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PubMed2025

Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

AIMS: Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. MATERIALS AND METHODS: Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. RESULTS: Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. CONCLUSIONS: This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

Humans↗

PubMed2026

Mocravimod as a repurposing drug against clinical isolates of Staphylococcus aureus by targeting cell membrane.

UNLABELLED: Staphylococcus aureus infections, particularly those caused by multidrug-resistant strains and associated with biofilm formation, pose a major therapeutic challenge in clinical practice. The objective of this study was to evaluate the antibacterial and antibiofilm activity of mocravimod (KRP-203), an FDA-approved S1P receptor modulator, against clinical S. aureus isolates and to explore its underlying mechanism of action. The antibacterial activity of KRP-203 was assessed against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) using MIC determination, time-kill assays, and biofilm inhibition models. KRP-203 exhibited strong bactericidal activity against planktonic MSSA and MRSA, with MIC values ranging 6.25-50μM. Time-kill assays demonstrated rapid bacterial eradication at 8× MIC within 2 h, showing superior killing kinetics compared with vancomycin. At sub-inhibitory concentrations, KRP-203 inhibited biofilm formation by up to 70% and reduced viable bacterial counts in mature biofilms by >2.5 logs. To elucidate the antibacterial mechanism, whole-genome sequencing and quantitative proteomic analyses were performed. These analyses revealed mutations in membrane-associated genes, including glnQ and BCAT, and significant alterations in proteins related to membrane integrity and redox regulation. Consistently, functional assays confirmed that KRP-203 disrupts bacterial cell membrane, as evidenced by dose-dependent membrane depolarization, increased permeability, and direct binding to cardiolipin and phosphatidylglycerol. Molecular docking further predicted a favorable interaction between KRP-203 and GlnQ. In conclusion, KRP-203 demonstrated notable antibacterial and antibiofilm activity against S. aureus, likely through membrane integrity disruption. While these findings highlight its potential as a repurposed antibacterial agent, further studies are required to fully elucidate its molecular targets, optimize antibacterial efficacy, and evaluate its in vivo safety profile. IMPORTANCE: Antibiotic resistance and the formation of biofilms, which protect bacteria from medications and immunological responses, present the significant challenges for the clinical treatment of Staphylococcus aureus infections. This study reveals mocravimod hydrochloride (KRP-203), a clinically approved drug initially intended to treat leukemia, as a viable new candidate against S. aureus infection. KRP-203 quickly kills both drug-susceptible and resistant S. aureus, including difficult-to-treat biofilm-associated cells. Its membrane-disrupting activity quickly kills drug-resistant bacteria while also destroying biofilm formations, presenting a dual action rarely accomplished by conventional antibiotics. Critically, KRP-203's established safety profile in human studies may hasten its repurposing as a new weapon against biofilm-associated infections, providing possible solutions for chronic and drug-resistant S. aureus infections where existing treatments commonly fail.

Biofilms↗

PubMed2025

Fingolimod as a potent anti-Staphylococcus aureus: pH-dependent cell envelope damage and eradication of biofilms/persisters.

BACKGROUND: The urgent need for new antibacterial drugs has driven interest in repurposing therapies to combat Gram-positive biofilms and persisters. Fingolimod, an Food and Drug Administration (FDA)-approved drug for multiple sclerosis, shows bactericidal activity, particularly against Methicillin-resistant Staphylococcus aureus (MRSA) and biofilm-related infections. With a well-documented safety profile and strong translational potential, it aligns with World Health Organization's goals for antimicrobial repurposing. However, the action mode and mechanism of Fingolimod against gram-positive bacteria remain elusive. METHODS: This study utilized clinical Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), Streptococcus agalactiae (S. agalactiae). And their susceptibility to Fingolimod and other antibiotics was tested via Minimum Inhibitory Concentration (MIC) assays. Biofilm inhibition and hemolytic activity were evaluated using crystal violet staining, Confocal Laser Scanning Microscopy (CLSM), and hemolysis assays, respectively, while the effect of phospholipids on Fingolimod efficacy was assessed with checkerboard assays. Membrane permeability and integrity were measured using SYTOX green staining and transmission electron microscopy. Whole-genome sequencing was performed on Fingolimod-resistant S. aureus isolates to identify Single Nucleotide Polymorphisms (SNPs) linked to resistance. RESULTS: Our data indicated that Fingolimod exerted bactericidal activity against a wide spectrum of gram-positive bacteria, including S. aureus, E. faecalis, S. agalactiae. Moreover, Fingolimod could significantly eliminate the persisters, inhibit biofilm formation and eradicate in-vitro mature biofilms of S. aureus. The mechanism by which Fingolimod rapidly eradicated S. aureus involved a pH-dependent disruption of bacterial cell permeability and envelope integrity. Concomitantly, exogenous supplementation of phospholipids in the culture medium resulted in a dose-dependent increase in the MIC of Fingolimod. Specifically, the addition of 64 μg/mL of cardiolipin (CL) and phosphatidylethanolamine (PE) completely nullified the bactericidal activity of Fingolimod at a concentration of 4 times the MIC. After four months of Fingolimod exposure, the MIC values of S. aureus showed a slight increase, indicating that it is not prone to developing drug resistance. CONCLUSION: Fingolimod exhibits bactericidal activity against diverse gram-positive bacteria, with remarkable effects on S. aureus (including MRSA), disrupting bacterial cell structural integrity in a pH-dependent way and eradicating biofilms and persisters of S. aureus.

Biofilms↗

PubMed2026

Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models.

BACKGROUND: Patients with asthma have an increased risk of developing depression, affecting their quality of life. To date, the processes contributing to this comorbidity remain unclear. METHODS: We integrated two large genome-wide association studies (88,486 patients with asthma and 447,859 controls; 412,024 patients with depression and 1,587,577 controls) with cross-sectional and longitudinal information available from the All of Us Research Program (N = 87,167) through polygenic risk scoring (PRS), Cox proportional-hazards models, one-sample Mendelian randomization (MR), and gene-set and drug-repurposing analyses. RESULTS: We observed that depression PRS was associated with increased asthma risk (hazard ratio, HR = 1.13, 95% CI = 1.09-1.17), also when accounting for comorbidity status (HR = 1.08, 95% CI = 1.04-1.12). Conversely, the effect of asthma PRS was null after accounting for comorbidity status. One-sample MR analysis showed an effect of depression genetic liability on asthma, ranging from beta = 0.36 ± 0.03 when considering a linear relationship to beta = 3.21 ± 0.31 when considering possible nonlinear relationships. Conversely, the effect of asthma genetic risk on depression was null after accounting for potential confounders. The gene-set analyses showed that asthma and depression polygenic risks share biological processes, molecular functions, and cellular components related to the immune system and the lung-brain axis. CONCLUSIONS: Genetic predisposition contributes to asthma-depression comorbidity through direct effects and shared pathogenic processes. These findings highlight the potential to develop targeted interventions to prevent and treat the co-occurrence of respiratory and neuropsychiatric disorders.

Comorbidity↗

PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife® combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗

PubMedDate not supplied

A homeostatic adaptive response to alpha-methyl-dopa in conscious dogs.

Repeated daily administration of an oral dose of 1000 mg of alpha-methyl-dopa (methyl dopa) to conscious dogs produced a conditioned adaptive hypertensive systolic and diastolic arterial pressure response along with the direct hypotensive pharmacological effect. The lower dose of 500 mg/day appeared to be devoid of direct or adaptive response effects, while the higher dose of 2000 mg/day only produced a blood pressure lowering response. The abrupt drug withdrawal unmasking the homeostatic state resulted in a marked systolic and diastolic pressor response which endured for about 10-days with peak effect reached at 17-days after termination of drug treatment. Comparable results were obtained whether the dogs were evaluated while in their normal horizontal body position or in a repositional upright condition.

Adaptation, Physiological↗

PubMed1978

Treatment prostheses in TMJ dysfunction-pain syndrome.

Various types of acrylic resin therapeutic prostheses commonly used in the treatment of TMJ dysfunction-pain syndrome were described. Each design was related to recent data concerning optimum condylar positions in the fossae, the physiologic condylar suspension system, and individual treatment objectives for repositioning the mandibular condyles. For example, alteration of the vertical dimension of occlusion is a popular treatment procedure that is empirical in nature and is usually used without TMJ radiographs or a differential diagnosis. It can violate the physiologic requirements of the interocclusal distance or the speaking space and does not necessarily move the condyles forward as has been commonly thought. The dangers of empirical treatment procedures for a multicausal dysfunction syndrome have been pointed out. An example was cited where the mandible was moved forward for a long period of time with a repositioning prosthesis; this produced pathologic TMJ remodeling and continued pain. It was recommended that specific mandibular repositioning be based on the type of condylar displacement observed on the radiographs. Sometimes the condyles should be retruded, and other times they should be repositioned anteriorly or occasionally inferiorly on one side. Long-standing use of any acrylic resin repositioning prosthesis is contraindicated, particularly without close supervision. Acrylic resin anterior bite plates (with a minimum opening of 1 mm) were recommended for the relief of acute trismus or intractable pain. Usually the prosthesis is used in conjunction with heat and drug therapy. This type of prothesis can also be utilized to deprogram the muscles when a strong habit of eccentric occlusion develops as a result of missing teeth. (This should be confirmed by TMJ radiographs.) Occasionally atypical pain is present and a differential diagnosis can be established between TMJ dysfunction or neurologic etiology by the physiologic response to bite plate therapy. When it is necessary to reposition the mandibular condyles anteriorly the occlusion is adjusted to provide the planned anterior movement without increasing the vertical dimension of occlusion. A temporary acrylic resin prosthesis is used to retrain the muscle programming to the anterior therapeutic mandibular position. When the symptoms are relieved and the corrective condylar position is confirmed with TMJ radiographs, a more permanent repositioning prosthesis is made. The treatment of TMJ dysfunction-pain syndrome should be based on documented data including the pain history, TMJ radiographs, condylar position in the fossae, electromyographic evidence, and occlusal analysis. This information will help determine if the patient's centric relation is functional or dysfunctional and will indicate the recommended treatment procedures.

Acrylic Resins↗

PubMed1979

Preliminary experience with the helifix electrode for transvenous atrial implantation.

A Helifix electrode was inserted transvenously in the right atrial appendage for temporary atrial stimulation in three patients. The low stimulation threshold as well as the excellent stability of the electrode encouraged us to proceed to permanent implantation of this lead in thirteen patients. The lead was introduced through the saphenous vein in twelve patients and through the cephalic vein in one patient. Five patients had sinoatrial dysfunction and five had bradycardia-tachycardia syndrome; they received atrial demand pacemakers. Two patients had atrioventricular block and received atrial synchronous ventricular pacemarkers. Our last patient had restrictive cardiomyopathy, heart failure and a drug-refractory atrial arrhythmia. She received a dual-chamber sequential pacing device. Atrial electrode displacement occurred in one patient soon after implantation. The lead was promptly repositioned without difficulty. Partial sensing of spontaneous P waves was observed in two patients. One recovered spontaneously, the second after substituting a pulse generator with a higher input sensitivity. Our clinical experience during the period from November 1977 to January 1979 has shown that the Helifix electrode is suitable for transvenous atrial implantation.

Adult↗

PubMedDate not supplied

Chronic dorsal column stimulation via percutaneously inserted epidural electrodes. Preliminary results in 31 patients.

31 patients suffering from intractable pain associated with chronic low back syndrome, terminal cancer, and other disorders have been studied after an average 6 months' treatment by electrical stimulation of the spinal cord applied via electrodes inserted through a Tuohy needle into the epidural space. As judged by three different subjective rating methods, epidural stimulation successfully relieved otherwise intractable chronic pain in from 23 to 26 of the 31 patients. Reported improvements in the ability to perform various everyday activities, and elimination of drug usage by many patients, corroborate this finding. The side effects of stimulation, both as reported subjectively and as measured objectively by sensory testing, were not clinically significant. Spontaneous electrode displacements, leading to loss of analgesia and requiring minor surgery for repositioning, were encountered frequently, as were lead wire failures necessitating replacement. The partially implanted, externally powered stimulation system presently in use also suffers from problems of reliability and convenience to the patient.

Electric Stimulation Therapy↗

PubMed1976

Orthostatic influences on cardiovascular responses to nitroglycerin in conscious dogs.

The influence of body position change on the arterial pressure and heart rate responses produced by acute short-acting and sustained-release dosage forms of nitroglycerin was evaluated in a series of chronically prepared, conscious beagle dogs. The upright repositioning of the dog to 60 degrees from horizontal markedly enhanced the hypotensive and bradycardic responses produced by both dosage forms. Since it has been suggested that the lowering of arterial pressure is an essential component resulting in the therapeutic usefulness of nitroglycerin in angina pectoris, the experimental orthostatic model could be a sensitive procedure for the laboratory assessment of drugs of this class.

Animals↗

PubMed1978

A new magnetic technique for the treatment of giant retinal tears.

Using surgical techniques similar to those for closed vitreous surgery, we introduced a small magnetic sphere into the intraocular cavity of experimental animals. The sphere was subsequently maneuvered gently over the retina to unfold and reposition it with a small external permanent magnet probe. We used 68 enucleated canine eyes; eight eyes were operated in vivo and then examined microscopically. Retinal damage was caused by friction and excessive pressure when we used external magnets that were too strong or spheres that were too large. When small intraocular magnetic spheres coated with silicone or teflon or encased in a hollow oversize epoxy sphere were used the damage to the retina was minimal, or absent. We suggest using this same technique to treat retinal tumors through the introduction of radioactive material or antitumoral drugs. The intraocular magnetic sphere of this type would be left inside the eye in contact with the lesion for an extended period (seven days to three months) by suturing a small magnet to the sclera over the lesion.

Animals↗