Himalayan medicinal herb. Due to its diverse chemical constituents it is having an increased demand in pharmaceutical industries, especially in international market. This herb is commercially useful as a major source of Xanthotoxin which is widely used to treat leucoderma and to prepare suntan lotions. During the present study direct shoot regeneration has been achieved from hypocotyl explants on MS (Murashige and Skoog, 1962) medium fortified with different plant growth hormones. Shoot bud regeneration was achieved on media augmented with auxins like Indoleacetic acid (IAA), 2,4 -dichlorophenoxyacetic acid (2,4-D) and cytokinins like Kinetin (KN) and Benzyladenine (BA). Due to the presence of 2,4-D in the medium friable callus development has been reported in some cultures. Regenerated shoots were transferred to MS basal medium for root induction and later on successfully acclimatized in vermiculite under controlled conditions. This is the first report on plant regeneration from hypocotyl explants of H. candicans and could be used as an alternative for large scale propagation and conservation of this vulnerable plant species. Key words: Apiaceae, explants, callus, auxins, cytokinins, MS medium.