Synthesis and biological evaluation of sulfonamide derivatives containing imidazole moiety as ALK5 inhibitors.

Four series of sulfonamide derivatives (13a-b, 14a-d, 15a-b, and 16a-d) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC50 = 0.130 µM) and 15a (IC50 = 0.130 µM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299. Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 µM, and effectively inhibited TGF-ß1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.

Application of enhanced recovery after surgery for oral dryness prevention after endoscopic sinus surgery.

OBJECTIVE: To investigate the efficacy of cluster nursing intervention based on Enhanced Recovery After Surgery (ERAS) for xerostomia in chronic rhinosinusitis after nasal endoscopic surgery. METHODS: A total of 80 patients with chronic rhinosinusitis who underwent functional nasal endoscopic surgery between January 2020 and December 2021 were selected and randomly divided into a control group (n = 40) and an experimental group (n = 40). Patients in the control group were treated with general nursing, while ERAS-based cluster nursing intervention was adopted for the experimental group, in addition to general nursing. Xerostomia stage and comfort level were observed at 2 h, 6 h, 24 h and 48 h after surgery; negative emotions before and after nursing were also observed. RESULTS: After the intervention, the xerostomia stage and comfort level at 6, 24 and 48 after surgery were higher in the experimental group (p < 0.05). Negative emotions in the experimental group were lower after nursing (p < 0.001). The self-rating depression scale and self-rating anxiety scale scores increased after nursing in both two groups (p < 0.05). CONCLUSION: Enhanced recovery after surgery-based cluster nursing intervention can alleviate xerostomia, improve patients' comfort levels, reduce their negative emotions and accelerate postoperative recovery.

Increased Incidence of Severe Adverse Events in Non-Small Cell Lung Cancer Patients with Previous Tuberculosis Episode Treated with PD-1 Inhibitors.

Lung cancer is the top cause of cancer deaths globally. Advances in immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but their use in lung cancer has led to more side effects. This study examined if past pulmonary tuberculosis (TB) affects ICIs' effectiveness and safety in lung cancer treatment. We reviewed lung cancer patients treated with ICIs at Beijing Chest Hospital from January 2019 to August 2022. We compared outcomes and side effects between patients with and without prior TB. Of 116 patients (40 with TB history, 76 without), prior TB didn't reduce treatment effectiveness but did increase severe side effects. Notably, older patients (≥ 65 years) faced a higher risk of severe side effects. Detailed cases of two patients with severe side effects underscored TB as a risk factor in lung cancer patients receiving ICIs, stressing the need for careful monitoring and personalized care.

Effects of compound probiotics on pharmacokinetics of CYP450s probe drugs in rats.

Compound probiotics have been widely used and commonly co-administered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (CYP450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin and chlorzoxazone. Male Wistar rats were administered with drinking water containing VSL#3 or not for 14 days and then intragastrically administered a CYP450s probe cocktail; This was done to investigate the host CYP450s metabolic phenotype. Stool, liver/jejunum and serum samples were collected for 16S rRNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both alpha and beta diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1,417 and 4,004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of CYP450s genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and the intestinal structure in rats, which could be reasons for pharmacokinetic changes. Significance Statement This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of CYP450s probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the current study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, here combined with the bile acid profile and histopathological analysis.

Microbial Biogeography along the Gastrointestinal Tract of a Wild Chinese Muntjac (Muntiacus reevesi).

The gut microbiota plays an important role in host nutrient absorption, immune function, and behavioral patterns. Much research on the gut microbiota of wildlife has focused on feces samples, so the microbial composition along the gastrointestinal tract of wildlife is not well reported. To address this gap, we performed high-throughput sequencing of 16s rRNA genes and ITs rRNA genes in the gastrointestinal contents of a wild adult male Chinese muntjac (Muntiacus reevesi) to comparatively analyze the microbial diversity of different gastrointestinal regions. The results showed that the dominant bacterial phyla were Firmicutes (66.19%) and Bacteroidetes (22.7%), while the dominant fungal phyla were Ascomycetes (72.81%). The highest bacterial diversity was found in the stomach, and the highest fungal diversity was found in the cecum. The microbial communities of the large intestine and small intestine were of similar structures, which were distinct from that of the stomach. These results would facilitate the continued exploration of the microbial composition and functional diversity of the gastrointestinal tract of wild Chinese muntjacs and provide a scientific basis for microbial resource conservation of more wildlife.

Specialized metabolites of the endophyte Annulohypoxylon areolatum hosted by Aconitum carmichaelii.

Seven previously undescribed compounds, including one amino acid hybrid sesquiterpene areolatol A (1), two unusual natural sesquiterpenoid skeleton areolatones A-B (2-3) and four benzo[j]fluoranthene areolaranes A-D (4-7) were characterized from Annulohypoxylon areolatum. The structures of the compounds were determined by extensive spectroscopic analysis, X-ray diffraction analysis, and ECD and NMR computational. Notably, areolatol A (1) was the first reported sesquiterpene featuring a 5/7/3-ring system and hybridized with two molecular amino acids. In addition, areolaranes A-D (4-7) were identified as possible chemophenetic markers.

Tetracycline Three Times Daily Versus Four Times Daily in Bismuth-Containing Quadruple Therapy as the First-Line Treatment of Helicobacter pylori Infection: A Multicenter, Noninferiority, Randomized Controlled Trial.

BACKGROUND: Current guidelines recommend bismuth-containing quadruple therapy for patients newly diagnosed with Helicobacter pylori (H. pylori) infection. We aimed to compare the efficacy and safety of tetracycline administered three times daily versus four times daily in bismuth-containing quadruple therapy for first-line treatment of H. pylori infection. METHODS: This multicenter, noninferiority, randomized controlled study, conducted in China, recruited treatment-naïve adults with H. pylori infection, randomized 1:1 into two treatment groups to receive either of the following bismuth-containing quadruple therapies: esomeprazole 20 mg twice-daily; bismuth 220 mg twice-daily; amoxicillin 1000 mg twice-daily; and tetracycline 500 mg three times daily (TET-T) versus 500 mg four times daily (TET-F). At least 6 weeks post-treatment, a 13C-urea breath test was performed to evaluate H. pylori eradication. RESULTS: In total, 406 patients were randomly assigned to the two treatment groups. Intention-to-treat eradication rates were 91.63% (186/203; 95% confidence interval [CI] 87.82%-95.44%) versus 90.15% (183/203; 95% CI 86.05%-94.25%) (p = 0.0005) and per-protocol eradication rates were 95.34% (184/193; 95% CI 92.36%-98.31%) versus 95.72% (179/187; 95% CI 92.82%-98.62%) (p = 0.0002) for the TET-T and TET-F group, respectively. TET-T-treated patients had a lower incidence of adverse effects than TET-F-treated patients (21.61% vs. 31.63%, p = 0.024), with no significant differences in compliance to treatment between the groups. CONCLUSION: As a first-line therapy for H. pylori infection, the eradication rate of the TET-T therapy was noninferior to that of the TET-F therapy while significantly reducing the incidence of adverse reactions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05431075.

Parathyroid carcinoma located in the thyroid gland: A case report.

BACKGROUND: Parathyroid carcinoma (PC) is a difficult-to-diagnose rare disease with low incidence. Relatively accurate preoperative diagnosis is very important in choosing surgical methods and patient prognosis. CASE SUMMARY: This study reported the clinical diagnosis and treatment of a rare patient with PC located in the thyroid gland and provided a case reference for the diagnosis and treatment of PC. A case of a 64-year-old male patient who presented to our hospital with systemic muscle and joint pain and palpitations is outlined. Subsequently, the patient was admitted to the Department of Nephrology for the treatment of "multiple myeloma nephropathy pending investigation". The patient was diagnosed with "primary hyperparathyroidism and hypercalcemic crisis" using thyroid color ultrasound. CONCLUSION: The intraoperative frozen section report considered the parathyroid tumor. Surgical tumor resection was promptly performed, and the diagnosis of PC was confirmed.

Heyingwuzi formulation alleviates diabetic retinopathy by promoting mitophagy via the HIF-1α/BNIP3/NIX axis.

BACKGROUND: Diabetic retinopathy (DR) is the primary cause of visual problems in patients with diabetes. The Heyingwuzi formulation (HYWZF) is effective against DR. AIM: To determine the HYWZF prevention mechanisms, especially those underlying mitophagy. METHODS: Human retinal capillary endothelial cells (HRCECs) were treated with high glucose (hg), HYWZF serum, PX-478, or Mdivi-1 in vitro. Then, cell counting kit-8, transwell, and tube formation assays were used to evaluate HRCEC proliferation, invasion, and tube formation, respectively. Transmission electron microscopy was used to assess mitochondrial morphology, and Western blotting was used to determine the protein levels. Flow cytometry was used to assess cell apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Moreover, C57BL/6 mice were established in vivo using streptozotocin and treated with HYWZF for four weeks. Blood glucose levels and body weight were monitored continuously. Changes in retinal characteristics were evaluated using hematoxylin and eosin, tar violet, and periodic acid-Schiff staining. Protein levels in retinal tissues were determined via Western blotting, immunohistochemistry, and immunostaining. RESULTS: HYWZF inhibited excessive ROS production, apoptosis, tube formation, and invasion in hg-induced HRCECs via mitochondrial autophagy in vitro. It increased the mRNA expression levels of BCL2-interacting protein 3 (BNIP3), FUN14 domain-containing 1, BNIP3-like (BNIP3L, also known as NIX), PARKIN, PTEN-induced kinase 1, and hypoxia-inducible factor (HIF)-1α. Moreover, it downregulated the protein levels of vascular endothelial cell growth factor and increased the light chain 3-II/I ratio. However, PX-478 and Mdivi-1 reversed these effects. Additionally, PX-478 and Mdivi-1 rescued the effects of HYWZF by decreasing oxidative stress and apoptosis and increasing mitophagy. HYWZF intervention improved the symptoms of diabetes, tissue damage, number of acellular capillaries, and oxidative stress in vivo. Furthermore, in vivo experiments confirmed the results of in vitro experiments. CONCLUSION: HYWZF alleviated DR and associated damage by promoting mitophagy via the HIF-1α/BNIP3/NIX axis.

The immune-inflammation factor is associated with diabetic nephropathy: evidence from NHANES 2013-2018 and GEO database.

Diabetic nephropathy (DN) is a common secondary kidney disease. Immune and inflammatory responses play an influential role in the development of DN. This study aims to explore the role and mechanisms of immune- and inflammatory-related factors in DN. Participants from the NHANES 2013-2018 were included to evaluate the association between the SII and DN. Considering the skewed distribution of SII, log SII was used for subsequent analysis. Then, the DEGs were extracted from the GSE96804 dataset by the "limma" package of R, which were further screened out genes in the key module based on WGCNA. The intersection genes between DEGs and key module genes were the key genes for the following mechanism exploration. The CyTargetlinker plug-in of Cytoscape software was used to construct the drug-genes network. Molecular docking was used to calculate the binding affinity between potential drugs and the hub genes. Among the 8236 participants from NHANES 2013-2018, Log SII was significantly associated with DN (p < 0.05). DEG and WGCNA revealed 30 DN-related genes, which mainly regulated immune- and inflammation pathways, and the NOD-like receptor signaling pathway was the core pathway highly involved in the DN occurrence. Moreover, NAIP, ZFP36, and DUSP1 were identified as hub genes in DN progression and there was a strong binding interaction between resveratrol and DUSP1.In conclusion, immune inflammation plays an influential role in the occurrence and development of DN. SII is an effective diagnostic marker for DN and resveratrol might have potential value in treating DN.

Multimodal abnormalities of brain structures in adolescents and young adults with major depressive disorder: An activation likelihood estimation meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in adolescents and young adults contributes significantly to global morbidity, with inconsistent findings on brain structural changes from structural magnetic resonance imaging studies. Activation likelihood estimation (ALE) offers a method to synthesize these diverse findings and identify consistent brain anomalies. AIM: To identify consistent brain structural changes in adolescents and young adults with MDD using ALE meta-analysis. METHODS: We performed a comprehensive literature search in PubMed, Web of Science, Embase, and Chinese National Knowledge Infrastructure databases for neuroimaging studies on MDD among adolescents and young adults published up to November 19, 2023. Two independent researchers performed the study selection, quality assessment, and data extraction. The ALE technique was employed to synthesize findings on localized brain function anomalies in MDD patients, which was supplemented by sensitivity analyses. RESULTS: Twenty-two studies comprising fourteen diffusion tensor imaging (DTI) studies and eight voxel-based morphometry (VBM) studies, and involving 451 MDD patients and 465 healthy controls (HCs) for DTI and 664 MDD patients and 946 HCs for VBM, were included. DTI-based ALE demonstrated significant reductions in fractional anisotropy (FA) values in the right caudate head, right insula, and right lentiform nucleus putamen in adolescents and young adults with MDD compared to HCs, with no regions exhibiting increased FA values. VBM-based ALE did not demonstrate significant alterations in gray matter volume. Sensitivity analyses highlighted consistent findings in the right caudate head (11 of 14 analyses), right insula (10 of 14 analyses), and right lentiform nucleus putamen (11 of 14 analyses). CONCLUSION: Structural alterations in the right caudate head, right insula, and right lentiform nucleus putamen in young MDD patients may contribute to its recurrent nature, offering insights for targeted therapies.

Effect of Wearing Noise-Canceling Headphones on Delivery Process in Natural Childbirth Puerperae: A Single-Center Study.

OBJECTIVE: To investigate the effect of incorporating noise-canceling headphones into the delivery process for natural childbirth puerperae. METHODS: We conducted a retrospective analysis of clinical data encompassing natural childbirth puerperae in the People's Hospital of Suzhou New District from January 2021 to February 2023. The implementation of routine noise reduction management was done from January 2021 to January 2022. During this interval, 69 natural childbirth puerperae were selected as subjects, with 7 excluded, resulting in 62 participants constituting the reference group. Subsequently, noise-canceling headphones were distributed to natural childbirth puerperae from February 2022 to February 2023. In this phase, 66 subjects were selected, and 6 were excluded, resulting in 60 participants forming the observation group. Following admission, both groups underwent corresponding nursing management. Emotional states, pain levels, and various indicators were systematically collected and meticulously compared. RESULTS: The observation group exhibited significantly lower Hamilton Anxiety Rating Scale scores than the reference group before delivery and during the first stage of labor (P < 0.05). The observation group demonstrated significantly lower visual analog scale scores and substance P, nitric oxide, and prostaglandin E2 levels than the reference group during the first stage of labor (P < 0.001). During the second stage of labor, the visual analog) scale scores were significantly lower in the observation group than in the reference group (P < 0.05). The durations of first and second labor stages were significantly shorter in the observation group than in the reference group (P < 0.05). No significant difference existed in Apgar scores between the two groups (P > 0.05). CONCLUSION: The utilization of noise-canceling headphones emerges as an effective intervention, alleviating anxiety, reducing pain during T1, and abbreviating total labor time in natural childbirth puerperae, suggesting its substantial clinical application value and potential as a beneficial addition to maternity care practices.

Generation of a competing endogenous RNA network and validation of BNIP1 expression in the lung of irradiated mice.

BACKGROUND: Radiation-induced lung injury (RILI) is a serious complication of radiation therapy, and it is mediated by long non-coding RNAs (lncRNAs). STUDY DESIGN AND METHODS: Mouse lung tissues were examined using RNA-Seq and RNA-Seq libraries 72 h after the administration of 6 Gy of X-ray irradiation. The target mRNAs were functionally annotated and the target lncRNA-based miRNAs and target miRNA-based mRNAs were predicted after irradiation to establish the lncRNA-miRNA-mRNA ceRNA axis. RESULTS: The analyses showed that relative to unirradiated controls, 323 mRNAs, 114 miRNAs, and 472 lncRNAs were significantly up-regulated following irradiation, whereas 1907 mRNAs, 77 miRNAs, and 1572 lncRNAs were significantly down-regulated following irradiation. Voltage-gated ion channels, trans-membrane receptor protein tyrosine kinases, and vascular endothelial growth factor have all been associated with dysregulated miRNA-mRNA relationships. KEGG pathway analysis of the dysregulated miRNA-mRNA targets revealed involvement in pathways associated with the hedgehog signaling pathway-fly, ErbB signaling, VEGF signaling, axon guidance, and focal adhesion. KEGG analysis of differentially expressed showed enrichment of mRNAs in primary immunodeficiency, the intestinal immune axis for IgA production, hematopoietic cell lineages, systemic lupus erythematosus, and Th1 and Th2 cell differentiation. Finally, the ceRNA network revealed that BNIP1 was a critical mRNA modulated by the most significant upregulation of lncRNA E230013L22Rik. CONCLUSION: In summary, the lncRNA-miRNA-mRNA ceRNA axis of RILI was constructed following irradiation in a mouse model. RNA dysregulation in the early stage of RILI may lead to severe complications at a later stage, with BNIP1 contributing to radiation-induced cellular apoptosis in RILI.

A novel NIR-II albumin-escaping probe for cerebral arteries and perfusion imaging in stroke mice model.

In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.

A Report of Two Cases of Meningoencephalitis Caused by Streptococcus intermedius.

Objective: In this paper, we analyzed the clinical data of patients with meningoencephalitis caused by Streptococcus intermedius to understand better the clinical characteristics of the disease and recommend auxiliary diagnostic mode as well as treatment experience. Methods: We reviewed the clinical data of two patients admitted to our department in 2019 with meningoencephalitis caused by S. intermedius. Results: Two female patients were examined, one of whom had a history of radiotherapy for nasopharyngeal carcinoma while the other had no underlying disease. These two patients were admitted with symptoms of meningoencephalitis. Cerebrospinal fluid examinations revealed elevated levels of leukocytes and protein. After treatment with meropenem, the condition improved for a brief time, but then worsened with a decline in mental status and limb movement. Blood and cerebrospinal fluid cultures demonstrated the absence of pathogenic bacteria, while genome sequencing of cerebrospinal fluids revealed the presence of S. intermedius. Cranial magnetic resonance imaging revealed multiple cerebral abscesses (CAs). After coadministration of linezolid as an anti-infective, clinical symptoms gradually improved, and the CAs shrank on follow-up imaging. The condition exhibited a pattern of improvement-deterioration-improvement. Conclusion: Meningoencephalitis caused by S. intermedius is complex and prone to fluctuation and formation of multiple CAs. The definitive clinical diagnosis of this disease can be aided by genome sequencing technology, and early clarification of the etiology combined with the use of potent antibiotics is effective.

The Integration of Systematic Pharmacology and Experimental Validation to Explain the Mechanism of Action of Wuling Capsule in the Treatment of NAFLD.

BACKGROUND: Wuling capsule is a traditional Chinese medicine composed of four herbals. It has been widely used to treat chronic active hepatitis and has shown significant efficacy in hyperlipidemia. However, the treatment of NAFLD disease has not been studied in depth. METHODS: Firstly, the potential bioactive compounds in Wuling capsules were identified by TCMSP (https://old.tcmsp-e.com/tcmsp.php). Secondly， the pathway and GO function were analyzed by using the DAVID database (https://david.ncifcrf.gov/). Then, the molecular docking techniques were used to confirm the accuracy of binding between key targets and components. Furthermore, the experimental pharmacology validation was conducted using RT-qPCR and WB of the NAFLD model. RESULTS: A total of 138 active compounds and 40 common potential targets associated with NAFLD were identified through network pharmacology. The pathway and functional enrichment analysis showed that the Wuling capsule was associated with the PI3K-AKT and HIF-1α signaling pathways. In vivo experiments showed that the Wuling capsule could reduce IL-6, TNF-α, and HIF-1α proteins and up-regulate STAT3 and VEGFA levels (P < 0.05), thus alleviating liver inflammation. CONCLUSIONS: With the support of network pharmacology and animal experiments, the study preliminarily investigated the effect of the Wuling capsule on liver inflammation by regulating the HIF-1α signaling pathway, thereby protecting liver function and treating NAFLD.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

Exploiting urine-derived induced pluripotent stem cells for advancing precision medicine in cell therapy, disease modeling, and drug testing.

The field of regenerative medicine has witnessed remarkable advancements with the emergence of induced pluripotent stem cells (iPSCs) derived from a variety of sources. Among these, urine-derived induced pluripotent stem cells (u-iPSCs) have garnered substantial attention due to their non-invasive and patient-friendly acquisition method. This review manuscript delves into the potential and application of u-iPSCs in advancing precision medicine, particularly in the realms of drug testing, disease modeling, and cell therapy. U-iPSCs are generated through the reprogramming of somatic cells found in urine samples, offering a unique and renewable source of patient-specific pluripotent cells. Their utility in drug testing has revolutionized the pharmaceutical industry by providing personalized platforms for drug screening, toxicity assessment, and efficacy evaluation. The availability of u-iPSCs with diverse genetic backgrounds facilitates the development of tailored therapeutic approaches, minimizing adverse effects and optimizing treatment outcomes. Furthermore, u-iPSCs have demonstrated remarkable efficacy in disease modeling, allowing researchers to recapitulate patient-specific pathologies in vitro. This not only enhances our understanding of disease mechanisms but also serves as a valuable tool for drug discovery and development. In addition, u-iPSC-based disease models offer a platform for studying rare and genetically complex diseases, often underserved by traditional research methods. The versatility of u-iPSCs extends to cell therapy applications, where they hold immense promise for regenerative medicine. Their potential to differentiate into various cell types, including neurons, cardiomyocytes, and hepatocytes, enables the development of patient-specific cell replacement therapies. This personalized approach can revolutionize the treatment of degenerative diseases, organ failure, and tissue damage by minimizing immune rejection and optimizing therapeutic outcomes. However, several challenges and considerations, such as standardization of reprogramming protocols, genomic stability, and scalability, must be addressed to fully exploit u-iPSCs' potential in precision medicine. In conclusion, this review underscores the transformative impact of u-iPSCs on advancing precision medicine and highlights the future prospects and challenges in harnessing this innovative technology for improved healthcare outcomes.