Recent Breakthroughs

Galmiche M, Meister I, Zufferey F, Rossier MF, Rahban R, Senn A, Nef S, Boccard J, Rudaz S.

Commun Med (Lond)

PMID:41991730

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Background Cannabis use has been hypothesized to alter endocrine function. We aimed at investigating this hypothesis through extended steroid profiling in young men. Methods Using liquid chromatography - tandem mass spectrometry (LC-MS/MS), 70 endogenous steroids were reliably identified in serum samples from 47 cannabis consumers and 47 controls. Seven major steroids were subject to absolute quantification, while the others were considered as relative concentrations. Results This cross-sectional study shows a global increase in androgen levels among cannabis consumers. Androstenedione (A4), testosterone (T), and dihydrotestosterone (DHT) are among the most significantly increased steroids. In contrast, C11-oxy androgens show no significant change upon cannabis use. This pattern suggests that phytocannabinoids might selectively affect gonadal androgen synthesis without altering adrenal or peripheral pathways, possibly via direct effects on the testes, or disruption of the hypothalamic-pituitary-gonadal (HPG) axis function. Additionally, two progesterone metabolites, 11β-hydroxyprogesterone (11β-OHP4) and 5β-dihydroprogesterone (5β-DHP4), are markedly elevated in cannabis consumers. When the cannabis user group is stratified according to the corresponding usage biomarkers, 11β-OHP4 proves to be a biomarker of general exposure, whereas 5β-DHP4 displays a dose-dependent relationship. Conclusions These findings highlight the value of extended steroid profiling for investigating hormonal variations and evidence a possible link between cannabis consumption and altered male endocrine function.

Malik DM, Kain P, Rhoades SD, Sengupta A, Zhang SL, Barber A, Haynes P, Arnardottir ES, Pack A, Kibbey RG, Sehgal A, Weljie AM.

PLoS Biol

PMID:41989995

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Biological clocks shape metabolism, but how circadian programs govern nutrient processing is unclear. Here, using human metabolomics and 13C6-glucose tracing in Drosophila, we delineate previously under characterized daily oscillations in glucose-derived metabolic networks, providing a mechanistic framework for a purpose-built isotope-tracing approach. In flies, we reveal a pronounced "rush hour" of glucose utilization early in the light phase, with carbons directed to biosynthetic and energetic pathways. By contrast, a dopamine reuptake-deficient hyperactive mutant (fumin) with elevated metabolic rate shows phase-shifted and amplified metabolic peaks, indicating that altered neural signaling reshapes temporal glucose flux. Neither altered feeding schedules nor short-term fasting disrupt these intrinsic metabolic rhythms, strongly suggesting that circadian timing, rather than nutrient availability, orchestrates temporal homeostasis. By integrating human metabolite profiling with isotope-tracing in flies, we define a conserved temporal architecture of glucose utilization and demonstrate that metabolic flux is dynamically gated across the day. Our findings establish a framework for understanding how circadian misalignment contributes to metabolic dysfunction and disease.

Kulkarni M, Parab M.

PMID:PPR1178156

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Abstract Purpose This study presents a novel testing application for co-elution chromatography of biguanide with two different drug classes, sulfonylurea and sodium-glucose co-transporter 2(SGLT2) inhibitors in tablet dosage form. The focus was to quantitate all three drugs in single run on newer chemistry column, additive free mobile phase, using greener solvent and covering wide concentration range. Method This chromatographic method was established on non-conventional C18- embedded polar shielding(EPS) column, an high-purity silica-based reversed-phase column and a simple mobile phase. This method is environmentally responsible, developed with excellent performance for most metrics of greenness indicated by AGREE score 0.73, BAGI score 80.0, AGREE-Prep score 0.73. MoGAPI score 80 and RAPI score 70.0. It showed sustainability and alignment with most of the principles of green analytical chemistry (GAC). A standardized testing protocol was set for estimating three prominent antidiabetic drugs and to overcome difficulty in estimating low-dose Glimepiride and inconsistent regulatory enforcement. Results The method operated at a column flow rate of 0.8 mL min − 1 with a UV detector at 225 nm. The validated method exhibited excellent linearity within 50–150% of the target concentration with correlation coefficients (r) > 0.99 for all analytes. Accuracy studies showed overall mean recoveries of 99.5% for MTH, 100.1% for GPD and 100.2% for CGF. Conclusion The method is precise, accurate, and environmentally responsible, offering a sustainable analytical approach for simultaneous estimation of three drugs in fixed-dose formulations. It exemplifies the sustainable solvent selection and resource-efficient analytical practices integrated to deliver an accessible greener method.

Srimontri P, Kingkaw A, Prapaiwan N, Sujittosakul R, Iamkaewprasert N, Piputwat J, Isama-Al P, Munkongdee T, Chotikaprakal T, Yanyongsirikarn P, Phaonakrop N, Roytrakul S, Vongsangnak W, Tesena P.

Vet Comp Oncol

PMID:41992374

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Equine melanocytic neoplasms (EMN) are aggressive tumours characterised by high metastatic potential and limited therapeutic options available. However, the molecular mechanisms underlying their progression remain poorly understood. This study therefore presents the integrative phosphoproteomic analysis of EMN tissue, with the aim of elucidating stage-specific alterations in signalling pathways and metabolism. Nineteen tissue samples from grey horses were categorised as normal-stage (n = 6), early-stage EMN (n = 7), and severe-stage EMN (n = 6) and subjected to in-depth analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 2035 phosphoproteins were identified, of which 219 were differentially expressed across the disease stages. Interestingly, early-stage EMN showed dysregulation of inositol phosphate metabolism and activation of the PI3K-Akt pathway which involved INPP5F and PKN2. In severe-stage EMN, upregulation of SYNJ1, STRN4 and VIM indicated enhanced membrane trafficking, cytoskeletal remodelling, and MAPK signalling. Additionally, ASPM and GNAO1 upregulation reflected heightened proliferation and altered Rap1 signalling, while UBR5 dysregulation suggested aberrant protein homeostasis. Metabolic reprogramming was also noticed, with elevated TKT and GAPDH expression supporting glycolysis and NADPH production. Observably, the severe-stage EMN exhibited a higher expression of Dickkopf-3 (DKK3) which suggests a role in aberrant Wnt/β-catenin activation and tumour progression. These findings reveal stage-specific molecular mechanisms in EMN pathogenesis and highlight potential biomarkers and therapeutic targets for equine melanoma.

Gupta HK, Jangra J, Ramesh VK, Mahindru I, Kumar R.

Drug Discov Today

PMID:42000124

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The blood-brain barrier (BBB) remains a critical limitation in central nervous system (CNS) drug development, restricting brain exposure to most therapeutics. Despite advances in macromolecular delivery, small molecules continue to predominate, necessitating the rational optimization of BBB permeability. This review integrates recent medicinal chemistry strategies focused on fine-tuning key physicochemical parameters, including lipophilicity, pK a , molecular weight, hydrogen bond donors, rotatable bonds and topological polar surface area, which govern passive diffusion and brain penetration. Structural modifications such as fluorination, bioisosteric replacement, intramolecular hydrogen bond masking and prodrug approaches are discussed alongside strategies to mitigate efflux and exploit carrier-mediated transport. The integration of in silico tools and experimental models provides a cohesive framework for designing next-generation CNS therapeutics with optimized permeability and efficacy profiles.