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[Electroacupuncture improves hypothalamic-pituitary-gonadal axis function and testosterone synthesis in high-fat diet-induced obese male rats].

Zhen Ci Yan Jiu

Jing-Yi Zhang, Yi-Feng Shen, Ke-Qiang Yu +8 more

To observe the effect of electroacupuncture (EA) on hypothalamic-pituitary-gonadal (HPG) axis function and the expression of key enzymes for testosterone synthesis in high-fat diet-induced obese male rats, so as to explore its mechanism in improving obesity-related reproductive dysfunction.

Mirtazapine alleviates depressive-like behaviors through the paraventricular SIK1-CRTC1 signaling pathway.

J Affect Disord

Haibo Zhang, Hongli Dong, Zhengrong Xi +3 more

The paraventricular nucleus (PVN) plays a pivotal role in integrating neuroendocrine responses to stress, with the salt-inducible kinase 1 (SIK1)-CREB-regulated transcription co-activator 1 (CRTC1) pathway critically regulating corticotropin-releasing hormone expression and hypothalamic-pituitary-adrenal (HPA) axis activity. Mirtazapine is a clinically effective antidepressant with a unique noradrenergic and specific serotonergic mechanism, yet whether its therapeutic actions involve modulation of this PVN pathway remains unexplored.

Renal-diabetic overlap in pulmonary arterial hypertension.

Heart

Matteo Toma, Suela Vani, Giulio Savonitto +15 more

Comorbidities add complexity to pulmonary arterial hypertension (PAH), but also open opportunities to use therapies with benefits beyond the cardiovascular (CV) system, particularly preserving renal function and maintaining glucose homeostasis.

SLD5/GINS4 controls dynein-dependent centrosome maturation and exposes a candidate mitotic vulnerability in cancer.

bioRxiv

Vipin Kumar, Vivek Singh, Raksha Singh +2 more

Faithful proliferation requires coordinated DNA replication with centrosome maturation and spindle-pole integrity. SLD5, encoded by GINS4, is a core component of the GINS replication complex and is frequently elevated in tumors, but whether it links replication-associated cancer states to centrosome control has remained unclear. Here, we show that GINS4/SLD5 is recurrently upregulated across human cancers at transcript and protein levels and marks tumor programs enriched for DNA replication, chromosome segregation, and mitotic control. In cancer cells, Sld5 depletion dispersed PCM1, AZI1, and CEP290-positive centriolar satellites without eliminating these satellite proteins, reduced dynein heavy chain expression, and destabilized dynein-dynactin localization at spindle poles. Direct depletion of dynein heavy chain, co-depletion analyses, and pharmacological inhibition of dynein motor activity with ciliobrevin D phenocopied Sld5 loss, causing satellite dispersion, defective recruitment of PLK1, Aurora A, CEP192, and CEP215 to centrosomes, and multipolar spindle formation. These defects occurred without detectable DNA damage or checkpoint activation, indicating a non-canonical Sld5 function beyond its role in the replisome. Cancer dependency and kinase network analyses further nominate SLD5-associated mitotic and checkpoint pathways as therapeutic targets. Our findings identify SLD5/GINS4 as a regulator of dynein-dependent centrosome maturation and a candidate vulnerability in replication-driven cancers, with potential value for biomarker-guided therapeutic stratification.

Satellite microglia-like cells in human dorsal root ganglia and changes with diabetic neuropathy.

bioRxiv

Khadijah Mazhar, Jayden A O'Brien, Michael A Wilde +9 more

Phagocytic and immune-like cells have been observed in the satellite envelope of neuronal somata in peripheral sensory ganglia of many species for several decades. These cells likely play an important role in normal function of sensory neurons and they may also play an important role in neuronal dysfunction and neurodegeneration seen with neuropathy. Recent findings have described a satellite macrophage population transcriptomically similar to microglia in peripheral ganglia of some mammalian species. The function of these cells, and the mechanisms by which they may influence neurons in neuropathy are unclear. We sought to understand the phenotype and localization of these cells in the human dorsal root ganglion (hDRG) using large-scale single nucleus and spatial transcriptomic datasets from individuals with and without a history of peripheral diabetic neuropathy. We observed a large population of macrophages that express classical microglia makers such as TMEM119 and P2RY12 in the hDRG, as previously described. Our findings confirm that these microglia-like cells (MLCs) localize to the satellite envelope around neuronal somata, yet are transcriptomically distinct from all glial cell types characterized in the hDRG. These MLCs exhibit changes in abundance and localization with diabetic painful neuropathy (DPN) in both the hDRG and sural nerves suggesting that they are not exclusively localized to the DRG. We conclude that microglia-like cells are likely the resident tissue macrophage (RTM) of the hDRG, and perhaps the peripheral nervous system (PNS) given their localization to the sural nerve and other ganglia, where they are predicted to regulate homeostatic neuronal functions and response to injury.

Overcoming LPS-mediated resistance in gram-negative pathogens: a review of LL-37 analogs and computational design strategies.

Arch Microbiol

Kirtan Dave, Payal Thapa

The increasing incidence of antimicrobial resistance (AMR) in Gram-negative bacteria has become a significant global health issue, driven primarily by the structural and adaptive characteristics of lipopolysaccharide (LPS) in the outer membrane. As a robust permeability barrier, LPS limits the entry of various antimicrobial agents; furthermore, adaptive alterations to the chemical configuration of lipid A and related compounds augment bacterial resistance to both conventional antibiotics and host defense peptides. The human cathelicidin LL-37, a prominent endogenous antimicrobial peptide, has attracted considerable interest for its potent antibacterial activity, high affinity for LPS, membrane-disrupting capabilities, and immunomodulatory functions. However, the direct therapeutic application of LL-37 is constrained by stability, toxicity, and cost-related challenges. Extensive research has focused on developing structurally diverse LL-37 analogs to overcome these limitations. Through rational sequence engineering, truncation, residue substitution, cyclization, and amphipathic optimization, researchers aim to augment antibacterial efficacy while minimizing host toxicity. This review comprehensively encapsulates the molecular diversity of LL-37 analogs and examines their structure-activity relationships (SAR), with a focus on charge distribution, helicity, hydrophobicity, selectivity, and LPS-binding efficiency. Special attention is given to analogs engineered to circumvent LPS-mediated resistance in multidrug-resistant Gram-negative pathogens. Moreover, we highlight recent progress in computational techniques-such as structure prediction, molecular docking, molecular dynamics (MD) simulations, and artificial intelligence-assisted design that facilitate the identification of critical interaction hotspots and expedite peptide optimization. A previously unrecognized computational gap is also noted: five of nine clinically relevant LL-37 analogs have never been the subject of a molecular dynamics simulation study, and none of the analogs has been targeted to gram negative outer membrane model containing lipopolysaccharide. This gap limits the mechanistic understanding of LL-37 based design strategies against Gram-negative bacteria. Ultimately, integrating molecular diversity with computational engineering establishes a solid foundation for developing next-generation LL-37-derived therapeutics characterized by enhanced stability, safety, and efficacy in the global effort to combat antibiotic resistance. To address these limitations we propose a conceptual computational pipeline, including sequence generation, physicochemical screening, structure prediction, molecular docking, and MD simulation, for prospective next-generation LL-37 analog development.

Correction: Discontinuation of oral semaglutide due to adverse effects: a database study on Japanese individuals with type 2 diabetes.

Diabetol Int

Mizuki Ishiguro, Rimei Nishimura

[This corrects the article DOI: 10.1007/s13340-025-00868-0.].

Tirzepatide attenuates doxorubicin-induced cardiotoxicity via mitochondrial function improvement.

Transl Cancer Res

Zhong Li, Conghui Li, Han Zhan +5 more

Doxorubicin (DOX) is a highly effective anthracycline chemotherapeutic agent, but its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to irreversible heart failure. This study investigated the cardioprotective potential of tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, against DOX-induced cardiac injury.

Tirzepatide Versus Intensified Conventional Care After 2 Years of Treatment in Early Type 2 Diabetes : A Randomized Clinical Trial.

Ann Intern Med

Stefano Del Prato, Robert J Heine, Federico C Pérez Manghi +8 more

Initiation of treatment with tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1RA), early after a diagnosis of type 2 diabetes (T2D) may establish better and more durable glycemic control than current treatment approaches per guidelines and clinical practice.

Immediate allergy against glucagon-like peptide-1 receptor agonist liraglutide.

Asia Pac Allergy

Öner Özdemir

Advances in GLP-1 receptor agonists delivery systems for obesity and diabetes.

Acta Pharm Sin B

Mehrnaz Abbasi, Kai Sun, Kevin W Huggins +4 more

Obesity and diabetes are chronic metabolic diseases affecting millions worldwide. Current treatments, including lifestyle changes, medications, and surgery, face challenges like poor adherence and side effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended innovative medications for these conditions, with studies showing significant clinical benefits. GLP-1RAs are traditionally delivered orally or via subcutaneous injections, but these methods have limitations, including low bioavailability, poor solubility, the need for high doses, gastrointestinal side effects, and frequent dosing requirements. Novel delivery technologies offer promising strategies to overcome these challenges and enhance therapeutic effectiveness. Recent advances in drug delivery technologies, including nanocarrier- and microcarrier-based systems, hydrogels, microneedles, and innovative formulations such as long-acting, co- and/or nano-formulated agents, offer promising strategies to enhance the delivery, efficacy, and patient adherence of GLP-1RAs for obesity and diabetes. This review focuses on innovative delivery technologies developed for three main GLP-1RAs: exenatide, liraglutide, and semaglutide. We present a review of advancements in drug delivery systems, exploring technologies employed in the development of these agents, as well as future challenges. It is crucial to note that these technologies are still in early development, and further studies are needed to confirm their long-term safety, efficacy, and cost-effectiveness in clinical use.

NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.

Autophagy

Jie Cui, Shifeng Ren, Bingjie Wang +10 more

The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.

Bone Marrow Skeletal Stem Cell Dysfunction: Adipocytes during skeletal aging and senescence.

Curr Opin Endocr Metab Res

Aqsa Komel, David Achudhan, Abhishek Chandra

The cell fate regulation of skeletal stem cells (SSCs) into bone marrow adipocytes (BMAd) during physiological and pathological conditions has been a subject of study. Identification, isolation, and characterization of progenitors that give rise to BMAd, is an extensive field of research. The skewing of the cell fate of SSCs to BMAd also alters the fate of the bone accrual process due to increased bone resorption. Among the several molecular pathways that alter cell fate of SSCs is accumulation of reactive oxygen species, DNA damage, and cellular senescence. The current short review will discuss the direct and indirect effects of cellular senescence in the marrow environment, that leads to SSC differentiation to BMAd. Preclinical studies using pharmacological and genetic clearance of senescent cells and suppression of the senescence associated proinflammatory signature lays the foundation for exploring these strategies as therapeutic interventions that could mitigate BMAd and associated bone loss.

Tanycytic degeneration impairs tau clearance and contributes to Alzheimer's disease pathology.

Cell Press Blue

Florent Sauvé, Ricardo Martinez-Gómez, Yvon Mbouamboua +23 more

Alzheimer's disease (AD) is characterized by pathological Tau protein accumulation in the brain and cerebrospinal fluid (CSF), instead of timely efflux into the blood. However, the underlying mechanisms are unclear. We show, using animal and cellular models and patient tissues, that tanycytes of the hypothalamic median eminence, which bridge the blood and CSF, are involved in Tau transport and AD pathogenesis. In mice, tanycytes take up CSF-borne Tau and release it into pituitary portal capillaries, whence it enters the systemic circulation. Blocking tanycytic vesicular transport blunts CSF-to-blood Tau efflux and potentiates Tau pathology. In AD patients, plasma-to-CSF ratios of total and p181 Tau are decreased. Tanycytes from postmortem AD patient brains display dramatically fragmented processes and significant transcriptomic alterations by single-nucleus RNA sequencing, notably in vesicular-transport-related genes, explaining this clearance deficit. The involvement of tanycytic dysfunction in human pathophysiology and evidence for a brain-to-blood tanycytic shuttle has far-reaching implications.

Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.

bioRxiv

Jasmin S Revanna, Karl Wessendorf-Rodriguez, Qiang Xiao +18 more

While Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for late-onset Alzheimer's disease, its mechanistic role in the brain-resident macrophage, microglia, remains elusive. Microglia are important in the clearance of pathology in disease, heavily relying on lysosome functionality; therefore, we sought to understand the impact of APOE4 on microglial function. APOE44 microglia have been shown to have lipid accumulation, yet the mechanisms leading to this accumulation are unknown. Using induced pluripotent stem cell-derived microglia, we found that the APOE4 haplotype resulted in transcriptional state shifts in microglia, suppressing activated-response microglia (ARMs) and promoting a G2 senescent-like state. We found that APOE44 microglia accumulate cholesterol esters and provide less lipid support to fibroblast-induced neurons, decreasing their synaptic connections. APOE44 microglia secrete significantly less lipoproteins, leading to the accumulation of lipoproteins within the cells including the lysosomes. APOE44 microglia exhibit impaired lysosomal acidification and degradation capacity. Further, our results elucidated that APOE44 microglia are proinflammatory and shift away from fatty acid oxidation towards glycolysis, due to dysfunctional mitochondria. Taken together, our findings indicate that a loss-of-function in lipoprotein secretion drives intracellular lipid accumulation, including within lysosomes, ultimately disrupting the lysosome-endoplasmic reticulum-mitochondrial axis. This drives a proinflammatory and metabolically compromised microglial phenotype with impaired neuro-supportive functions.

Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.

Front Aging Neurosci

Tomomichi Iizuka, Toshiaki Watanabe, Masashi Kameyama

Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.

Pathological Mechanism-Inspired Biomimetic Nano-Senotherapy for Reversing Experimental Atherosclerosis in ApoE-/- Mice.

Adv Sci (Weinh)

Yuhan Tian, Yanrui Yang, Qiuyu Li +7 more

The greatest challenge in atherosclerosis (AS) management lies in achieving lesion reversal, not merely slowing progression. Senescent cell accumulation-driven by continuous generation and apoptotic resistance-perpetuates plaque pathology and obstructs regression. This study addresses the reversal conundrum through a dual-action strategy: blocking new senescent cell formation while enhancing clearance of existing senescent cells. We developed a ROS-responsive dimeric prodrug (K2A) from the MPO-inhibitory tripeptide KYC, which co-assembles with the senolytics Navitoclax into a nano-Senotherapy (N@K2A). Further cloaked with neutrophil membranes from AS mice, the biomimetic N@K2A@NEM precisely targets plaques, responds to local ROS, and orchestrates senescent cell formation and removal. This targeted senotherapeutic intervention demonstrates effective reversal of established experimental AS, offering a potential solution to the field's most pressing clinical dilemma.

The double-edged sword of tumor-targeted treatment: the influence of targeted therapy on the heart.

Transl Cancer Res

Yexuan Huang, Liwen Chen, Cheng Ding +4 more

As an important means of modern cancer treatment, targeted therapy has significant efficacy, but cardiac toxicity cannot be ignored. From subclinical myocardial injury to severe heart failure (HF), it poses significant challenges to the long-term survival and quality of life of patients. This article summarizes the impact of targeted therapy drugs on cardiac function and their mechanisms, including cardiomyocyte damage, myocardial hypertrophy, and HF, and conducts in-depth research into potential molecular mechanisms. These include direct cardiomyocyte damage through targeted pathway inhibition [e.g., human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR)], and off-target effects that lead to oxidative stress, mitochondrial dysfunction, iron deposition, and immune-mediated damage (e.g., checkpoint inhibitors). While the review also outlines strategies for preventing and treating cardiac toxicity of targeted therapy, these include pre-treatment cardiovascular risk stratification, advanced imaging modalities [such as speckle tracking echocardiography and cardiac magnetic resonance imaging (MRI)], biomarker-based monitoring [such as high-sensitivity cardiac troponin (hs-cTn), B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP)], timely drug intervention, and strategic modification of cancer treatment plans. The main objective of the review is to elucidate and enhance clinical understanding of the cardiotoxicity associated with contemporary targeted anti-cancer therapies. By deepening their understanding of the different mechanisms and clinical manifestations of drug-induced heart injury, early detection, multidisciplinary collaboration, and personalized treatment decisions can be promoted. Ultimately, this approach aims to optimize cancer treatment outcomes while maintaining patients' overall quality of life and cardiovascular health.

Hidden in the Mediastinum: A Grade 1 Neuroendocrine Tumor Revealed by Refractory Hypokalemia and Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing's Syndrome.

Cureus

Sofía Paola Agüero-Pineda, Rodrigo Grimaldo-Rivera, José Abraham Camacho-Muñoz +8 more

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) is a rare, fulminant variant of endogenous hypercortisolism that demands rapid localization of the ACTH source to achieve a cure. A 51-year-old woman presented with progressive proximal muscle weakness, centripetal obesity, new-onset hypertension with a blood pressure of 150/90 mmHg at arrival, and persistent hypokalemia (2.2 mmol/L). Biochemical testing confirmed severe hypercortisolism that failed to suppress after an overnight 1-mg dexamethasone test. Plasma ACTH was markedly elevated (798 pg/mL), indicating ACTH-dependent disease. Pituitary MRI showed no adenoma, so an ectopic source was suspected. Contrast-enhanced thoracoabdominal CT revealed a 24 × 14-mm anterior mediastinal node, which was excised via video-assisted thoracoscopic surgery (VATS). Histopathology confirmed a grade 1 neuroendocrine tumor with diffuse positivity for synaptophysin, chromogranin A, and neuron-specific enolase. Twenty-four hours after surgery, serum cortisol decreased to 11.1 µg/dL and ACTH to 2.0 pg/mL; serum potassium normalized without supplementation. Octreotide receptor scintigraphy showed no residual or metastatic disease, and the patient remained normotensive and normokalemic at follow-up. Rapidly progressive hypercortisolism accompanied by refractory hypokalemia should prompt consideration of ectopic ACTH secretion. A stepwise diagnostic approach, including biochemical confirmation, exclusion of pituitary disease, and targeted thoracic localization, enabled early minimally invasive resection and biochemical cure in this case. Early recognition and surgery remain the cornerstones of management for ectopic ACTH-producing neuroendocrine tumors. Prompt identification and anatomical localization of the ectopic source are essential to prevent prolonged exposure to severe hypercortisolism and its associated metabolic and cardiovascular complications. Timely surgical resection allows rapid biochemical remission and improvement in short- and long-term outcomes.

A case report of acute carcinoid heart failure during lutetium-177 dotatate-triapine treatment for well-differentiated neuroendocrine tumors.

Front Oncol

Aman Chauhan, Elise C Kohn, S Percy Ivy +7 more

Well-differentiated neuroendocrine tumors (NETs) have a high indolent local progression rate when resistance develops to biologic or cytotoxic chemotherapy. Radiopharmaceuticals like single-agent [177Lu]lutetium-177 dotatate confer a 17% objective NET partial response rate with prolongation of progression-free survival.