Bisphenol A (BPA) is a chemical compound found in a wide range of everyday consumer products, resulting in human exposure. BPA has been described as an endocrine disruptor, affecting different systems of the human body. Notably, nanomolar levels of BPA have been detected in human matrices, including plasma and milk. BPA exposure has been associated with the development of breast cancer, and the increase in breast cancer incidence prompted us to investigate the effects of BPA in MCF10A, a model of non-transformed mammary epithelium. Cells were treated with 10 nM BPA for 24 h to capture early molecular alterations preceding phenotypic transitions. Comprehensive transcriptomic analyses were conducted to identify differentially expressed genes and enriched signaling pathways. Subsequent validations included assessment of cytokine release, protein expression, immunofluorescence for subcellular localization of Nuclear Factor-Kappa B (NF-κB), and evaluation of actin cytoskeletal organization. Transcriptome analysis revealed enrichment in interleukin signaling and activation of the NF-κB pathway following BPA exposure. Functional assays demonstrated that BPA treatment enhanced cell motility, accompanied by increased phosphorylation of NF-κB. Inhibition of NF-κB effectively mitigated BPA-induced effects, including augmented cell motility, nuclear translocation of NF-κB, and cytoskeletal rearrangements. Notably, inhibition of the Mitogen-Activated Protein Kinase (MAPK) pathway, and to a lesser extent of the AKT pathway, counteracted BPA-induced NF-κB activation and the associated increase in cell motility. In conclusion, we show that nanomolar concentration of BPA induces significant changes in the molecular setting and behaviour of non-tranformed breast cells, activating NF-κB signalling that in turn controls inflammation, cell cycle, proliferation and cell motility. Our findings indicate that nanomolar concentrations of BPA can induce significant molecular and behavioral changes in non-transformed breast epithelial cells. These results contribute to a deeper understanding of how environmental pollutants like BPA may perturb breast epithelial cell function and potentially contribute to carcinogenesis.

The modern diet contains a substantial level of fat which is believed to be one of the leading causes of the progression of kidney disease. Several studies have already demonstrated that consumption of a high-fat diet (HFD) induces inflammation and oxidative stress, causing activation of upstream mechanisms associated with kidney injury. For the prevention of such pathological events, a change in diet or the taking of nutritional supplements are recommended as alternative treatments. One of the forms of vitamin B6, pyridoxine (PN), has been shown to be an effective antioxidant and can also inhibit the formation of advanced-glycation end products (AGEs). In this study, the protective effects of PN (100 mg/kg/day for a period of eight weeks) against HFD-induced complications in obese rats were investigated. Rats fed on a HFD developed obesity which promoted inflammation, glucose intolerance, AGE receptor upregulation, oxidative stress, and kidney dysfunction. Intervention using PN mitigated obesity-related events and the impairment of kidney function by markedly reducing oxidative stress and also restoring the activity of antioxidant enzymes. Other studies have shown that some vitamin B6 derivatives inhibit the formation of AGEs but our study shows for the first time that PN exerted an antiglycative effect in this HFD-induced obesity model. Consequently, PN could potentially be a novel supplement for obese individuals to avoid kidney injury.

Steroidal and non-steroidal anti-inflammatory drugs are widely used for treating a spectrum of inflammatory conditions; however, their systemic adverse effects hinder their usage. Therefore, alternate therapeutic strategies are required to treat inflammatory disorders. Parthenin, a lactone derived from Parthenium hysterophorus, has demonstrated anti-inflammatory activity; however, its toxic nature limits its application. We proposed modifications of parthenin to enhance its efficacy while reducing toxicity. In this context, we screened parthenin derivatives for anti-inflammatory efficacy and identified dispiro-indanedione hybrid of parthenin (DIHP) as a potent anti-inflammatory agent. Macrophages were pre-treated with DIHP followed by LPS stimulation to evaluate the in-vitro anti-inflammatory and anti-oxidant activity. We assessed in-vivo anti-inflammatory effect of DIHP in carrageenan-induced paw edema and LPS-induced sepsis model. Our findings showed that DIHP exerts negligible effect on cell viability, effectively attenuates the production of inflammatory markers (NO, TNF-α, IL-6 &IL-1β) and down-regulates NF-κB, MAPK pathways in in-vitro and in-vivo system. Additionally, DIHP inhibited LPS-induced generation of prostaglandin E2, leukotriene B4, ROS and upregulated the expression of superoxide dismutase, catalase, nuclear factor-E2-related factor 2 and peroxisome proliferator-activated receptor gamma. Furthermore, DIHP effectively reduced carrageenan-induced paw edema and curtailed the levels of liver, and kidney damage markers (AST, ALT, CRE, and BUN), protected the lung, liver and kidney against pathological damage and enhanced the survival rate in LPS-challenged mice. DIHP demonstrated comparable efficacy to dexamethasone in reducing inflammatory markers. In conclusion, our study strongly suggests that DIHP curtailed inflammation and oxidative stress by down regulating NF-κB and MAPK pathways and enhanced anti-oxidant response.

Although the antibacterial properties of glycine-rich peptides from prokaryotes to eukaryotes have been well characterized, their role in skin wound healing remains poorly understood, especially non-bactericidal glycine-rich peptides. Herein, a novel glycine-rich (46.5%) peptide (Smaragin, SRGSRGGRGGRGGGGRGGRGRSGSGSSIAGGGSRGSRGGSQYA) was identified from the skin of the tree frog Zhangixalus smaragdinus. Unlike other glycine-rich peptides, Smaragin showed no antimicrobial activity in vitro but significantly enhance wound healing in full-thickness dermal wounds in mice. In comparison with other wound healing-promoting peptides, Smaragin did not directly affect the proliferation and migration of keratinocytes, vascular endothelial cells, and fibroblasts. However, it notably increased phagocytes infiltration at the wound site by 0.5-day post-injury. Smaragin was not a direct chemoattractant for phagocytes, but it stimulated macrophages to secrete chemokines CXCL1 and CXCL2, which indirectly enhanced the migration of phagocytes, keratinocytes and vascular endothelial cells. Moreover, Smaragin promoted the polarization of macrophages from a pro-inflammatory M1-type to an anti-inflammatory M2 phenotype at the wound, which is associated with angiogenic activity. As expected, CD31, the most common analyzed marker of angiogenesis, showed a significant increase in vascular network area. Subsequent studies revealed that Smaragin promoted the chemokine level and polarization of macrophages via the TLR4/MAPK/NF-κB pathway, which enhanced the number of phagocytes and the regeneration of the epidermis and blood vessels at the wound, thereby accelerating skin wound healing in mice. These findings highlight the skin healing properties of non-bactericidal glycine-rich peptides and display the potential of Smaragin as a promising candidate for developing effective wound healing therapies.

This study investigated the photoperiod-dependent effects of eight phenolic-enriched fruit extracts on postprandial blood triacylglyceride (TAG) levels and serum cytokine and CRP levels in F344 rats after an oral lipid tolerance test (OLTT) and lipopolysaccharide (LPS)-induced inflammatory challenge, respectively. Animals were exposed to short (6-h light, L6) or long (18-h light, L18) photoperiods and orally supplemented with fruit extracts (100 mg/kg) for 2 weeks. Extracts were obtained from seasonal fruits (cherries, plums, apricots, strawberries, persimmon kakis, grapes, oranges, and pomegranates). Temporal homeostasis disruption was induced by an OLTT and LPS challenge. No differences in blood postprandial TAG levels were observed in the L6- and L12-control groups. However, in the experimental groups, the postprandial TAG response depended on the photoperiod and fruit extract consumption, mainly cherry and plum extracts in L6 (p < 0.05). In addition, control rats exposed to L6 exhibited higher blood IL-6 and TNF-α levels after inducing LPS-inflammatory response. Notably, winter-fruit and strawberry extracts were the most efficient at lowering proinflammatory cytokines. These findings show the effectiveness of specific fruit extracts in modulating postprandial TAG levels and acute inflammatory responses, being their effects photoperiod-dependent, opening the door to the design of functional ingredients specific for each season.

Inflammation plays a crucial role in the development of Polycystic Ovary Syndrome (PCOS) via modulation in Toll-like receptor (TLR) signaling pathways and over the recent couple of years, there has been an increase in the cardiovascular events associated with PCOS. To overcome this condition, the development of targeted drugs to modulate the TLR signaling pathway, a major trigger in the development of cardiovascular complications with PCOS patients is required. This review aims to explore the therapeutic targets with TLR pathways and their implications for cardiovascular management in PCOS. The chronic activation of TLRs contributes significantly to inflammation and endothelial dysfunction, which are critical factors in the development of cardiovascular diseases in patients with PCOS. Various novel therapeutic approaches are taken into consideration, such as TLR antagonists, naturally occurring TLR inhibitors like curcumin, Cryptotanshinone (CRY), quercetin, berberine, omega-3 fatty acids, and some novel targeted therapies like exosome and gene therapy. The literature findings indicated that targeting specific TLR pathways, TLR2 and TLR4 presents a promising avenue for mitigating cardiovascular complications associated with PCOS which play a major role in disease pathogenesis. The findings underscore the importance of understanding TLR-mediated mechanisms to develop effective interventions tailored to this population. This exploration not only enhances our understanding of immune responses, specific TLRs such as TLR2 and TLR4 in relation to cardiovascular health but also lays the groundwork for innovative therapeutic strategies.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.

Type 2 diabetes (T2D) is a complex metabolic disorder with a growing global prevalence, and there is a linking between inflammation in pancreatic β-cell and impaired glucose homeostasis which has emerged as a key player in the pathogenesis of T2D. Recent advances in research have provided new insights into various inflammatory signaling cascades in β-cell among which we focus on Toll-like Receptor 4 (TLR4), Nuclear Factor kappa B (NF-κB), Janus Kinase-Signal Transducer and Activator of Transcription (JAK/STAT), Platelet-Derived Growth Factor Receptor α (PDGFR-α), Stimulator of Interferon Genes (STING), and the death receptor TMEM219. TLR4 activation by pathogen- or damage-associated molecular patterns initiates NF-κB and mitogen-activated protein kinase (MAPK) cascades, promoting pro-inflammatory cytokine release and β-cell apoptosis. NF-κB acts as a central hub, integrating metabolic stress signals (e.g., glucolipotoxicity, ER stress) and amplifying inflammatory responses through crosstalk with JAK/STAT and STING pathways. Meanwhile, JAK/STAT signaling exhibits dual roles in β-cell survival and inflammation, influenced by cytokine milieu and feedback regulation. PDGFR-α, traditionally linked to β-cell proliferation, paradoxically contributes to pathological hyperplasia in obesity, while STING activation by cytosolic DNA triggers β-cell senescence and ferroptosis via IRF3/NF-κB. In this review, we synthesize recent advancements of these inflammatory signaling pathways in β-cells, and current therapeutic strategies targeting TLR4/NF-κB inhibitors, JAK/STAT modulators, STING antagonists, and the death receptor TMEM219 are discussed, alongside challenges in pathway specificity and clinical translation. Understanding these inflammatory signaling pathways and their interactions in pancreatic β-cell is essential for the development of novel therapeutic strategies to prevent or treat T2D.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) of unknown etiology, characterized by increasing incidence and intricate pathogenesis. Current FDA-approved drugs suffer from significant side effects and limited efficacy, highlighting the urgent need for innovative therapeutic agents for IPF. Natural products (NPs), with their multi-target and multifaceted properties, present promising candidates for new drug development. This review delineates the anti-fibrotic pathways and targets of various natural products based on the established pathological mechanisms of IPF. It encompasses over 20 compounds, including flavonoids, saponins, polyphenols, terpenoids, natural polysaccharides, cyclic peptides, deep-sea fungal alkaloids, and algal proteins, sourced from both terrestrial and marine environments. The review explores their potential roles in mitigating pulmonary fibrosis, such as inhibiting inflammatory responses, protecting against lipid peroxidation damage, suppressing mesenchymal cell activation and proliferation, inhibiting fibroblast migration, influencing the synthesis and secretion of pro-fibrotic factors, and regulating extracellular matrix (ECM) synthesis and degradation. Additionally, it covers various in vivo and in vitro disease models, methodologies for analyzing marker expression and signaling pathways, and identifies potential new therapeutic targets informed by the latest research on IPF pathogenesis, as well as challenges in bioavailability and clinical translation. This review aims to provide essential theoretical and technical insights for the advancement of novel anti-pulmonary fibrosis drugs.

Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation.

A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation.

Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn.

This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment.

Polycystic ovary syndrome (PCOS) and diabetes mellitus (DM) are prevalent endocrine disorders with overlapping pathophysiological mechanisms. Type 2 diabetes mellitus (T2DM) is commonly associated with PCOS, with both conditions strongly linked to insulin resistance (IR), while recent studies have also reported an increased prevalence of PCOS among women with type 1 diabetes mellitus (T1DM). This study evaluated the potential of Lythrum salicaria L. ethanol extract (LSEE) to mitigate oxidative stress (OS), inflammation, and metabolic and hormonal imbalances in separate experimental models of Streptozotocin (STZ)-induced DM and Letrozole (LET)-induced PCOS. LSEE underwent phytochemical analysis to quantify total phenolic and flavonoid content and HPLC-MS for polyphenols identification. In vitro, antioxidant capacity was investigated through FRAP, DPPH, NO, and H2O2 scavenging assays. Subsequently, in vivo, studies utilized STZ-induced DM and LET-induced PCOS rat models, with 10-day treatments of LSEE, metformin, or trolox (TX) administered by gavage. Dysregulation of hormonal profiles, ultrasound, and histological examinations confirmed PCOS development. At the end of the treatment period, serum samples were collected to assess OS markers (TOS, OSI, MDA, AOPP, 8-OHdG, NO, 3-NT, AGEs, TAR, SH) in both models. Inflammatory markers were also measured (IL-1β, NF-κB, IL-18, and Gasdermin D in DM and IL-1β, NF-κB, IL-18, and IL-10 in PCOS). Additionally, metabolic markers (glucose, lipids, TG-glucose index, liver enzymes) were assessed in DM rats, and hormones (LH, FSH, estrogen, testosterone, insulin, HOMA-IR) were determined in PCOS rats. LSEE demonstrated a high polyphenolic content and notable in vitro antioxidant activity. In vivo, it effectively reduced OS by lowering oxidant levels and enhancing antioxidant defenses, reduced inflammatory markers and blood glucose levels, and improved lipid profiles along with the TyG index and liver injury markers in diabetic rats. In PCOS rats, LSEE lowered the total oxidants, increased antioxidants, reduced LH, FSH, testosterone, and insulin, and increased estrogen levels. The effects exhibited a dose-dependent pattern, with higher doses producing more pronounced benefits comparable to those observed with metformin and TX. In conclusion, LSEE may be a promising complementary treatment for DM and PCOS.

Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry.

Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet.

This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that modulates metabolic homeostasis and cell proliferation. Inverse agonism of PPARγ is an emerging anticancer strategy, particularly for the treatment of bladder cancer. The first-in-class PPARγ inverse agonist, FX-909, is currently being studied in clinical trials for cancer treatment. However, PPARγ inverse agonists are still in the early stages of development. The discovery of compounds with novel chemical structures, potent efficacy, and favorable pharmacokinetic properties is urgently needed. In this perspective, the biological functions of PPARγ and its role in cancer pathology are introduced, and currently available PPARγ inverse agonists and their preliminary structure-activity relationships (SARs) are discussed from a medicinal chemistry viewpoint. These findings inform the development of anticancer agents that act as PPARγ inverse agonists. Furthermore, our discussion of the complex biological functions of PPARγ provides insights into the exploration of its role in various diseases.

Tumor necrosis factor-alpha (TNF-α) is a pivotal cytokine in the pathogenesis of numerous inflammatory and autoimmune diseases. Precise and sensitive detection of TNF-α is essential for both clinical applications and research endeavors. In the realm of cytokine detection, particularly TNF-α, the development of highly sensitive and specific biosensors has become a focal point. The biosensing landscape encompasses a variety of biorecognition elements, each with its unique set of characteristics. TNF inhibitors come with a significant price tag and, notably, do not yield positive responses in all patients. Despite the availability of numerous FDA-approved biologic agents (e.g., infliximab, adalimumab, certolizumab pegol, etc.) and monoclonal antibodies (e.g., adalimumab) targeting TNF-α, aptamers tailored for blocking TNF-α activities have yet to receive approval. Aptamers have rapidly gained recognition as readily available, versatile, and highly effective molecular tools for both therapeutic and diagnostic purposes in the context of TNF-alpha. In this manuscript, we explore the potential of short single-stranded DNA or RNA sequences known as aptamers as biorecognition elements in biosensors designed for the detection of TNF-α. We delve into the progress made in the development of aptamer-based TNF-α inhibitors and shed light on successful studies in this burgeoning field.

Early-life exposure to endocrine-disrupting chemicals, such as phenols and phthalates, is suspected to impact various dimensions of child health. Using a multi-outcome approach, this study aimed to estimate their cumulative effect on the child cardiometabolic, respiratory and neurodevelopmental health.

In 373 children of 3 years old from the SEPAGES cohort, a multi-domain health score was built from twenty-three health parameters. Fourteen metabolites of parabens, phenols, and phthalate/DINCH were measured several times during pregnancy (trimester 2 and 3) and infancy (2 and 12 months of age). Two mixture models, quantile g computation (q-gcomp) and Bayesian Kernel Machine Regression (BKMR), estimated associations between increased concentration of parabens, phenols, and phthalates/DINCH and the child health score.

Q-gcomp showed that the paraben mixture and the phthalate mixture were associated with a poorer health score (β = -0.11, 95% Confidence Interval (CI): -0.22, 0.00; β = -0.14, 95% CI: -0.27, -0.01, respectively), while no significant association was found for the mixture of phenols (β = -0.06, 95% CI: -0.18, 0.06). A trend for an association was observed between the whole mixture (parabens, phenols and phthalates combined) with a poorer health score (β = -0.14, 95% CI: -0.32, 0.04). Similar patterns of association, while subject to large uncertainty, have been observed with BKMR.

This study provides further evidence for the adverse health effects of early-life exposure to parabens and phthalates. Based on their potential impact on multiple areas of child health, public health policies targeting these chemical compounds are recommended.

Atherosclerosis (AS) is a disease with high global incidence and mortality rates. Currently, the treatment of AS in clinical practice carries a high risk of adverse effects and toxic side effects. The pretreatment of mesenchymal stem cells (MSCs) with drugs may enhance the bioactivity of MSC‑derived exosomes (MSC‑exos), which could be a promising candidate for inhibiting the progression of AS. The aim of the present study was to investigate the ability of exos derived from baicalin‑preconditioned MSCs (Ba‑exos) to exhibit an inhibitory effect on AS progression and to explore the potential molecular mechanisms. Exos were isolated from untreated MSCs and MSCs pretreated with Ba, and were characterized using transmission electron microscopy, nanoparticle tracking analysis and western blotting. Subsequently, Cell Counting Kit‑8 and Transwell assays, reverse transcription‑quantitative PCR, immunofluorescence, western blotting and ELISA were used to evaluate the effects of Ba‑exos on AS, and the possible molecular mechanisms. Oil Red O and Masson staining were used to assess AS pathological tissue in a high‑fat diet‑induced mouse model of AS. Notably, MSC‑exos and Ba‑exos were successfully isolated. Compared with MSC‑exos, Ba‑exos demonstrated superior inhibitory effects on the viability and migration, and the levels of inflammatory factors in oxidized low‑density lipoprotein (ox‑LDL)‑induced vascular smooth muscle cells (VSMCs). Additionally, compared with MSC‑exos, Ba‑exos significantly inhibited NF‑κB activation by upregulating sirtuin 1 (SIRT1), thereby suppressing inflammation in ox‑LDL‑induced VSMCs to a greater extent. In mice with high‑fat diet‑induced AS, Ba‑exos exhibited the ability to inhibit AS plaque formation and to alleviate AS progression by reducing the levels of inflammatory factors compared with MSC‑exos; however, the difference was not significant. In conclusion, Ba‑exos may serve as a potential strategy for treating AS by regulating the SIRT1/NF‑κB signaling pathway to suppress inflammation.

Recent research has extensively explored the critical role of energy metabolism in shaping the inflammatory response and polarization of macrophages in obesity. This rapidly growing field emphasizes the need to understand the connection between metabolic processes that support macrophage polarization in obesity. Although most published research in this area has focused on glucose and fatty acids, how the flux through other metabolic pathways (such as ketone and amino acid oxidation) in macrophages is altered in obesity is not well defined. This review summarizes the main alterations in uptake, storage, and oxidation of oxidative substrates (glucose, fatty acids, ketone bodies, and amino acids) in macrophages and how these alterations are linked to macrophage polarization and contribution to augmented inflammatory markers in obesity. The review also discusses how oxidative substrates could modulate macrophage energy metabolism and inflammatory responses via feeding into other nonoxidative pathways (such as the pentose phosphate pathway, triacylglycerol synthesis/accumulation), via acting as signalling molecules, or via mediating post-translational modifications (such as O-GlcNAcylation or β-hydroxybutyrylation). The review also identifies several critical unanswered questions regarding the characteristics (functional and metabolic) of macrophages from different origins (adipose tissue, skeletal muscle, bone marrow) in obesity and how these characteristics contribute to early vs late phases of obesity. We also identified a number of new therapeutic targets that could be evaluated in future investigations. Targeting macrophage metabolism in obesity is an exciting and active area of research with significant potential to help identify new treatments to limit the detrimental effects of inflammation in obesity.

This study aims to investigate the potential protective effect of levomilnacipran (LVM) against cyclophosphamide (CPA)-induced hepatotoxicity by targeting α-Klotho/TLR4/p38-MAPK/NF-κB p65 and Caspase-3-dependent apoptosis signaling pathways.

The toxicity of CPA was assessed using biochemical analysis of the serum hepatotoxicity parameters (AST, ALT, and direct bilirubin) and histopathological examination. Hepatic MDA and SOD were evaluated. The ELISA procedure was employed to evaluate the levels of hepatic TNF-α, IL-1β, and IL-18, hepatic caspase-3, and serum α-Klotho. The expression of hepatic TLR4 and NF-κB p65 was examined using an immunohistochemical technique. A western blot assay was used to determine the expression of MYD88, and p38-MAPK.

LVM abrogated CPA-induced hepatotoxicity by reducing the elevated hepatoxicity markers and mitigating the histopathological aberrations. It also lowered MDA content and increased SOD activity. Furthermore, it reduced TNF-α, IL-1β, and IL-18 contents, as well as caspase-3 activity. Additionally, LVM diminished TLR4, MYD88, NF-κB p65, and p38 MAPK expression and boosted the levels of α-Klotho.

LVM alleviated hepatic injury generated by CPA via downregulating TLR4/p38 MAPK/NF-κB p65 signaling cascade through the participation of α-Klotho, as well as inhibiting caspase-3-driven apoptosis.

Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.

The pathophysiology associated with type 2 diabetes mellitus (T2DM) includes insulin resistance, increased oxidative stress, a pro-inflammatory macrophage population, and dysfunction of pancreatic β cells in the islets of Langerhans, along with hepato- and nephro-toxicity. In this study, an injectable glucose-responsive hydrogel (Diabogel) was developed using alginate and 3-aminophenyl boronic acid to deliver modified glucagon-like peptide-1, insulinoma cell-derived extracellular vesicles, and telmisartan. Diabogel demonstrated cytocompatibility, decreased reactive oxygen species, enhanced insulin synthesis, and improved glucose uptake in vitro. In a high-fat diet/streptozotocin-induced murine model of T2DM, Diabogel lowered blood glucose levels, maintained body weight, and increased insulin expression. Furthermore, it promoted an anti-inflammatory microenvironment in the pancreas by regulating macrophage phenotype and the expression of NF-κB, supported cellular proliferation, and restored the pancreatic islets. In addition, Diabogel treatment significantly lowered the serum levels of pro-inflammatory cytokines and enhanced anti-inflammatory cytokines. Interestingly, Diabogel treatment also lowered diabetes-associated hepato- and nephro-toxicity. Taken together, Diabogel may serve as a potential approach for the treatment of T2DM, regulating blood glucose levels, restoring pancreatic β cell function, and reducing hepatic and renal toxicities.

Previous studies have suggested that women with higher follicle-stimulating hormone (FSH) levels have a greater incidence of osteoarthritis (OA) compared to women with lower FSH despite normal estrogen levels. Our previous studies also showed that FSH has a negative effect on cartilage in postmenopausal OA. However, no studies have investigated the effect of FSH on the synovium. Here, we showed that the FSH receptor (FSHR) is expressed on RAW264.7 cells and BMDM (Bone Marrow-Derived Macrophages), and found that FSH stimulation promotes the production and secretion of inflammatory cytokines in synovial macrophages. In RAW264.7 cells, FSH stimulation enhances phosphorylation and nuclear translocation of P65, suggesting the activation of NFκB signaling, while the knockdown of FSHR eliminates the proinflammatory effect of FSH. To further validate these results, we used an ovariectomy mouse model supplemented with FSH and estrogen, and a mouse model with FSH neutralization. We noted that FSHR was expressed on mouse synovial joint membranes. Furthermore, in ovariectomy mice supplemented with estrogen and treated with FSH, synovial macrophages were significantly increased, while the opposite was the case in the FSH neutralizing group, which suggest that FSH triggers an inflammatory response in the synovial tissue in mice. Taken together, our results indicate that FSH is an important regulator in synovial inflammation via NFκB signaling activation and, to some extent, appears to accelerate the development of osteoarthritis.

Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.

RING finger protein 2 (RNF2) has been shown to promote tumor growth in various cancer types. However, the immune regulatory function of RNF2 in the tumor microenvironment is unclear. Here, we report that upregulation of RNF2 is positively correlated with the tumor burden and poor prognosis in hepatocellular carcinoma patients and fosters an immunosuppressive microenvironment with increased MDSCs recruitment, and reduced T cell activation. Mechanistically, RNF2 binds with TRAF2 and directly mediates K63-linked TRAF2 ubiquitination. This modification of TRAF2 enables NF-κB hyperactivation in tumor cells, which subsequently induces CXCL1 transcription to enhance MDSCs migration. Furthermore, RNF2 knockout improves responsiveness to anti-PD-1 therapy in immunocompetent mice, as evidenced by enhancing infiltration of CD8+T cells into the tumor and a reduction in MDSC levels. Collectively, our experiments support that perturbing RNF2 and targeting MDSCs may afford therapeutic opportunities for hepatocellular carcinoma interception and prevention.

Western-style dietary patterns have been linked with obesity and associated metabolic disorders and gut dysbiosis, whereas prudent dietary and snacking choices mitigate these predispositions. Using a multi-omics approach, we investigated how almond snacking counters gut imbalances linked to adiposity and an average American Diet (AAD). Fifteen adults with overweight or obesity underwent a randomized, crossover-controlled feeding trial comparing a 4-week AAD with a similar isocaloric diet supplemented with 42.5 g/day of almonds (ALD). Almond snacking increases functional gut microbes, including Faecalibacterium prausnitzii, while suppressing opportunistic pathogens, thereby favorably modulating gut microecological niches through symbiotic and microbe-metabolite interactions. Moreover, ALD elevates health-beneficial monosaccharides and fosters bacterial consumption of amino acids, owing to enhanced microbial homeostasis. Additionally, ALD enhances metabolic homeostasis through a ketosis-like effect, reduces inflammation, and improves satiety-regulating hormones. The findings suggest that prudent dietary choices, such as almond snacking, promote gut microbial homeostasis while modulating immune metabolic state.

Oocyte quality can affect mammal fertilization rate, early embryonic development, pregnancy maintenance, and fetal development. Oxidative stress induced by reactive oxygen species (ROS) is one of the most important causes of poor oocyte maturation in vitro. To reduce the degree of cellular damage caused by ROS, supplementation with the antioxidant N-Acetyl-L-cysteine (NAC) serves as an effective pathway to alleviate glutathione (GSH) depletion during oxidative stress. This study investigated the effects of NAC supplementation during in vitro maturation of goat oocytes and explored the molecular mechanisms of maturation by transcriptome sequencing of MⅡ oocytes. The results showed that 1.5 mM NAC significantly increased the rates of oocyte maturation and cumulus cell expansion and improved the subsequent development of embryos. During the subsequent culture of parthenogenetically activated embryos, 1.5 mM NAC significantly increased the division rate of oocytes and blastocyst rate. It also reduced the accumulation of ROS, increased the level of GSH, alleviated oxidative stress, and enhanced the antioxidant capacity and cell metabolic activity. Transcriptome sequencing results revealed that NAC treatment significantly increased the expression of SIRT1, GGCT, and MITF genes related to the cellular antioxidant system, as well as the IDH3G gene related to energy metabolism, and decreased the expression of CASP8, FOS, and MMP1 genes related to apoptosis and cell invasion, as well as the CCL2. and CXCL8 genes related to the inflammatory response. In conclusion, the findings suggest that NAC supplementation significantly reduces oxidative stress, improves antioxidant capacity and metabolic activity, promotes oocyte maturation, and improves oocyte quality.

The cellular enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is required for NF-κB to activate inflammatory and immune response gene expression. NF-κB is also an important transcription factor in HIV-1 gene expression during active replication and latency reactivation. Therefore, enhancing NF-κB signaling is an alternative for HIV-1 latency reactivation, but significant systemic side effects related to the NF-κB role in inflammatory and immune responses are predictable. To verify this prediction, we determined whether PARP-1 is required in NF-κB-dependent HIV-1 gene expression in a human CD4+ T lymphoblastoid cell line (SUP-T1) and HEK 293T cells. Our findings indicated that PARP-1 knockout does not impair HIV-1 infection or gene expression. Specifically, NF-κB-dependent HIV-1 gene expression was not impaired by PARP-1 deficiency, highlighting an important transcriptional regulatory difference between HIV-1 and inflammatory and immune activation genes. Our findings define a negligible role of PARP-1 in HIV-1 gene expression, suggesting that PARP-1 antagonism could ameliorate the expected inflammatory response with latency-reactivating agents that act through the NF-κB signaling pathway.

Metabolically unhealthy obesity (MUO) poses significant health risks, including increased susceptibility to type 2 diabetes and cardiovascular diseases. Hesperetin is a key bioactive compound found in citrus fruits. Previous studies have shown that hesperetin can correct metabolic abnormalities and mitigate the progression of various metabolic disorders, but the underlying mechanisms remain unclear. Here, we explored the impact of hesperetin on MUO using ob/ob mice and investigated its potential pharmacological mechanisms. The present data indicated that administration of hesperetin for 12 weeks led to notable improvements in metabolic parameters, including reduced fasting blood glucose, fasting insulin levels, and the HOMA-IR index in ob/ob mice. Glucose and insulin tolerance tests demonstrated that hesperetin effectively enhanced insulin sensitivity, with high-dose effects comparable to metformin. Hesperetin treatment decreased inguinal white adipose tissue (iWAT) weight and improved insulin signaling by increasing AKT phosphorylation. Additionally, it reduced the expression of pro-inflammatory cytokines (Il-6 and Il-1β), chemokine Ccl2 and its receptor Ccr2, and macrophage activation markers Nos2 and Ptgs2 within iWAT of ob/ob mice, likely by inhibiting NF-κB activation and macrophage-mediated inflammation. In vitro studies further confirmed hesperetin's anti-inflammatory effects in LPS-stimulated macrophages, where it suppressed cytokine production and NF-κB signaling. Hesperetin also impaired CCL2-induced macrophage chemotaxis, reducing migration velocity and distance. Mechanistically, hesperetin directly interacts with and inhibits IKKβ kinase activity by binding to key residues (LEU21, VAL465, CYS99, and GLU97) and stabilizing the complex, as demonstrated by molecular docking and molecular dynamics simulations. These findings underscore hesperetin's therapeutic potential in mitigating metabolically unhealthy obesity, obesity-induced insulin resistance, and inflammation through direct modulation of the IKKβ and NF-κB pathways.

Transcription factor specificity protein (SP2) regulates various cellular functions, including cell division, proliferation, invasion, metastasis, differentiation, and death; however, its role has not been studied in prominent medical conditions including diabetic encephalopathy (DE). Therefore, this study addressed its physiological function in the context of DE to also better characterize its possible use in the context of predictive, preventive, and personalized medicine (PPPM).

The anti-inflammatory and anti-DE actions of SP2 were investigated using three animal models (SP2-/- mice, streptozocin-treated mice, and db/db mice) and two cell lines (primary cultured hippocampal neurons and N2A cells). The db/db mice were a leptin deficiency model often used to study type 2 diabetes. An equal number of males and females (8-12 weeks of age) was selected. Behavioral changes in mice were determined using both morris water maze (MWM) test and Y-maze (YM) test. The alterations in oxidative stress and inflammation were examined via immunofluorescence assay, flow cytometry, co-immunoprecipitation, and immunoblotting.

Mechanistically, SP2-knockout (SP2-/-) mice showed dysregulation of insulin/glucose homeostasis, neuroinflammation, and cognitive loss. Otherwise, in db/db DE mice and STZ-induced DE mice, neuroinflammation, neuroapoptosis, and cognitive decline were significantly attenuated when SP2 was overexpressed in the brain. On the other hand, SP2 overexpression activates the insulin signaling pathway and improves insulin resistance via targeting X-box binding protein 1 (XBP1) in neurons. Moreover, SP2 overexpression significantly reduces oxidative stress by interacting with XBP1 and nuclear factor erythroid 2-related factor 2 (NRF2) in neurons. Furthermore, SP2 enhances the suppression of inflammatory response triggered by nuclear factor kappa B (NFκB) through the recruitment of XBP1 and NRF2 and by the in vitro inactivation of IκB kinase (IKK) complex.

These findings highlight SP2 as key biological targets for DE and reveal the infammation-related potential molecular mechanism of DE, which is helpful for early risk prediction and targeted prevention of DE. In conclusion, our study provides a new perspective for developing a PPPM method for managing DE patients.

The online version contains supplementary material available at 10.1007/s13167-024-00394-0.

In the present study, we developed and synthesized novel hydrangenol derivatives and featured their anti-inflammatory activities. Especially, a synthetic derivative 11 (compound 11), which possesses the 4H-1-benzopyran-4-one moiety, 5-hydroxyl group in A-ring, and 4'-hydroxyl group in B-ring, most dominantly downregulated nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. In addition, compound 11 suppressed the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) expression by inhibiting nuclear factor kappa-B (NF-κB), activator protein 1 (AP-1), and signal transducer and activator of transcription protein (STAT) pathways in LPS-provoked RAW264.7 macrophages. Additionally, we confirmed that compound 11 had better plasma stability than hydrangenol with a plasma-labile δ-valerolactone moiety. In carrageenan-induced rats, compound 11 potently reduced paw inflammation (as measured by paw volume, width, and thickness) by inhibiting the iNOS and COX-2 expression in paw tissue, thereby reducing inflammatory pain. All things considered, as compound 11 shows anti-inflammatory and antinociceptive properties, converting metabolically unstable hydrangenol into a stable compound 11 could be a promising strategy for developing new drugs.

Aging is a natural process that affects the majority of organs within the organism. The liver, however, plays a pivotal role in maintaining the organism's homeostasis due to its robust regenerative and metabolic capabilities. Nevertheless, the liver also undergoes the effects of aging, which can result in a range of metabolic disorders. The function of extracellular vesicles and the signals they convey represent a significant area of interest within the field of ageing research. However, research on liver ageing from the perspective of EVs remains relatively limited.

In the present study, we extracted liver tissue small extracellular vesicles (sEVs) of mice at different ages and performed transcriptome and proteome analyses to investigate the senescence-associated secretory phenotype (SASP) and mechanisms. sEVs in the older group were rich in miR-23b-3p, which was abundant in the sEVs of induced aging cells and promoted cell senescence by targeting TNF alpha induced protein 3 (Tnfaip3). After injecting adeno-associated virus (AAV) expressing miR-23b-3p into mice, the liver of mice in the experimental group displayed a more evident inflammatory response than that in the control group. Additionally, we found elevated miR-23b-3p in blood-derived-sEVs from patients with familial hypercholesterolemia.

Our findings suggest that miR-23b-3p plays a pivotal role in liver aging and is associated with abnormal lipid metabolism. The upregulation of miR-23b-3p in liver EVs may serve as a potential biomarker for aging and metabolic disorders. Targeting miR-23b-3p could provide new therapeutic strategies for ameliorating age-related liver dysfunction and associated metabolic abnormalities.

Herein, a water-soluble Ganoderma tsugae acidic polysaccharide (GTP-2) was isolated and purified from the fruiting bodies of G. tsugae. GTP-2 has a molecular weight of 13.059 kDa, composed of →3)-β-d-Glcp-(1 → 3)-β-d-Glcp-(1 → 4)-GlcpUA-(1 → 4)-β-d-Glcp-1→ glucan backbone and branches ending with β-d-Glcp-(1 → 6)-β-d-Glcp-(1→, which is attached at C6 of →3,6)-β-d-Glcp-(1→. Subsequently, the antiatherosclerotic activity of GTP-2 was examined in apolipoprotein E deficient (ApoE-/-) mice fed with high-fat diet, and its potential mechanism of action was investigated. GTP-2 ameliorated blood lipid levels (total cholesterol, triglycerides, and low-density lipoprotein), while improving the serum levels of high-density lipoprotein. Furthermore, GTP-2 alleviated the atherosclerotic lesions and reduced levels of inflammatory cytokines. Analysis of the gut microbiota revealed that GTP-2 enhanced the abundance of beneficial bacteria (Lactobacillu and Akkermansia). The serum metabolite composition was further altered, with a significant reduction in octadecanoic acid level. GTP-2 regulated the nuclear factor kappa-B signaling pathway by inhibiting macrophage polarization to M1 phenotype. Collectively, these findings support the potential use of GTP-2 as an antiatherosclerotic therapy.

Pancreatic β-cells are susceptible to inflammation, leading to decreased insulin production/secretion and cell death. Previously, we have identified a novel triceps-derived myokine, DECORIN, which plays a pivotal role in skeletal muscle-to-pancreas interorgan communication. However, whether DECORIN can directly impact β-cell function and susceptibility to inflammation remains unexplored.

The effect of DECORIN was assessed in sorted human and rat β-cell and human islets from healthy and type 2 diabetes (T2D) donors. We assessed glucose-stimulated insulin secretion (GSIS) and cytokine-mediated cell death. We then challenged sorted β-cells and human islets with inflammatory cytokines commonly associated with diabetes, such as tumor necrosis factor-α (TNF-α) alone or in combination with interleukin1-β (IL1-β) and interferon-γ (cytomix).

DECORIN enhanced cell spreading and the localization of phosphorylated FAK at adhesions, promoting GSIS under basal conditions. It also increased insulin granule docking adhesion length and countered the inhibitory effects of TNF-α on adhesion and actin remodeling at the β-cell surface, resulting in preserved GSIS. DECORIN protected from cell death in sorted β-cells and islets challenged with TNF-α alone or TNF-α + cytomix. Interestingly, DECORIN increased both insulin content and secretion in human islets from T2D individuals. Additionally, DECORIN treatment reversed the impaired gene expression caused by T2D and enhanced the expression of genes essential for islet function and metabolism.

Collectively, we have shown that DECORIN had a beneficial effect on human islets, protecting them from inflammation-induced cell death. In T2D islets, DECORIN restores islet function and reverses the expression of T2D-associated genes. Based on our data, we propose that DECORIN is a promising therapeutic target for diabetes-associated inflammation and diabetes itself.

NASH confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed the safety and efficacy of Meriva in NASH.

In this double-blind trial, 52 patients with biopsy-proven NASH (71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a chronic kidney disease) were randomized 1:1 to receive Meriva 2 g/d or placebo for 72 weeks. The primary endpoint was NASH resolution with no worsening of fibrosis. The secondary endpoints included a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant (ie, stage ≥F2) fibrosis and CKD; and improvement in renal, glucose, lipid, and inflammatory parameters. We also explored the treatment effect on hepatic activation of NF-kB, a key proinflammatory transcription factor and a major target of curcumin. Fifty-one patients (26 on Meriva and 25 on placebo) completed the trial. Sixteen (62%) patients on Meriva versus 3 (12%) patients on placebo had NASH resolution (RR = 5.33 [95% CI = 1.76-12.13]; p = 0.003). Thirteen (50%) patients on Meriva versus 2 (8%) patients on placebo had ≥1 stage fibrosis improvement (RR = 6.50 [1.63-21.20]; p = 0.008). Eleven (42%) patients on Meriva versus 0 (0%) on placebo had regression of significant liver fibrosis (RR = 18.01 [1.43-36.07]; p = 0.02). Hepatic NF-kB inhibition predicted NASH resolution (AUC = 0.90, 95% CI = 0.84-0.95) and fibrosis improvement (AUC = 0.89, 95% CI = 0.82-0.96). Thirteen (50%) patients on Meriva versus 0 (0%) on placebo had chronic kidney disease regression (RR = 10.71 [1.94-17.99)]; p = 0.004). Compared with placebo, Meriva improved eGFR (difference in adjusted eGFR change: +3.59 [2.96-4.11] mL/min/1.73 m 2 /y, p = 0.009), fasting glucose(-17 mg/dL; 95% CI = -22, -12), HbA1c (-0.62%; 95% CI = -0.87%, -0.37%), LDL-C (-39 mg/dL; 95% CI = -45, -33), triglycerides (-36 mg/dL, 95% CI = -46, -26), HDL-C (+10 mg/dL; 95% CI = +8, +11), and inflammatory markers. Adverse events were rare, mild, and evenly distributed.

In patients with NASH, Meriva administration for 72 weeks was safe, well-tolerated, and improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.

Insulin resistance is major factor in the development of metabolic syndrome and type 2 diabetes (T2D). We extracted 430 genes from literature associated with both insulin resistance and inflammation. The highly significant pathways were Toll-like receptor signaling, PI3K-Akt signaling, cytokine-cytokine receptor interaction, pathways in cancer, TNF signaling, and NF-kappa B signaling. Among the 297 common genes in all datasets of various T2D patients' tissues including blood, muscle, liver, pancreas, and adipose tissues, 71% and 60% of these genes were differentially expressed in pancreas (GSE25724) and liver (GSE15653), respectively. A total of 169 genes contain highly conserved motifs for various transcription factors involved in immune response, thereby suggesting coordinated expression. Through co-expression analysis, we obtained three modules. The respective modules had 78, 158, and 55 genes, and TRAF2, HMGA1, and RGS5 as hub genes. Further, we used the BioNSi pathways simulation tool and identified the following five KEGG pathways perturbed in four or more tissues, namely Toll-like receptor signaling pathway, RIG-1-like receptor signaling pathway, pathways in cancer, NF-kappa B signaling pathway, and insulin resistance pathway. The genes NFKBIA and IKBKB are common to all these five pathways. In addition, using the NF-κB computational activation model, we identified that the reversal of NF-κB constitutive activation through overexpression of NFKB1 (P50 homodimer), PPARG, PIAS3 could reduce insulin resistance by almost half of its original value. To conclude, co-expression studies, gene expression network simulation, and NF-κB computational modeling substantiate the causal role of NF-κB pathway in insulin resistance. These results taken together with other published evidence suggests that the TNF-TRAF2-IKBKB-NF-κB axis could be explored as a potential target in combination with available metabolic targets in the management of insulin resistance.

The online version contains supplementary material available at 10.1007/s13205-024-04202-4.