Trehalose is a principal circulating sugar in insects, maintaining a critical balance between energy supply and storage through systemic insulin signalling. Among different tissues, insect muscle functions as a metabolic hub, coordinating trehalose utilization and glucose uptake to sustain energy homeostasis. In Helicoverpa armigera, we examined whether paramyosin (key muscle gene) silencing influence carbohydrate metabolism. HaPrm silencing led to muscle defects and delayed pupation, indicating a crucial role of HaPrm in development. Transcriptomics revealed dysregulation of genes involved in carbohydrate metabolism and insulin-mTOR signalling. Notably, expression and enzymatic activities of HaTPS/TPP and HaTreh(s) were reduced in HaPrm-silenced insects, accompanied by their altered metabolite intermediate levels. Given that trehalose metabolism fuels both glycolysis and glycogen synthesis, HaPrm silencing also altered the expression of glycolytic, glycogen metabolism and energy-sensing genes. Metabolomics further demonstrated differential accumulation of intermediates from glycolysis, glycogen recycling, the TCA cycle and amino acid metabolism. Moreover, insulin-mTOR signalling genes and the glucose-sensing transcription factor were significantly affected, highlighting the sensitivity of nutrient-sensing mechanisms to HaPrm silencing. Taken together, these results suggest that HaPrm disruption affects muscle integrity and is linked to changes in insulin-mTOR signalling and trehalose metabolism. These data highlight the close relationship between muscle architecture and energy homeostasis in H. armigera.

Obesity arises when a chronic energy surplus overwhelms the storage capacity of adipocytes and subsequently causes systemic metabolic dysfunction. Adaptive thermogenesis, primarily mediated by uncoupling protein 1 (Ucp1) in adipocytes, serves to counteract obesity by dissipating excess energy as heat. Despite extensive studies on thermogenic regulation, the phosphatases that regulate this protective metabolic pathway remain poorly understood. Here we identify dual-specificity phosphatase 4 (Dusp4) as a critical modulator of adipocyte thermogenesis via direct modulation of CREB-regulated transcription coactivator 3 (Crtc3). Dusp4-knockout mice exhibit impaired thermogenic capacity, diminished Ucp1 expression, and increased susceptibility to diet-induced obesity coupled with severe insulin resistance. Mechanistically, Dusp4 directly dephosphorylates serine residues on Crtc3, facilitating its nuclear translocation and subsequent transcriptional activation of Ucp1. Depot-targeted restoration of catalytically active Dusp4 in inguinal adipose tissue rescues local thermogenic gene expression and reinstates Crtc3 dephosphorylation-dependent Ucp1 induction in Dusp4-knockout mice. Collectively, these findings identify Dusp4 as a key upstream phosphatase orchestrating the Crtc3-Ucp1 thermogenic axis, and highlight its potential as a therapeutic target for obesity-associated metabolic disorders.

The immune response is essential in shaping bone healing outcomes and is of particular interest in mandible fractures, as opposed to other fractures, because of the presence of teeth that are colonised by a multitude of microbes that can cause infection or complicate healing. This study investigated the peripheral blood cell transcriptome during mandibular fracture healing phases with particular focus on immune-related indicators. Blood samples from mandibular fracture patients who had normal healing were collected at the time of injury, then 2 weeks and 6 weeks following the injury, corresponding to the inflammation, repair, and remodelling phases of bone healing, respectively. RNA sequencing was performed for blood cells and analysed using the Ingenuity Pathway Analysis (IPA) software. Data validation was conducted using ELISA for soluble serum factors and blood cell counting using Sysmex. The results indicated distinctive systemic changes between the three healing phases. A significant increase in activity and counts of blood neutrophils and monocytes was noted during the inflammatory and repair phases compared to the remodelling phase. In contrast, a prominent activity and increased quantity of lymphocytes were detected in the remodelling phase. Furthermore, increased serum levels and activated signalling of interleukin 10 (IL10) were detected at the systemic level, mainly during the inflammation and repair phases. Interestingly, blood cells were found to express high levels of osteogenesis-related markers during the repair phase, with significantly increased serum levels of Insulin-like growth factor 2 (IGF2). In conclusion, systemic blood cell transcriptomic profiling showed a shift from predominantly innate toward adaptive immune response during mandible healing, with serum IL10 and IGF2 levels indicating the resolution of inflammation and the start of osteogenic repair. Therefore, peripheral blood cells and serum factors could be a promising source of non-invasive biomarkers for monitoring healing trajectories of mandible injuries.

Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly known as Polycystic Ovary Syndrome, PCOS) is a common, heterogeneous endocrinopathy of reproductive-age women with a frequency of 5-26% worldwide. PMOS is characterized by hyperandrogenemia, ovulatory dysfunction, and polycystic ovarian morphology. A systematic search of the NHGRI-EBI GWAS Catalog and the literature in PubMed identified 17 PMOS GWAS or GWAS Meta-analyses with loci with significant evidence for association with PMOS. The PMOS GWAS identified 120 genomic regions significantly associated with PMOS. Thirty-eight of the PMOS GWAS loci are detected in at least two cohorts, and the majority of replicated regions were observed in multiple ancestries. The genes encoded by PMOS GWAS loci are implicated in gonadotropin secretion and action, folliculogenesis, sex hormone function, age at menopause, adiposity, insulin signaling, T2DM, calcium signaling, endocytosis, lipid and cholesterol levels, and cardiometabolic disease.

The polysaccharide VVPI-3a (21.8 kDa) from Volvariella volvacea was isolated and identified, and its insulin resistance-improving activity was evaluated in insulin-resistant HepG2 (IR-HepG2) cells. VVPI-3a is composed of unsubstituted residues including →6)-α-D-Galp-(1→, →6)-α-D-(3-O-Me)-Galp-(1→, →2)-β-D-Galp-(1→, →6)-β-D-Galp-(1→ and →6)-β-D-(3-O-Me)-Galp-(1→. It also contains monosubstituted residues including (→2,6)-α-D-Manp-(1→ and →2,6)-α-D-(4-O-Ac)-Manp-(1→). Its backbone contains alternating →6)-Galp-(1→ and →2,6)-Manp-(1→ residues. Branching occurs at O-2 of mannose, where terminal glucosyl units are attached. The conformation of VVPI-3a was further confirmed by Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD) and Congo red analysis, indicating that it is a neutral polysaccharide with pores and projections on a uniformly distributed surface. In the glucosamine-induced insulin-resistant HepG2 cell model of HepG2 cells, VVPI-3a (0.25-1 mg/mL) significantly enhances glucose uptake in IR-HepG2 cells. VVPI-3a may improve glucose uptake by increasing the mRNA transcription of GLUT4, thereby enhancing insulin sensitivity in IR-HepG2 cells and inhibiting the key enzymes G6pase and PEPCK. These findings contribute to the growing body of research on the polysaccharides of Volvariella volvacea and their roles in insulin resistance-improving activity.

Circulating sex hormone-binding globulin (SHBG) regulates bioavailable sex hormones that influence bone metabolism. We investigated whether genetically higher SHBG increases lumbar fracture (LF) risk and identified the biological pathways mediating this effect, including bone mineral density (BMD), C-reactive protein (CRP), and insulin use. A two-sample bidirectional and mediation Mendelian randomization (MR) framework was applied using genome-wide significant single-nucleotide polymorphisms (P < 5 × 10-8) from large-scale genome-wide association study datasets (FinnGen, UK Biobank, and IEU OpenGWAS). Instrumental variables were linkage disequilibrium-pruned (r2 < 0.01), and analyses were conducted using inverse-variance weighted, MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier methods. Genetically predicted SHBG was causally associated with higher LF risk (FinnGen: odds ratio [OR] = 1.201; 95% confidence interval, 1.028-1.404; P = .021; UK Biobank: OR = 1.005; 95% confidence interval, 1.002-1.008; P = .002). SHBG showed significant negative effects on lumbar BMD (OR = 0.934; P = .0029) and CRP (OR = 0.921; P = .0065), and a modest decrease in insulin medication use (OR = 0.9963; P = 6.1 × 10-6). Mediation analysis revealed that 64.8% of SHBG's total effect on LF was mediated through BMD, 63.8% through CRP, and 38.7% through insulin pathways. Sensitivity tests confirmed robustness without evidence of pleiotropy. Genetically elevated SHBG increases LF risk mainly through impaired bone density and systemic inflammation. These findings suggest that interventions targeting SHBG-related metabolic pathways may help reduce skeletal fragility.

Cardiometabolic diseases (CMD) encompass a group of disorders sharing a common pathophysiology that increases the risk of cardiovascular disease and mortality. Key events underlying CMD pathophysiology include insulin resistance, low-grade inflammation, altered hormonal and myokine profiles, and mitochondrial dysfunction. The latter manifests as reduced mitochondrial mass and oxidative function, increased oxidative stress, altered Ca2+ handling and decreased mitochondrial membrane potential. Skeletal muscle plays a pivotal role in CMD pathophysiology through two main mechanisms: i) the storage and oxidation of energy substrates and ii) the release of myokines, which in turn modulate metabolism and mitochondrial function. Here, we propose that the unfavorable myokine profile associated with CMD pathophysiology leads to mitochondrial alterations, and that restoring a healthy myokine profile helps improve mitochondrial structure, function, and overall metabolic health. To test this idea, in this narrative review, we critically present evidence of an altered myokine profile in CMD and highlight the most important mitochondrial alterations in CMD before examining the direct effect of specific myokines on mitochondria and CMD-associated mitochondrial dysfunction. Finally, we summarize the effects of therapeutic interventions on both the myokine profile and mitochondrial function, also appraising human trials that use myokine-based interventions to improve CMD. We focus on molecular mechanisms and causal relationships, while also indicating novel perspectives in the field. Understanding the role of mitochondria in the effect of myokines on metabolic health may open new preventive and therapeutic strategies for addressing CMD more efficiently.

Gallic acid (GA), a natural polyphenol, has been enormously recognized for its anticancer properties across multiple cancer types, including triple-negative breast cancer (TNBC), yet its precise molecular mechanisms underlying its effects on TNBC, particularly those related to autophagy, remain unclear. This investigation sought to elucidate the autophagy-related targets and pathways modulated by GA in TNBC by integrating network pharmacology, bioinformatics, molecular docking, and in vitro validation. Network pharmacology identified 23 overlapping targets between GA, TNBC, and autophagy-related gene sets, including key genes such as CASP3, TP53, AKT1, PIK3CA, and HIF-1 A. Protein-Protein Interaction network analysis revealed ten hub genes as central nodes in GA's action mechanism. Gene Ontology enrichment highlighted biological processes such as DNA damage response, protein phosphorylation, and regulation of apoptosis and autophagy. KEGG pathway analysis further indicated enrichment in pathways related to EGFR inhibitor resistance, insulin signaling, autophagy, and apoptosis, among others. Molecular docking demonstrated strong binding affinities between GA and the identified autophagy modulatory genes. In vitro experiments showed that GA inhibited the proliferation and migration of BT-549 and HCC1395 TNBC cells while inducing autophagy. Induction of autophagy by GA in the BT-549 and HCC1395 cell lines was proved by acridine orange, MAP1LC3B fluorescence, and western blotting of key autophagy regulators. Taken together, this integrated approach, combining network pharmacology and experimental validation, identified key targets and signaling pathways through which GA regulates autophagy in TNBC. These findings enhance our understanding of GA's anticancer mechanisms and support its plausible development as a therapeutic entity for TNBC.