Asthma is characterised by variable airflow obstruction and is associated with symptoms of cough, wheeze, and dyspnoea, and with airway inflammation and hyperresponsiveness. There are approximately 300 million people with asthma worldwide. Despite a current plateau, the burden of this disease is likely to increase due to population growth, urbanisation, and ageing. Disease onset is associated with low birthweight, preterm birth, viral infections, in-utero passive smoke exposure, urbanisation, and occupational exposures. Obesity is associated with increased incidence and severity of asthma, whereas exposure to small allergen particles leads to severe disease. In adults and adolescents, inhaled corticosteroids in combination with formoterol (as anti-inflammatory reliever or as maintenance and anti-inflammatory reliever therapy) are widely recommended to control the symptoms of asthma. For children, low-dose inhaled corticosteroid is the preferred first-line treatment. Monotherapy with short-acting β-agonists is strongly discouraged. The WHO Global Action Plan for the Prevention and Control of Non-communicable Diseases includes availability of affordable combination inhalers for asthma. Co-ordinated national asthma policies, ensuring access to inhalers, have resulted in fewer hospitalisations and school and work absences. Future asthma prevalence could be reduced by good maternal and infant care, with reduction in premature births and reduction in infant respiratory infections, and by reduction in obesity at all ages.

Gestational diabetes mellitus is defined as any glucose intolerance that begins during pregnancy, and it is one of the most common metabolic disorders complicating pregnancies, affecting approximately 10-14% of all pregnancies. Maternal carbohydrate metabolism changes during pregnancy to ensure adequate nutrition for the fetus, with the human umbilical vein and the placenta being important regulators of this physiological state. This study aimed to evaluate fractalkine (FKN) immunoreactivity in GDM pregnancies and its association with maternal/fetal health outcomes.

In this case-control study, a total of 89 pregnant women (44 GDM and 45 non-GDM) underwent a 50 g glucose loading test (GCT) between 24 and 28 weeks of gestation. GCT cutoff value was chosen as <140 mg/dl. Women with high GCT values underwent rapid diagnostic testing with a 3-hour glucose tolerance test (GTT). Placenta samples were obtained after cesarean section. Immunohistochemistry for FKN was performed on formalin-fixed and paraffin-embedded sections. Finally, the relationship between FKN expression and clinical manifestations of GDM was evaluated.

FKN expression was significantly different between pregnant women with and without GDM. Specifically, FKN expression was increased in the capillary endothelium (p < 0.0001) and human umbilical vein endothelial cells (HUVECs) (p = 0.0011) in pregnant women with GDM compared to those without GDM. Furthermore, FKN expression in HUVECs was found to be associated with fetal macrosomia (p = 0.0099) and neonatal hypoglycemia (p = 0.0291). Additionally, FKN expression in the capillary endothelium was found to be associated with preeclampsia (p = 0.0250). Regarding the pathological changes of the placenta with FKN expression, significant correlations were identified with both capillary endothelial FKN expression and HUVEC FKN expression.

The observed differences suggest a potential association between the immunohistochemical expression of FKN and the presence of GDM, placental changes, and adverse outcomes of pregnancy.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently at the forefront of type 2 diabetes mellitus (T2DM) and obesity treatment development and usage. However, recent focus on multi-receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) receptors has been investigated to assess for improved glycemic control, weight loss, and safety profile.

Several dual GLP-1/GIP RAs are currently in development, with the GIP receptor assisting GLP-1 in modulating central and peripheral pathways to prompt weight loss by increasing lipolysis and fat oxidation. Dual GLP-1/Gcg is another novel combination that utilizes the Gcg receptor which increases energy expenditure by stimulating glucose production, fat oxidation, and mobilization of energy stores to promote weight loss. Triple agonism of GLP-1/GIP/Gcg is still mainly being investigated in clinical trials, but preliminary results show similar if not improved glycemic control and weight loss. However, despite the multi-agonist approach, gastrointestinal adverse events do not seem to be mitigated compared to traditional GLP-1 RAs.

The current literature shows promising results for the efficacy of dual and triple agonism of GLP-1/GIP/Gcg receptors. Further research should focus on direct comparative studies between current GLP-1 RAs against these multi-receptor agonist agents.

Huanglian Zhimu decoction (HLZMD), a classical formulation in traditional Chinese medicine, has historically been utilized in the management of diabetes. However, its therapeutic efficacy and the underlying mechanisms in the context of T2DM, particularly in relation to hepatic lipid dysregulation, have yet to be systematically investigated.

To explore the potential therapeutic effects and molecular mechanisms of HLZMD on T2DM.

Initially, a T2DM model was established in spontaneously diabetic Goto-Kakizaki (GK) rats through high-fat diet induction. To elucidate the molecular mechanisms underlying the therapeutic effects of HLZMD, an integrative approach combining hepatic lipidomic profiling and transcriptomic sequencing was employed to identify HLZMD-responsive pathways. Furthermore, the expression levels of key proteins within the PDE4D/cAMP/PKA signaling pathway were quantified via western blotting in both rat liver tissues and palmitic acid-stimulated HepG2 cells. To validate the pathway specificity, pharmacological inhibition experiments were performed using roflumilast, a selective PDE4D antagonist. Lastly, the chemical composition of HLZMD was characterized through ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and molecular docking analysis was conducted to predict potential active components interacting with PDE4D.

In vivo experiments demonstrated that HLZMD significantly ameliorated fasting blood glucose levels and hepatic steatosis in T2DM rats. Lipidomic analysis further revealed that HLZMD effectively restored the homeostasis of diacylglycerols (DG), triglycerides (TG), sterols (ST), sphingolipids (SP), and glycerophospholipids (GP) in the liver. Integrative analyses incorporating lipidomics, transcriptomics, and western blotting suggested that HLZMD-mediated hepatic lipid modulation may be attributed to the regulation of the PDE4D/cAMP/PKA signaling pathway. In vitro, HLZMD treatment resulted in a significant reduction in extracellular glucose concentrations as well as intracellular TC and TG levels. Concurrently, HLZMD markedly upregulated the expression of PDE4D, SIRT1, and PPARγ proteins while downregulating the expression of cAMP, phosphorylated PKA (p-PKA/PKA), and phosphorylated hormone-sensitive lipase (p-HSL/HSL). Notably, pharmacological inhibition with roflumilast, a selective PDE4D antagonist, partially reversed the HLZMD-induced reduction in lipid deposition, supporting the specificity of this pathway in mediating HLZMD's effects. Furthermore, UPLC-Q-TOF-MS identified 80 chemical constituents in HLZMD. Molecular docking analysis predicted that 21 of these compounds may exhibit direct binding affinity for PDE4D, potentially modulating the cAMP/PKA signaling cascade.

This study is the first to provide evidence that HLZMD exerts its pharmacological effects through multi-component interactions with PDE4D, thereby modulating the cAMP/PKA signaling pathway. This regulatory mechanism contributes to the reduction of hepatic lipid accumulation, attenuation of hepatic insulin resistance, and restoration of glucose and lipid metabolic homeostasis.

Cholangiocarcinoma (CCA), a devastating malignancy originating from the bile ducts, is of significant clinical importance due to its rising incidence and poor prognosis. Quinones as being naturally occurring compounds and their frequent utility in anticancer drug development studies seem to be potential sources for the discovery of new chemotherapeutics. In this study, a synthetic naphthoquinone derivative newly synthesized and previously published by our group, named as MK13, has been tested against intrahepatic-CCA (iCCA) cell lines (CCLP1 and HUCCT1). Cell viability was measured with the MTT assay at the doses of 1.56-50 µM for 48 h treatment. Cell death was showed both morphologically with fluorescent double staining and biochemically with flow cytometry analysis of phosphatidylserine translocation. Oxidative stress and DNA damage were also measured with flow cytometry and gene expressions were interpreted via qPCR analysis. MK13 resulted in a strong reduction (about 80%) in viability, especially against CCLP1 cells when compared with doxorubicin. Cell death resulted from apoptosis was shown to be triggered by severe DNA damage that is independent of oxidative stress. Apoptosis was confirmed at molecular level with the upregulation of BAX, a pro-apoptotic BH-3 only protein, and DR5, a cell surface death receptor. MK13 seems to be a promising anticancer compound against iCCA and deserves further attention for in vivo proof-of-concept studies.

Hepatocellular carcinoma (HCC) is a major global health concern due to its high prevalence and mortality rate. Although emodin, a natural anthraquinone derivative, has demonstrated in vitro anticancer activity against HCC cells, its specific molecular targets in HCC remain unclear.

This study used an integrated approach combining in silico network pharmacology, molecular docking, molecular dynamics simulations (MDS), and in vitro cytotoxicity assays to evaluate three emodin derivatives: emodin, 3-acetyl emodin (ACE), and 1,3,8-triacetyl emodin (TAEM). Target predictions were performed using the SwissTargetPrediction database, and HCC-related genes were retrieved from cBioPortal. Functional annotations (Gene Ontology and Reactome) identified EGFR and KIT as key targets. Docking simulations were conducted to assess binding affinities, followed by 100 ns MDS to evaluate stability. Cytotoxic effects on HepG2 cells were also assessed.

TAEM showed the strongest binding affinity to both EGFR and KIT and demonstrated the highest cytotoxicity against HepG2 cells (IC50 = 0.021 mM). MDS results indicated that the KIT-TAEM complex was the most stable among all tested combinations, supported by RMSD, RMSF, Rg, protein-ligand distance, and MM-GBSA binding energy analyses.

These findings highlight TAEM as a promising therapeutic candidate for HCC. The study demonstrates the value of integrating computational predictions with experimental validation in early-stage drug discovery.

Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment.

This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility.

Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE.

Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.