Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.

OBJECTIVES: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. METHODS: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. RESULTS: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. CONCLUSIONS: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. TRIAL REGISTRATION NUMBER: NCT04991753.

Status of vector protection measures and awareness regarding vector borne diseases in families residing in a Nirmal Gram Puraskar village in India.

BACKGROUND OBJECTIVES: Mosquito-borne diseases are increasing problems in various parts of the world, causing high mortality and morbidity for humans. This study was done to assess the vector protection measures taken by rural BPL (below-poverty-line) families, and to assess the awareness about vector-borne diseases along with Total Sanitation Campaign (TSC) in rural BPL families. METHODS: A cross-sectional study was conducted in rural areas, which won Nirmal Gram Puraskar Award, among 96 BPL families for a period of three months. These families (every 5th) were selected by systematic random sampling until we reached a sample size. Basic sociodemographic details, status of vector protection measures, solid waste management, vector- borne diseases and total sanitation campaign details were collected from the study participants. Pre-tested, semi-structured questionnaire was applied to the head of the families which included sanitation status at home by a house-to-house visit. The data collected was analysed using SPSS version 20. Data was presented as frequency, percentages, mean and SD. RESULTS: Among 96 families (454 adults and children) studied 84 (87.5%) were males and 12 (12.5%) were females. 291 (64.1%) were using one or the other mosquito protection measures, 52 (54.2%) were using bednets and 23 (23.9%) were using coils. 12 families (12.5%) were not using any mosquito protection measures. In our study, 66 (68.8%) families had individual household latrine (IHHL) and 50 (52.1%) had open drainage. Even though 314 participants had an access to individual household latrine, 20 (6.36%) had practice of open-air defecation compared to 127 (90.7%) who practiced open-air defecation without an access to individual household latrine. When asked about the awareness regarding vector-borne diseases, 56 (58.3%) were aware about chikungunya, 47 (48.9%) about dengue, 46 (47.9%) about malaria, 14 (14.6%) and only 5 (5.2%) families were aware about Japanese encephalitis. In this study, 37 (38.5%) were aware about the total sanitation campaign and 40 (41.6%) were aware about government support for sanitation. INTERPRETATION CONCLUSION: While there is a general awareness of vector-borne diseases, the implementation of vector protection measures is not uniform across the village. There is a need for targeted interventions to improve the effectiveness of vector protection measures and increase awareness among the community.

Decoding Immuno-Competence: A Novel Analysis of Complete Blood Cell Count Data in COVID-19 Outcomes.

BACKGROUND: While 'immuno-competence' is a well-known term, it lacks an operational definition. To address this omission, this study explored whether the temporal and structured data of the complete blood cell count (CBC) can rapidly estimate immuno-competence. To this end, one or more ratios that included data on all monocytes, lymphocytes and neutrophils were investigated. MATERIALS AND METHODS: Longitudinal CBC data collected from 101 COVID-19 patients (291 observations) were analyzed. Dynamics were estimated with several approaches, which included non-structured (the classic CBC format) and structured data. Structured data were assessed as complex ratios that capture multicellular interactions among leukocytes. In comparing survivors with non-survivors, the hypothesis that immuno-competence may exhibit feedback-like (oscillatory or cyclic) responses was tested. RESULTS: While non-structured data did not distinguish survivors from non-survivors, structured data revealed immunological and statistical differences between outcomes: while survivors exhibited oscillatory data patterns, non-survivors did not. In survivors, many variables (including IL-6, hemoglobin and several complex indicators) showed values above or below the levels observed on day 1 of the hospitalization period, displaying L-shaped data distributions (positive kurtosis). In contrast, non-survivors did not exhibit kurtosis. Three immunologically defined data subsets included only survivors. Because information was based on visual patterns generated in real time, this method can, potentially, provide information rapidly. DISCUSSION: The hypothesis that immuno-competence expresses feedback-like loops when immunological data are structured was not rejected. This function seemed to be impaired in immuno-suppressed individuals. While this method rapidly informs, it is only a guide that, to be confirmed, requires additional tests. Despite this limitation, the fact that three protective (survival-associated) immunological data subsets were observed since day 1 supports many clinical decisions, including the early and personalized prognosis and identification of targets that immunomodulatory therapies could pursue. Because it extracts more information from the same data, structured data may replace the century-old format of the CBC.

Metabolic Messengers: Thyroid Hormones.

Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action have been associated with genetic and endocrine diseases in man. Over the past few years, there has been renewed interest in TH action and the therapeutic potential of THs and thyromimetics to treat several metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. Recent advances in the development of tissue and TH receptor isoform-targeted thyromimetics have kindled new hope for translating our fundamental understanding of TH action into an effective therapy. This review provides a concise overview of the historical development of our understanding of TH action, its physiological and pathophysiological effects on metabolism, and future therapeutic applications to treat metabolic dysfunction.

Targeting nuclear receptors for NASH/MASH: From bench to bedside.

The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.

Half a Century in Hiding: A Unique Case of Tuberculoid Leprosy with an Unprecedented Incubation Period.

BACKGROUND Leprosy, also known as Hansen's disease, is a neglected tropical disease with low prevalence in the United States. The disease's long incubation period can cause delayed presentation, and most affected individuals have a history of travel or work in leprosy-endemic regions. The immune response to Mycobacterium leprae determines the clinical characteristics of leprosy, with tuberculoid leprosy being characterized by well-defined granulomas and involvement of peripheral nerves. The recommended treatment is a combination of dapsone and rifampin for 12 months. CASE REPORT A 78-year-old man with a history of extensive travel to Africa and Asia 50 years ago, presented with a non-tender, non-pruritic, and hypopigmented skin lesion on his left knee. Biopsy results confirmed granulomatous inflammation and the presence of Mycobacterium leprae, leading to a diagnosis of tuberculoid/paucibacillary leprosy. The patient received dapsone and rifampin treatment, which resulted in symptom improvement. CONCLUSIONS The patient's long incubation period of 50 years between exposure and symptom onset is remarkable and possibly one of the longest reported for tuberculoid leprosy. It emphasizes the importance of considering leprosy in cases with an extensive travel history and long incubation periods. Our patient's case presented contradictory staining results, suggesting potential sampling variation or a rare mixed leprosy form. Based on his clinical findings, he was diagnosed with tuberculoid leprosy. Early diagnosis and treatment are crucial to prevent irreversible nerve damage and improve patient outcomes. Healthcare providers should be vigilant in acquiring a detailed travel history to facilitate early diagnosis and appropriate management of leprosy cases.

Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease.

ABSTRACT: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

KV7 but not dual small and intermediate KCa channel openers inhibit the activation of colonic afferents by noxious stimuli.

In numerous subtypes of central and peripheral neurons, small and intermediate conductance Ca2+-activated K+ (SK and IK, respectively) channels are important regulators of neuronal excitability. Transcripts encoding SK channel subunits, as well as the closely related IK subunit, are coexpressed in the soma of colonic afferent neurons with receptors for the algogenic mediators ATP and bradykinin, P2X3 and B2, highlighting the potential utility of these channels as drug targets for the treatment of abdominal pain in gastrointestinal diseases such as irritable bowel syndrome. Despite this, pretreatment with the dual SK/IK channel opener SKA-31 had no effect on the colonic afferent response to ATP, bradykinin, or noxious ramp distention of the colon. Inhibition of SK or IK channels with apamin or TRAM-34, respectively, yielded no change in spontaneous baseline afferent activity, indicating these channels are not tonically active. In contrast to its lack of effect in electrophysiological experiments, comparable concentrations of SKA-31 abolished ongoing peristaltic activity in the colon ex vivo. Treatment with the KV7 channel opener retigabine blunted the colonic afferent response to all applied stimuli. Our data therefore highlight the potential utility of KV7, but not SK/IK, channel openers as analgesic agents for the treatment of abdominal pain.NEW & NOTEWORTHY Despite marked coexpression of small (Kcnn1, Kcnn2) and intermediate (Kcnn4) conductance calcium-activated potassium channel transcripts with P2X3 (P2rx3) or bradykinin B2 (Bdkrb2) receptors in colonic sensory neurons, pharmacological activation of these channels had no effect on the colonic afferent response to ATP, bradykinin or luminal distension of the colon. This is in contrast to the robust inhibitory effect of the KV7 channel opener, retigabine.

Cardiovascular Stents: Types and Future Landscape.

One of the prominent reasons for mortality and morbidity worldwide is coronary artery disease (CAD), an ailment that manifests itself by the narrowing of the artery with the deposition of plaque. The definitive mode of action for dealing with this condition is using a medical device known as a stent at the affected location. This extremely important tubular equipment helps tremendously with vessel support. It also helps by keeping the path of blood flow clear for the heart muscle masses, its crucial nutrients, and oxygen supply. Several generations of stents have been continuously developed to improve patient outcomes and reduce side effects post-stent implantation. As we move from bare metal stents (BMSs) to drug-eluting stents (DESs) and, more recently, to bioabsorbable stents, the research area continues to develop. The use of this biomedical device has increased the standard of living in many cases; therefore, it is much needed to work on the possible growth areas in the cardiovascular stents and improve them to such an extent that the patients suffering from cardiovascular ailments get to live a comfortable life. Most articles deal with stents that are available for current use and their various types. They also cover the topic of stent optimization, as it is one of the key factors in enhancing stent usability and plays a prominent role in optimizing stent placement in the vessels of the body. To keep in touch with advances in stent technology over the past few decades, this article reviews advances in the devices, working on how available stents can be optimized to create new stents.

Targeting Extracellular RNA Mitigates Hepatic Lipotoxicity and Liver Injury in NASH.

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration, and fibrosis, NASH, at a molecular level, involves lipid-induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen for NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage induced by lipotoxicity results in the release of extracellular RNAs (eRNAs), which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravate inflammation, and lead to cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increases cellular viability and reduces NF-kB-mediated cytokine production. Similarly, RNase 1 administration significantly improves hepatic steatosis, inflammatory and injury markers in a murine NASH model. Therefore, this study, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.

Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.

Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.

Tension pneumocephalus following bariatric surgery: case report.

Bariatric surgery is an effective treatment for patients with idiopathic intracranial hypertension (IIH), a condition that is associated with skull base defects. A 55-year-old woman presented with symptoms of intractable nausea and vomiting, followed by headache and confusion two weeks after an elective laparoscopic vertical sleeve gastrectomy procedure. She had a presumed diagnosis of IIH and a remote history of CSF oto/rhinorrhea treated with a lumbar peritoneal (LP) shunt. Computed tomography (CT) scan of the head revealed tension pneumocephalus with midline shift and dehiscence of the tegmen. The patient underwent emergent craniotomy for decompression of the air-filled temporal lobe, clamping of the LP shunt, and repair of the skull base defect. Caution should be exercised in obese patients with a history of CSF leak secondary to a middle fossa skull base defect when being evaluated for bariatric surgery.

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease.

Autophagy, a cellular degradative process, has emerged as a key regulator of cellular energy production and stress mitigation. Dysregulated autophagy is a common phenomenon observed in several human diseases, and its restoration offers curative advantage. Non-alcoholic fatty liver disease (NAFLD), more recently renamed metabolic dysfunction-associated steatotic liver disease, is a major metabolic liver disease affecting almost 30% of the world population. Unfortunately, NAFLD has no pharmacological therapies available to date. Autophagy regulates several hepatic processes including lipid metabolism, inflammation, cellular integrity and cellular plasticity in both parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells) with a profound impact on NAFLD progression. Understanding cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as NAFLD. Modulating autophagy in specific cell types can have varying effects on liver function and pathology, making it a promising area of research for liver-related disorders. This review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.

ULK1 inhibition attenuates telomerase activity in hepatic cells.

Autophagy and telomere maintenance are two cellular survival processes that show a strong correlation during human ageing and cancer growth, however, their causal relationship remains unclear. In this study, using an unbiased transcriptomics approach, we uncover a novel role of autophagy genes in regulating telomere extension and maintenance pathways. Concomitantly, the pharmacological inhibition of ULK1 (Unc-51 like autophagy activating kinase 1) attenuated human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity in HepG2 cells. Furthermore, the suppression of telomerase activity upon ULK1 inhibition was associated with telomere shortening and onset of cellular senescence in HepG2 cells. These results, thus, demonstrate a direct role of autophagy in maintaining cellular longevity via regulation of telomerase activity, which may have implications in the pathophysiology of ageing and cancers.

The Correlation of Mineral Density of Jaws With Skeletal Bone and Its Effect on Implant Stability in Osteoporotic Patients: A Review of Patient-Based Studies.

Osteoporosis has been an enigma in terms of the administration of implant therapy. It has been implicated as a cause of implant failure as it directly affects the quality of the bone. The diagnosis of osteoporosis is mainly done by measuring skeletal bone mineral density (BMD). During implant therapy, the BMD of jaws can be evaluated on routine orthopantomogram (OPG) or cone beam CT (CBCT). The various advantages of CBCT include establishing a correlation between skeletal bone density and bone density of jaws and estimating its effect on implant stability in osteoporotic patients, which in turn will help in determining the prognosis of the implant in osteoporotic patients. This review is a summary of all patient-related studies conducted in the mentioned context of implant placement in patients with osteoporosis, treatment modalities, and prognosis. We performed a search of relevant articles on Google Scholar, PubMed, and Cochrane, which yielded a total of 25 articles for full-text reviews. After excluding some articles based on the exclusion criteria, a review was conducted along with a pilot study on implant placement in osteoporotic patients. Regional bone density can be a helpful parameter in predicting primary implant stability and it can be a useful indicator of skeletal BMD. With a careful evaluation of BMD, dental implants can be placed in patients with osteoporosis with a better prognosis for the treatment.

C-terminal deletion-induced condensation sequesters AID from IgH targets in immunodeficiency.

In activated B cells, activation-induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C-terminal peptide. In immunodeficient-patient cells expressing mutant AID lacking its C-terminus, a catalytically active AID-delC protein accumulates in the nucleus but nevertheless fails to support CSR. To resolve this apparent paradox, we dissected the function of AID-delC proteins in the CSR process and found that they cannot efficiently target antibody genes. We demonstrate that AID-delC proteins form condensates both in vivo and in vitro, dependent on its N-terminus and on a surface arginine-rich patch. Co-expression of AID-delC and wild-type AID leads to an unbalanced nuclear AID-delC/AID ratio, with AID-delC proteins able to trap wild-type AID in condensates, resulting in a dominant-negative phenotype that could contribute to immunodeficiency. The co-condensation model of mutant and wild-type proteins could be an alternative explanation for the dominant-negative effect in genetic disorders.

Environmental Toxicants and NAFLD: A Neglected yet Significant Relationship.

The liver is an organ of vital importance in the body; it is the center of metabolic activities and acts as the primary line of defense against toxic compounds. Exposure to environmental toxicants is an unavoidable fallout from rapid industrialization across the world and is even higher in developing countries. Technological development and industrialization have led to the release of toxicants such as pollutant toxic gases, chemical discharge, industrial effluents, pesticides and solvents, into the environment. In the last few years, a growing body of evidence has shed light on the potential impact of environmental toxicants on liver health, in particular, on non-alcoholic fatty liver disease (NAFLD) incidence and progression. NAFLD is a multifactorial disease linked to metabolic derangement including diabetes and other complications. Environmental toxicants including xenobiotics and pollutants may have a direct or indirect steatogenic/fibrogenic impact on the liver and should be considered as risk factors associated with NAFLD. This review discusses the contribution of environmental toxicants toward the increasing disease burden of NAFLD.

Role of AKR1B10 and AKR1B8 in the pathogenesis of non-alcoholic steatohepatitis (NASH) in mouse.

Non-alcoholic steatohepatitis (NASH) is a clinically important spectrum of non-alcoholic fatty liver disease (NAFLD) in humans. NASH is a stage of NAFLD progression wherein liver steatosis accompanies inflammation and pro-fibrotic events. Presently, there are no approved drugs for NASH, which has become a leading cause of liver transplant worldwide. To discover novel drug targets for NASH, we analyzed a human transcriptomic NASH dataset and found Aldo-keto reductase family 1 member B10 (AKR1B10) as a significantly upregulated gene in livers of human NASH patients. Similarly murine Akr1b10 and Aldo-keto reductase family 1 member B8 (Akr1b8) gene, which is a murine ortholog of human AKR1B10, were also found to be upregulated in a mouse model of diet-induced NASH. Furthermore, pharmacological inhibitors of AKR1B10 significantly reduced the pathological features of NASH such as steatosis, inflammation and fibrosis in mouse. In addition, genetic silencing of both mouse Akr1b10 and Akr1b8 significantly reduced the expression of proinflammatory cytokines from hepatocytes. These results, thus, underscore the involvement of murine AKR1B10 and AKR1B8 in the pathogenesis of murine NASH and raise an intriguing possibility of a similar role of AKR1B10 in human NASH.

Adiponectin receptors by increasing mitochondrial biogenesis and respiration promote osteoblast differentiation: Discovery of isovitexin as a new class of small molecule adiponectin receptor modulator with potential osteoanabolic function.

Previously, we established adiponectin receptors (AdipoRs) as osteoanabolic target. To discover small molecule agonists of AdipoRs, we studied apigenin and apigenin-6C-glucopyranose (isovitexin) that induced osteoblast differentiation. In-silico, in vitro and omics-based studies were performed. Molecular docking using the crystal structures of AdipoRs showed different interaction profiles of isovitexin and apigenin. In osteoblasts, isovitexin but not apigenin rapidly phosphorylated AMP-activated protein kinase (pAMPK) which is downstream of AdipoRs and a master regulator of cellular energy metabolism, and upregulated expression of AdipoRs. Blocking AMPK abolished the osteogenic effect of isovitexin and its effect on AdipoR expression. Isovitexin upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the mitochondrial biogenesis factor in osteoblasts, and the effect was blocked by AMPK inhibition. Upregulation of PGC-1α by isovitexin was accompanied by increased mitochondrial membrane proteins and mitochondrial DNA (mtDNA). Isovitexin via AdipoRs and PGC-1α induced oxidative phosphorylation (OxPhos) and ATP synthesis that resulted in osteoblast differentiation. Isovitexin had no agonistic/antagonistic activity and stimulatory/inhibitory effect in screening platforms for G protein-coupled receptors and kinases, respectively. In vivo, isovitexin upregulated AdipoRs and osteogenic genes, and increased mtDNA in rat calvarium. We conclude that isovitexin selectively via AdipoRs induced osteoblast differentiation that was fuelled by mitochondrial respiration.