Clinical science最新文献

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, including in the United States. Risk factors such as high cholesterol, diabetes, obesity, smoking, physical inactivity, and hypertension contribute significantly to their development. Emerging evidence highlights a central role for chemokines-small signaling molecules that guide immune cell migration to sites of infection, inflammation, or tissue damage-in the initiation and progression of hypertension. This positions chemokines and their receptors as promising pharmacological targets for blood pressure regulation and vascular protection. In this review, we explore the therapeutic potential of targeting chemokines and their receptors and summarize the main strategies reported in the literature for managing hypertension through these pathways. For this purpose, an analysis of drugs that act on the most relevant receptors at the preclinical and clinical levels was performed. After this analysis, their mechanisms of action, selectivity, and possible adverse effects were discussed. In conclusion, we reinforce that the modulation of chemokines and their receptors represents a promising approach in the control of CVDs, especially hypertension, although further clinical studies are needed to validate the efficacy and safety of this strategy, considering possible impacts on other essential immune responses.

Delayed diabetic wound healing is a global health issue with unclear pathogenesis. Ferroptosis, a form of cell death involving iron and lipid peroxidation, may contribute to delayed diabetic wound. This study investigates the role of ferroptosis in diabetic wound keratinocytes. We measured lipid peroxidation products (MDA, 4-HNE), ACSL4, and GPX4 protein levels in diabetic keratinocytes and assessed mitochondrial morphology. Ferrostatin-1 (Fer-1) was used to inhibit ferroptosis in diabetic rat wounds, and its effects on healing and expression levels were evaluated. Pull-down assays, silver staining, and mass spectrometry were employed to study ACSL4 mRNA regulation. A YTHDF2 knockdown adenovirus was used to manipulate YTHDF2 expression in rat wounds. Ferroptosis was detected in diabetic keratinocytes, hindering wound healing, a process reversible with Fer-1. High glucose induced ACSL4 expression, driving keratinocyte ferroptosis and delayed healing. YTHDF2 interacts with N6-methyladenosine-modified ACSL4 mRNA, affecting its stability and expression. YTHDF2 knockdown increased ACSL4, promoting ferroptosis and impairing healing. Our findings illustrate the significant involvement of ferroptosis in the dysfunction of diabetic keratinocytes, suggesting that targeting ferroptosis may offer a viable therapeutic approach for improving diabetic wound healing.

Limited drug therapies for peripheral artery disease (PAD)-related walking impairment exist. There has been a recent interest in repurposing the diabetes medication metformin to treat PAD. Animal studies designed to develop new PAD drug therapies have mainly used a model of temporary hind limb ischaemia (HLI). The aim of this study was to test whether metformin improved blood supply and ambulation in a novel mouse model with ongoing HLI. Stable HLI was created in apolipoprotein E-deficient mice by a two-stage surgical procedure. Five days after HLI was induced, mice were randomly allocated to receive metformin (n = 16; 300 mg/kg/day) or vehicle control (n = 15) by oral gavage for four weeks. The primary outcome was hind limb blood supply assessed by laser Doppler. Other outcomes included treadmill performance and molecular changes in the ischaemic limb. Metformin improved hind limb blood supply (P<0.001), but not physical performance, associated with increased phosphorylation of 5' adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase (P<0.05), reduced expression of thioredoxin interacting protein (P<0.05) and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (P<0.05) in the ischaemic muscles and increased circulating nitric oxide levels (P<0.05). Metformin improved blood supply in a novel model of limb ischaemia associated with molecular changes previously linked with promoting angiogenesis, but these changes did not translate to improved physical performance. The findings suggest that laser Doppler hind limb blood supply may not be an ideal outcome measure to gauge the success of a drug in patients with PAD-related walking impairment.

There is an important gap of knowledge regarding the mechanisms behind the greater prevalence of chronic kidney disease (CKD) in females compared with males. Most of the published reports suggest that females are protected from acute kidney injury (AKI) and from the AKI-to-CKD transition; however, in this issue of Clinical Science, Moronge et al. demonstrate that female rats present with subclinical markers of kidney damage post-ischemic reperfusion injury despite normalized levels of plasma creatinine. These studies underscore the potential for this AKI-induced subclinical injury to underlie the higher sensitivity of females to develop CKD later in life.

Angiotensin II AT2 receptor (AT2R) activation leads to significant anti-fibrotic and anti-inflammatory effects in diseased organs, which has led to clinical trial evaluation of the AT2R agonist, Compound 21 (C21), as a treatment for idiopathic pulmonary fibrosis (IPF). In this study, the anti-fibrotic effects of a more selective AT2R ligand, β-Pro7 angiotensin III (β-Pro7 Ang III), with >20,000-fold affinity for the AT2R over the AT1R, were compared with that of C21 or the currently used IPF medication, pirfenidone, in mice with bleomycin (BLM)-induced pulmonary fibrosis. Adult female BALB/c mice received a double intranasal instillation of BLM (20 mg/kg/day) seven days apart and were maintained until day 35, while control mice were instilled with saline (SAL) seven days apart and maintained for the same time period. Sub-groups of BLM-injured mice were then treated on day 28 with vehicle (SAL), C21 (0.3 mg/kg/day) or β-Pro7 Ang III (0.1 mg/kg/day) via seven-day subcutaneously implanted osmotic minipumps, or daily from days 28 to 35 via orally administered pirfenidone (100 mg/kg/day). At day-35 post-injury, measures of lung fibrosis and compliance were evaluated. Compared with their SAL-instilled counterparts, SAL-treated BLM-injured mice presented with a significantly increased lung Ashcroft score, Masson's trichrome-stained and second harmonics generation-measured fibrosis, myofibroblast accumulation, and TGF-β1 expression, but reduced lung dynamic compliance at day-35 post-injury. While all treatments evaluated attenuated the BLM-induced lung myofibroblast accumulation and TGF-β1 expression, AT2R stimulation, but not pirfenidone, attenuated lung collagen deposition after seven days. β-Pro7 Ang III also significantly restored lung compliance and promoted collagen-degrading matrix metalloproteinase-2 activity. These findings highlighted the therapeutic value of selectively targeting the AT2R for treating IPF.

Abnormal fetal growth is associated with perinatal complications and adult disease. The placental mechanistic target of rapamycin (mTOR) signaling activity is positively correlated with placental nutrient transport and fetal growth. However, if this association represents a mechanistic link, it remains unknown. We hypothesized that trophoblast-specific Mtor knockdown in late pregnant mice decreases trophoblast nutrient transport and inhibits fetal growth. PiggyBac transposase-enhanced pronuclear injection was performed to generate transgenic mice containing a trophoblast-specific Cyp19I.1 promoter-driven, doxycycline-inducible luciferase reporter transgene with a Mtor shRNAmir sequence in its 3' untranslated region (UTR). We induced Mtor knockdown by administration of doxycycline starting at E14.5. Dams were killed at E 17.5, and trophoblastspecific gene targeting was confirmed. Placental mTOR protein expression was reduced in these animals, which was associated with a marked inhibition of mTORC1 and mTORC2 signaling activity. Moreover, we observed a decreased expression of System A amino acid transporter isoform SNAT2 and the System L amino acid transporter isoform LAT1 in isolated trophoblast plasma membranes and lower fetal, placental weight, and fetal:placental weight ratio. We also silence the MTOR in cultured primary human trophoblast cells, which inhibited the mTORC1 and C2 signaling, System A and System L amino acid transport activity, and markedly decreased the trafficking of LAT1 and SNAT2 to the plasma membrane. Inhibition of trophoblast mTOR signaling in late pregnancy is mechanistically linked to decreased placental nutrient transport and reduced fetal growth. Modulating trophoblast mTOR signaling may represent a novel intervention in pregnancies with abnormal fetal growth.

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Renal involvement is a major complication, yet diagnosis often requires an invasive kidney biopsy, and follow-up relies on indirect biomarkers or imaging, which lack specificity. Here, we present human urine-derived renal epithelial cells (hURECs) as a minimally invasive alternative for phenotyping renal Fabry disease and monitoring treatment response. Using hURECs from a newly diagnosed male Fabry disease patient, transmission electron microscopy (TEM) revealed lysosomal inclusions consistent with native kidney biopsy findings. Bulk RNA sequencing (RNA-seq) identified a transcriptomic disease signature, including dysregulated pathways involved in lipid metabolism homeostasis, ion transport, endoplasmic reticulum stress response, and collagen processing. Following systemic treatment of the patient with chaperone therapy, partial amelioration of the hUREC transcriptomic signature was observed during the first few months. However, by nine months, the signature began reverting toward baseline, correlating with continued kidney function decline. This prompted a transition to enzyme replacement therapy, with early evaluations showing transcriptomic stabilization. Our findings demonstrate that hURECs replicate key structural and molecular markers of renal Fabry disease and offer a non-invasive platform for longitudinal assessment of treatment response. TEM of hURECs provides a diagnostic alternative to biopsy, while RNA-seq-based transcriptomic profiling offers a sensitive and dynamic view of molecular changes, including key dysregulated pathways. This dual utility positions hURECs as a novel tool for improving the diagnosis, monitoring, and personalized management of kidney involvement in Fabry disease.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are characterized by relapsing-remitting immune activation and inflammation within the gastrointestinal tract. The immune system activity displays diurnal variation, which is regulated by the circadian clock. This is achieved by modulating the number of circulating lymphocytes, antibody production, cytokine production, host- pathogen interactions, and the activation of innate and adaptive immunity around the circadian cycle. Indeed, intestinal biopsies and peripheral blood cells obtained from patients with active IBD demonstrated reduced circadian clock gene expression. Key clock regulatory proteins, such as retinoic acid receptor-related orphan receptors, REV-ERBs, peroxisome proliferator-activated receptors (PPARs), PPARγ transcriptional co-activator 1α, adenosine monophosphate-activated protein kinase and Sirtuin 1, have a dual function as they regulate clock gene expression as well as the expression of certain pro- and anti-inflammatory factors through the NF-κB signaling pathway. All the aforementioned clock regulatory proteins are also key regulators of metabolism. Thus, these factors form a complex triangular network that regulates the circadian clock, inflammation, and metabolism. Emerging data support the notion that clock disruption is associated with inflammation and aberrant metabolic regulation and that regulators of the circadian clock may play a role in inflammatory and metabolic processes. In this review, we will focus on the interrelations among the circadian clock, metabolism, and inflammation in IBD.