Kulbhushan Tikoo

The salutary effects of physical exercise in mitigating metabolic disorders, particularly type 2 diabetes, are well recognized. Several studies have demonstrated that endurance training boosts the production of exercise-induced myokines, which are pivotal for interorgan communication enhancing insulin sensitivity. However, several challenges, including an incomplete understanding of underlying molecular mechanisms, hinder their therapeutic application. Here, we have identified a potential exercise-induced mediator, neuroligin-3 (NLGN3), that enhances insulin sensitivity and abrogates inflammation. Mechanistic studies in white adipocytes revealed that NLGN3 interacts with neurexin-3 (NRXN3) to modulate their function and insulin sensitivity, while in macrophages, NLGN3 engages with NRXN1 to attenuate inflammation and promote an anti-inflammatory phenotype. Administration of NLGN3 in high-fat diet (HFD)–fed mice significantly ameliorated obesity-induced visceral adipose tissue dysfunction and insulin insensitivity; however, these attributes are markedly abolished in NRXN1/3-deficient mice. In addition, elevated serum NLGN3 levels following swimming exercise training correlated with improved metabolic outcomes in HFD-fed obese diabetic mice. These findings suggest that NLGN3 may serve as a key mediator of exercise-induced metabolic benefits and highlight the NLGN3-NRXN1/3 pathway as a promising target for managing obesity-induced insulin resistance. Article Highlights: This study aimed to identify novel exercise-induced myokines and their role in improving insulin sensitivity and reducing inflammation. We identified neuroligin-3 (NLGN3) as an exercise-induced mediator that enhances insulin sensitivity and alleviates inflammation. Exercise-induced NLGN3 upregulation or recombinant NLGN3 administration improved metabolic function in high-fat diet–fed mice via neurexin-1 and -3 (NRXN1/3), but these benefits were lost upon NRXN1/3 ablation. NLGN3 emerges as a key mediator of exercise-driven metabolic benefits and a promising therapeutic target for obesity-associated insulin resistance.

Persistent lower levels of adiponectin are associated with hyperandrogenism, predisposing PCOS women to NAFLD. This study elucidated the therapeutic potential of a small molecule adiponectin receptor agonist-AdipoRon, utilizing an in-vivo PCOS rat model mimicking the manifestation of PCOS along with hepatosteatosis. Our study demonstrated that Adiporon reduced lipid accumulation in PCOS-associated NAFLD by alleviating insulin resistance & lipogenesis. AdipoRon also reversed hyperandrogenism and adiponectin deficiency in PCOS animals. In addition, AdipoRon was found to restore altered PCOS-induced hepatic circadian gene expression (Bmal1, Clock, Per3, Cry2, Reverba, and Rora). Interestingly, at the epigenetic level, global transcription activation marks, i.e., H3K4me3, H3K9/14ac, and H3K36me2, were upregulated in disease conditions. Furthermore, our ChIP data confirmed that circadian genes Bmal1, Reverba, And Rora are epigenetically regulated. ChIP assay data showed an increased H3K36 dimethylation at the Bmal1 and Rora promoter, whereas a significant decrease was observed at the Reverbα promoter in PCOS-associated NAFLD. AdipoRon ameliorated these PCOS-induced epigenetic alterations, modulating the hepatic circadian gene expression. We present the preliminary evidence illustrating the epigenetic modulation of AdipoRon, thereby regulating hepatic circadian gene expression. This study provides insights regarding the therapeutic potential of AdipoRon in PCOS-associated NAFLD, which can be of profound clinical significance.

In this study, we evaluated the impact of a potent DNA methyl transferase (DNMT) inhibitor zebularine on imiquimod‐induced psoriatic mice, revealing its efficacy in mitigating hyperproliferation and keratinocyte differentiation. Molecular analyses demonstrated a marked inhibition of p38, ERK, and JNK signaling pathways, accompanied by a notable reduction in proliferative markers such as Ki‐67. The crucial regulator of keratinocyte proliferation, Ki‐67, exhibited significant downregulation upon zebularine treatment. Moreover, significant anti‐inflammatory effects were evident through the suppression of the imiquimod‐induced p65 NF‐κB signaling cascade. This robust inhibition extended to the reduction in the cytokine storm associated with psoriasis‐like skin inflammation. Consequently, there was a restoration of the normal epidermal architecture, accompanied by a decrease in epidermal hyperplasia and splenomegaly. Importantly, zebularine's inhibition of DNMT1 underscores its role in modulating epigenetic pathways. By altering DNA methylation, zebularine might effectively inhibit the expression of genes responsible for both inflammation and proliferation, contributing to improved skin structure. These findings collectively highlight zebularine's potential as a therapeutic agent in the management of psoriasis, supported by its anti‐inflammatory effects and observed inhibition of DNMT1.

This study evaluates the therapeutic potential of Pterostilbene (PTN), a natural stilbenoid, in an imiquimod (IMQ)-induced psoriasis model. Due to PTN's poor solubility and bioavailability, a pterostilbene nano-emulsion gel (PTN-NEG) formulation (0.1% and 0.2% w/w) was developed to enhance its therapeutic efficacy. Psoriasis was induced in C57BL/6J mice by applying IMQ (62.5 mg/day) on a 5 cm² shaved dorsal skin area for 7 days. PTN-NEG was topically applied, and its effects on oxidative stress, inflammatory cytokines (IL-17, TNF-α, IL-22), NF-κB pathway activation, and keratinocyte proliferation markers (Ki-67, Bcl-xL) were assessed. The expression of dual-specificity phosphatase-1 (DUSP-1) and its role in modulating mitogen-activated protein kinase (MAPK) signaling were evaluated. Additionally, DNA methyltransferase-1 (DNMT-1) inhibition was examined to explore PTN's epigenetic impact. PTN-NEG restored antioxidant balance, reduced pro-inflammatory cytokines, inhibited NF-κB activation, and suppressed keratinocyte proliferation. It unregulated DUSP-1, modulating MAPK signaling and preventing psoriasis progression. PTN-NEG also improved epidermal structure, reduced hyperplasia, and prevented splenomegaly. Notably, PTN inhibited DNMT-1, suggesting a novel epigenetic mechanism for psoriasis. To our knowledge, this study is the first to demonstrate that PTN-NEG mitigates psoriasis through anti-inflammatory, antioxidant, and epigenetic regulatory mechanisms, highlighting its therapeutic potential in psoriasis management.

Despite the worldwide surge in the prevalence of non‐alcoholic fatty liver disease (NAFLD), however, no efficacious treatment has been clinically approved to date for combating this condition, necessitating elucidation of new therapeutic compounds. Our research presented evidence pertaining to the successful induction of NAFLD in C57BL/6 mice using a multiple liver insults paradigm. This was achieved by concurrently administering thioacetamide (100 mg/kg i.p.) along with high‐fat and high‐fructose diet (HFFrD) for 10 weeks. Following this, the beneficial effect of borneol, a bicyclic monoterpenoid, was observed in NAFLD mice in a dose‐dependent manner. Borneol administration for 4 weeks led to significant improvement in morphometric, metabolic profiles, liver functions, and oxidative stress parameters. Accumulation of lipids in hepatic tissues, which is characteristic feature of NAFLD, was confirmed by H&E, as well as oil‐red O staining was alleviated by borneol. Our investigation elucidated the pro‐autophagic effect of borneol via AMPK activation, thereby leading to the downstream activation of autophagy effector proteins, that is, Beclin1, ATG5, ATG7, and LC3 I‐II, which helps to diminish the hepatic lipid loads through augmentation of lipophagy. This study demonstrates that borneol combats NAFLD through augmentation of AMPK‐mediated lipophagy offering a promising therapeutic strategy against NAFLD.

The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential. Our findings revealed that the compound 5c significantly produced anticancer effects in vitro and in vivo by reducing the tumor growth and its size in the A549 cell-induced lung cancer xenograft model through multiple mechanisms, primarily by multi-inhibition of hTopoI/II and HDACs, especially HDAC1 via atypical binding. The present paper discusses detailed mechanistic biological investigations, structure-activity effects supported by computational docking studies, and DMPK studies and provides future scope for lead optimization and modification.

Certain medicinal plants utilized in the traditional ayurvedic system are poisonous when used raw, but are used following a detoxification process. The Ayurvedic Formulary of India (AFI) provides details about these detoxification (known as "sodhana") processes as per traditional procedures. This research endeavor aimed to uncover the fundamental principles underlying the detoxification approach applied to Plumbago zeylanica, commonly referred to as "swet chitrak", in which plumbagin is the primary toxic constituent. Both unprocessed and processed (detoxified) extracts as well as the detoxification media were subjected to analysis for secondary metabolites using different analytical techniques. This investigation revealed a reduction in plumbagin content, its conversion to epoxyplumbagin and zeylanone and a noteworthy decrease in cis- and trans-isoshinanolone during detoxification. Furthermore, it was confirmed that pure plumbagin when subjected to the same detoxification conditions, is partially converted into epoxyplumbagin, and that cis and trans-isoshinanolone showed interconversion. The current work establishes the chemical basis of the age-old traditional ayurvedic process of detoxification of P. zeylanica.

Background: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. Results: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1–6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1–6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1–6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. Conclusion: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases. Graphical