Pathological Indicators Research Articles

Protective effect of a newly probiotic Lactobacillus reuteri LY2-2 on DSS-induced colitis.

This study aimed to investigate the role of a newly isolated strain L.reuteri LY2-2 in colitis in mice and explored the underlying mechanisms. METHODS L. LY2-2 was orally administered to mice with dextran sulfate sodium (DSS)-induced colitis. 5-Aminosalicylic acid (5-ASA) treatment was used as the drug control. The results showed that the disease severity of colitis mice was significantly alleviated. The intestinal inflammation was restricted by synergistically reducing pro-inflammatory cytokines, inhibiting TLR4-NF-κB signaling, restoring the abnormal immune response, and enhancing intestinal barrier function. Of note, L.reuteri LY2-2 showed great potential in modulating macrophages polarization in colonic tissues. Moreover, the gut dysbiosis was improved. The potentially pro-inflammatory pathogenic bacteria such as Helicobacter and Romboutsia decreased and the probiotics including L.rhamnosus and L.plantarum increased. Interestingly, the above pathological indexes in the L.reuteri LY2-2 group were better than those in the 5-ASA group. L.reuteri LY2-2 had a better protective effect on DSS-induced colitis via its anti-inflammatory and microbiota-balancing properties, which supports the potential value of this probiotic against colitis. These results contribute to product development of functional probiotics for colitis and provide valuable insights for their mechanisms of biological function to affect human health status.

Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy.

Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model. Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose. Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis. These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.

The survival rate of biological therapy in immunosuppressive diseases in children

Genetically engineered biological preparations (GEBP) are successfully used in various immunosuppressive diseases. Despite the effectiveness of GEBP, some patients experience primary non-response, as well as loss of effect from therapy. There is a need to objectively assess the effect of the therapy for its timely correction. The aim of the work was to determine the survival rate of GIBP depending on the form of pathology, drug, age, and immune indices in children with Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PS), multiple sclerosis (MS). Materials and methods. Three hundred eighty three children (1394 observations) were examined in dynamics: 117 children with BC (treated by infliximab (IFX)/adalimumab (ADA), 83 children with UC (IFX/ADA), 87 children with PS (ADA), 96 children with PC (IFNβ1α) during the maintenance course therapy. Lymphocytes were immunophenotyped by flow cytometry with the determination of Treg (CD4+CD25highCD127low), Th17 lymphocytes (CD4+CD161+CD3+), succinate dehydrogenase (SDH) activity in Treg. Data processing was carried out using Statistica 16.0 application. Kaplan–Mayer survival curves are constructed. The significance of the differences between the groups was assessed using the Gehan–Wilcoxon criterion (p &lt; 0.05). Results. The survival rate of biological therapy in CD patients on IFX therapy is significantly higher than in children with UC — 161 weeks versus 135 weeks. There was no difference in CBT on ADA therapy between patients with CD and UC. The IBT index depends on the age of the patients: on IFX therapy (159 weeks) the best indices were in CD patients over 12 years. Combination therapy improves the survival of TNF blockers in patients with IBD (azathioprine) and PS (methotrexate). The survival of GIBP is influenced by the ratio of effector and regulatory cells (Th17|Treg) and the functional activity of Treg (SDH activity). A decrease in IBD was revealed in patients with IBD, PS, and MS with an increase in the Th17/Treg index above the age norm and a decrease in the activity of SDH in Treg below the norm. Conclusion. The survival rate of biological therapy for immunosuppressive diseases in children depends on the form of pathology, the drug, the age of patients, previous therapy, combination therapy, as well as immune indices during the maintenance course. Monitoring of Th17/Treg and SDH activity in Treg may be an important laboratory criterion for the effectiveness of GIBP.

Distinctive grade based on Ki67 index and immune microenvironment of metastatic pancreatic neuroendocrine tumors responding to capecitabine plus temozolomide

BackgroundKi67 index changes during the treatment of metastatic pancreatic neuroendocrine tumor (PanNET) treatment. The study aimed to detect alterations of grade based on Ki67 index and immune microenvironment in PanNET responding to capecitabine/temozolomide (CapTem).MethodRetrospective data of patients with PanNET were collected. In control group, 35 patients underwent surgery immediately after biopsy. In CapTem group, 38 patients received CapTem after biopsy and responded well to treatment (defined as either stable disease or partial response), and subsequently underwent surgery. All patients have pathological Ki67 index at biopsy and after surgery. CD163 + CD68 + CD206 + M2 macrophages, CD68 + CD86 + CD80 + M1 macrophages, CD11b + CD33 + myeloid-derived suppressor cells, and CD4 + CD25 + regulatory T cells were stained using multiplex immunofluorescence.ResultsIn control group, the paired grade based on Ki67 index directly after surgery showed no upgrade or downgrade compared to biopsy. In patients who responded well to CapTem, the grade based on Ki67 index before and after CapTem was altered. Thirteen patients had upgraded Ki67 index and 11 patients had downgraded. The proportion of stable disease was higher in the upgraded group compared to downgraded group (p = 0.0155). And upgraded group had a significantly shorter mPFS than patients in the downgrade group (8.5 months vs. 20 months, HR 4.834, 95% CI 1.414 to 16.53, p = 0.012). M1 macrophages was significantly lower in the downgraded group than in the Ki67 upgraded group (p < 0.001).ConclusionGrade based on Ki67 index and immune environment change in PanNET patients responding well to CapTem. Patients with downgraded had longer mPFS compared to those with upgraded. It is necessary to reassess the Ki67 index after CapTem treatment, even in patients responding well to CapTem.

Coronary physiology: no complete diagnosis without acteylcholine

Abstract Introduction In up to 40% of patients with pectanginous symptoms, no obstructive coronary artery disease (NOCAD, no stenosis &amp;gt; 50%) can be detected as the cause, so that the terms ANOCA (angina with no obstructive CAD) or INOCA (ischemia with no obstructive CAD) have been defined. In patients with acute myocardial infarction, 5-20% are diagnosed with MINOCA (myocardial infarction with no obstructive CAD). Microvascular dysfunction (CMD) or coronary spasm has been identified as one of the leading causes of these entities. Further clarification by determining the coronary flow reserve (CFR) an microvascular resistance (IMR) is used to diagnose CMD and is also included in the ESC guidelines. The indices can be determined using thermodilution or ultrasound/doppler wires methods. According to current recommendations, the acteylcholine provocation test is administered in cases of suspected coronary spasm. Despite extensive studies on the safety of ACh testing, many clinics refrain from testing for vasoconstriction disorder although microvascular coronary spasm has been shown to be the leading subgroup of CMD in registry studies. Purpose We want to investigate the necessity of a complete coronary physiological examination, consisting of CRF/IMR and ACh provocation test, when compared to testing without ACh. Methods All 299 patients who underwent complete physiological testing in our clinic between 2021 and 2024 due to ANOCA, INOCA or MINOCA were evaluated retrospectively. Patients completed a coronary physiological examination using thermodilution and an acetylcholine provocation test. The IMR, CFR, fractional flow reserve (FFR), resting full-cycle ratio (RFR) and the ACh test (defined as epicardial spasm &amp;gt;90% reduction in coronary diameter with symptoms and/or ischemic electrocardiographic changes, respectively no epicardial spasm &amp;gt;90% reduction in coronary diameter with symptoms and and ischemic electrocardiographic changes for microvascular spasm) are thus routinely measured. Results Of the total of 299 patients included, 244 (81%) were found to have impaired vasoconstriction with pathologic ACh testing, either alone or in combination with pathologic indices CFR/IMR. The leading finding of pathological spasms was microvascular coronary spasm (66%). 119 patients with normal CFR/IMR had a diagnosis of microvascular (72 patients) or macrovascular spasm (47 patients). 40% of the total patient cohort would have not had a compete diagnosis without the use of Ach testing. Conclusion Physiological testing without the systematic use of ACh testing will misdagnose a significant amout of patients with ANOCA/MINOCA/INOCA. ACh testing should be always performed to complete the diagnosis for these patients

Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway

Abstract Background The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney. Purpose In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF. Methods 14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms. Results Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway. Conclusions The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.

Potentials of pretreatment [18F]FDG PET/CT for non-invasive prediction of the tumor unfavorable pathological indices and microenvironment in NSCLC

Potentials of pretreatment [18F]FDG PET/CT for non-invasive prediction of the tumor unfavorable pathological indices and microenvironment in NSCLC

Apolipoprotein B gene expression and regulation in relation to Alzheimer’s disease pathophysiology

Apolipoprotein B (APOB), a receptor-binding protein present in cholesterol-rich lipoproteins, has been implicated in Alzheimer's disease (AD). High levels of APOB-containing low-density lipoproteins (LDL) are linked to the pathogenesis of both early-onset familial and late onset sporadic AD. Rare coding mutations in the APOB gene are associated with familial AD, suggesting a role for APOB-bound lipoproteins in the central nervous system.This research explores APOB gene regulation across the AD spectrum using four cohorts: BRAINEAC (elderly control brains), DBCBB (controls, AD brains), ROSMAP (controls, MCI, AD brains), and ADNI (control, MCI, AD clinical subjects). APOB protein levels, measured via mass spectrometry and ELISA, positively correlated with AD pathology indices and cognition, while APOB mRNA levels showed negative correlations. Brain APOB protein levels also correlated with cortical Aβ levels.A common coding variant in the APOB gene locus affected its expression but didn't impact AD risk or brain cholesterol concentrations, except for 24-S-hydroxycholesterol. Polymorphisms in the CYP27A1 gene, notably rs4674344, were associated with APOB protein levels. A negative correlation was observed between brain APOB gene expression and AD biomarker levels. CSF APOB correlated with Tau pathology in presymptomatic subjects, while cortical APOB was strongly associated with cortical Aβ deposition in late-stage AD.The study discusses the potential link between blood-brain barrier dysfunction and AD symptoms in relation to APOB neurobiology. Overall, APOB's involvement in lipoprotein metabolism appears to influence AD pathology across different stages of the disease.

Overall survival and prognostic factors associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with intraoperative radiation therapy in patients with advanced abdominopelvic malignancies: A single center retrospective analysis of 159 patients.

The aim of this study was to look at the overall survival (OS), progression-free survival (PFS), and prognostic factors associated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined with intraoperative radiation therapy (IORT). This study is a single center retrospective study performed on 159 patients who underwent treatment with CRS and HIPEC combined with IORT for abdominopelvic malignancies. OS and PFS were used to evaluate the efficacy of this treatment strategy amongst patients with abdominopelvic malignancies. The cohort's median age was 53 years, with a male predominance (58.5%). The median OS was not reached, but the mean OS was 76.87 months. In univariate analysis, several factors, including synchronous organ metastasis, Pathologic Peritoneal Carcinomatosis Index(pPCI)≥10, increased estimated blood loss, and severe postoperative complications, were associated with worse OS. However, multivariate analysis identified pPCI ≥ 10 as the sole independent predictor of worse OS. The 1-and 3-year survival rates were 83% and 70.4%, respectively. pPCI ≥ 10 and severe postoperative complications were significant predictors of worse survival outcomes. Radical surgery alone is not enough, and CRS combined with HIPEC and IORT, when indicated, was proven to be safe and effective with no added morbidity or mortality.

Integrative transcriptomics and lipidomics unravels the amelioration effects of Radix Bupleuri on non-alcoholic fatty liver disease

Ethnopharmacological relevanceRadix Bupleuri (Bupleurum chinense DC.) is the most commonly used traditional Chinese medicine (TCM) for the treatment of liver diseases. While the effects of Radix Bupleuri (BR) on lipid-lowering and liver protection have been established, its role in the development of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet remains unclear. Aim of the studyThe objective of this study was to evaluate the alleviation effects of the active fraction of BR on NAFLD in vivo and to explore the underlying mechanisms through an analysis of liver transcriptome and lipidomics. Materials and methodsThe NAFLD model was established in SD rats by administering a high-fat diet (HFD) for 8 weeks. Subsequently, the NAFLD model rats were continuously gavaged with different polarity fractions of BR (25 g/kg/d) and melatonin (MT) (30 mg/kg/d) for an additional 6 weeks to assess therapeutic effects. The potential mechanism of the low polarity fraction of BR (LBR) in treating NAFLD was investigated through hepatic transcriptome analysis, non-targeted lipidomics, RT-qPCR, protein-protein interaction (PPI) network construction, molecular docking, and Western blotting, aiming to elucidate the underlying mechanisms by which LBR may ameliorate NAFLD. ResultsThese results demonstrated that LBR significantly alleviated the effects of HFD-induced NAFLD, as evidenced by reductions in body weight (BW), liver weight (LW), and epididymal fat weight (EFW) compared to model rats and other polarity fractions of BR. Furthermore, LBR notably down-regulated serum and liver levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while up-regulating high-density lipoprotein cholesterol (HDL-C) in serum. Mechanistically, liver transcriptome analysis indicated that fatty acid metabolism may be a crucial pathway for the improvement of NAFLD following LBR treatment. Lipidomics data suggested that LBR can modulate the metabolic profile in NAFLD rats. Enrichment analysis revealed that glycerophospholipid and glycerolipid metabolism might be key pathways involved in the development of NAFLD. RT-qPCR analysis demonstrated that LBR could regulate the expression of lipid-related genes in these critical pathways. Additionally, Spearman correlation analysis showed a strong relationship between lipid metabolic biomarkers, pathological indices, and lipid-related genes. Moreover, protein-protein interaction (PPI) network and molecular docking analyses identified seven key targets with six ingredients of LBR exhibiting good binding capacity (< -5.0 kcal/mol). Finally, Western blotting analysis indicated that LBR up-regulates the expression levels of PPARα, CPT1, and FABP1 while down-regulating the expression levels of SREBF1 and SCD1, thereby improving metabolism and exerting a lipid-lowering effect. ConclusionIn conclusion, the present research elucidated the lipid-lowering mechanisms of the active fractions of BR. Both BR and LBR presented themselves as promising candidates for the development of novel pharmacological agents targeting NAFLD. LBR effectively ameliorated lipid disturbances associated with HFD-induced NAFLD by modulating the metabolism of fatty acids, cholesterol, glycerolipid, and glycerophospholipids. Consequently, LBR held significant potential for development as an effective lipid-lowering therapeutic.

Local molecular and connectomic contributions of tau-related neurodegeneration.

Neurodegeneration in Alzheimer's disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.

Impact of adding preoperative magnetic resonance imaging to ultrasonography on male breast cancer survival: a matched analysis with female breast cancer.

The study investigated whether incorporating magnetic resonance imaging (MRI) alongside ultrasonography (US) in the preoperative evaluation is associated with differing survival outcomes between male and female breast cancer patients in a matched analysis. Additionally, clinicopathological prognostic factors were analyzed. Between January 2005 and December 2020, 93 male and 28,191 female patients who underwent breast surgery were screened. Exact matching analysis was conducted for age, pathologic T and N stages, and molecular subtypes. The clinicopathological characteristics and preoperative imaging methods of the matched cohorts were reviewed. Disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan-Meier analysis, and Cox proportional hazards regression analysis was used to identify prognostic factors. A total of 328 breast cancer patients (61 men and 267 women) were included in the matched analysis. Male patients had worse DFS (10-year DFS, 70.6% vs. 89.2%; P=0.001) and OS (10-year OS, 64.4% vs. 96.3%; P&lt;0.001) than female patients. The pathologic index cancer size (hazard ratio [HR], 2.013; 95% confidence interval [CI], 1.063 to 3.810; P=0.032) was associated with worse DFS, whereas there were no significant factors associated with OS. Adding MRI to US for preoperative evaluation was not associated with DFS (HR, 1.117; 95% CI, 0.223 to 5.583; P=0.893) or OS (HR, 1.529; 95% CI, 0.300 to 7.781; P=0.609) in male patients. Adding breast MRI to US in the preoperative evaluation was not associated with survival outcomes in male breast cancer patients, and the pathologic index cancer size was associated with worse DFS.

Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration

BackgroundThe anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking.MethodsABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing.ResultsA total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48–0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62–1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival.ConclusionThis retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

Post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance predict proton pump inhibitor response in patients with reflux hypersensitivity.

Post-reflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) have been shown to influence proton pump inhibitor (PPI) response in GERD patients. However, currently, little data concerning these variables in patients with reflux hypersensitivity (RH) are available. In this study, we aimed to evaluate, in RH patients, the prevalence of PPI responders and nonresponders and investigate the predictive value of impedance-pH variables, including PSPW and MNBI, on responses to PPI. A total of 108 RH patients who met ROME IV criteria were prospectively recruited from June 2018 to December 2022. The prevalence of PPI responders/nonresponders was calculated, and impedance-pH variables were compared between the response and nonresponse groups. Multiple logistic regression was used to investigate predictors for PPI response. Among 108 patients with RH, 60 patients (55.56%) were the PPI responders, and 48 (44.44%) were the nonresponders. Compared with the nonresponders, the PPI responders had a lower PSPW index (47.05±4.43 vs 51.33±3.50, P=0.004) and a decreased value of MNBI (1866.68±390.62 vs 2181.14±338.42, P=0.017). Multivariate logistic regression revealed that only the pathologic PSPW index (OR: 2.064) and MNBI (OR: 1.800) significantly influenced PPI response. Nearly half of RH patients were PPI nonresponders. Impedance-pH monitoring was more valuable than pH-only monitoring in associating PPI response to reflux in RH patients owing to the appraisal of the PSPW index and MNBI.

Insights into phenotypic variability caused by GARS1 pathogenic variants.

Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy. This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed. The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients. GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

Discovery of 3-bromoflavone derivative D5 as a novel TLR4-MD2 antagonist for treatment of acute lung injury and sepsis

The aberrant activation of immune responses mediated by Toll-like receptor 4 (TLR4) generates severe inflammatory syndromes such as acute lung injury (ALI) and sepsis, thus targeting TLR4 is attractive as a potential pharmacological therapy for these diseases. The aim of this study is to develop a novel structural TLR4 inhibitor for the treatment of ALI and sepsis. Herein, we designed and synthesized a new series of 3-bromoflavone derivatives by screening and incorporating molecular docking. Their anti-inflammatory effects were evaluated by ELISA in macrophages and compound D5 was identified as the most potential anti-inflammatory candidate. Compound D5 inhibited lipopolysaccharide (LPS)-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in RAW264.7 cells with IC50 values of 0.215 and 4.211 µM, respectively. Immunoprecipitation, SPR, and immunoblotting demonstrated that D5 targeted TLR4-MD2 complex and competitively inhibited the binding of LPS to TLR4-MD2, resulting in inhibition of NF-κB and MAPK signaling pathways. In vivo administration of D5 significantly ameliorated various pathological indexes in LPS-induced ALI model and promoted the survival rate in LPS-induced septic model. Overall, our studies have identified a 3-bromoflavone derivative, D5, as a potent TLR4-MD2 antagonist and represented a very promising starting point for the development of anti-inflammatory agents for the treatment of ALI and sepsis.

Uromodulin and progression of IgA nephropathy.

This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P=.480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P=.009) was associated with faster IgAN progression. The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.

Can We Go beyond Pathology? The Prognostic Role of Risk Scoring Tools for Cancer-Specific Survival of Patients with Bladder Cancer Undergoing Radical Cystectomy.

Radical cystectomy (RC) remains a mainstay surgical treatment for non-metastatic muscle-invasive and BCG-unresponsive bladder cancer. Various perioperative scoring tools assess comorbidity burden, complication risks, and cancer-specific mortality (CSM) risk. We investigated the prognostic value of these scores in patients who underwent RC between 2015 and 2021. Cox proportional hazards were used in survival analyses. Risk models' accuracy was assessed with the concordance index (C-index) and area under the curve. Among 215 included RC patients, 63 (29.3%) died, including 53 (24.7%) cancer-specific deaths, with a median follow-up of 39 months. The AJCC system, COBRA score, and Charlson comorbidity index (CCI) predicted CSM with low accuracy (C-index: 0.66, 0.65; 0.59, respectively). Multivariable Cox regression identified the AJCC system and CCI > 5 as significant CSM predictors. Additional factors included the extent of lymph node dissection, histology, smoking, presence of concomitant CIS, and neutrophil-to-lymphocyte ratio, and model accuracy was high (C-index: 0.80). The internal validation of the model with bootstrap samples revealed its slight optimism of 0.06. In conclusion, the accuracy of the AJCC staging system in the prediction of CSM is low and can be improved with the inclusion of other pathological data, CCI, smoking history and inflammatory indices.

Anoectochilus roxburghii polysaccharide reduces D-GalN/LPS-induced acute liver injury by regulating the activation of multiple inflammasomes.

Acute liver injury (ALI) is a serious syndrome with a high mortality rate due to viral infection, toxic exposure, and autoimmunity, and its severity can range from mildly elevated liver enzymes to severe liver failure. Activation of the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is closely associated with the development of ALI, and the search for an inhibitor targeting this pathway may be a novel therapeutic option. Anoectochilus roxburghii polysaccharide (ARP) is a biologically active ingredient extracted from Anoectochilus roxburghii with immunomodulatory, antioxidant, and anti-inflammatory bioactivities and pharmacological effects. In this study, we focused on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury by ARP through inhibition of NLRP3 inflammasome. An inflammasome activation model was established in bone marrow-derived macrophages (BMDMs) to investigate the effects of ARP on caspase-1 cleavage, IL-1β secretion, and ASC oligomerization in inflammasomes under different agonists. We used the D-GalN/LPS-induced acute liver injury model in mice, intraperitoneally injected ARP or MCC950, and collected liver tissues, serum, and intraperitoneal lavage fluid for pathological and biochemical indexes. ARP effectively inhibited the activation of the NLRP3 inflammasome and had an inhibitory effect on non-classical NLRP3, AIM2, and NLRC4 inflammasomes. It also effectively inhibited the oligomerization of apoptosis-associated speck-like protein (ASC) from a variety of inflammatory vesicles. Meanwhile, ARP has good therapeutic effects on acute liver injury induced by D-GaIN/LPS. The inhibitory effect of ARP on a wide range of inflammasomes, as well as its excellent protection against acute liver injury, suggests that ARP may be a candidate for acute liver injury.

Huangqin Qingre Chubi Capsule improves rheumatoid arthritis accompanied depression through the Wnt1/β-catenin signaling pathway

Aim of the studyResearch on the mechanism of Huangqin Qingre Chubi Capsules (HQC) in improving rheumatoid arthritis accompanied depression (RA-dep) model rats. MethodsWe employed real-time qPCR (RT-qPCR), western blotting (WB), confocal microscopy, bioinformatics, and other methods to investigate the anti-RA-dep effects of HQC and its underlying mechanisms. ResultsHQC alleviated the pathological indexes of inflammation and depression in RA-dep model rats, decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, increased the levels of norepinephrine(NE) and serotonin(5-HT), and improved the injury of hippocampus. The analysis of network pharmacology suggests that HQC may target the Wnt/β-catenin pathway in the treatment of RA-dep. Furthermore, molecular dynamics simulations revealed a strong affinity between HQC and the Wnt1 molecule. RT-qPCR and Western Blot (WB) experiments confirmed the critical role of the Wnt1/β-catenin signaling pathway in the treatment of RA-dep model rats with HQC. In vitro, the HQC drug-containing serum (HQC-serum) activates the Wnt1/β-catenin signaling pathway in hippocampal cells and, in conjunction with Wnt1, ameliorates RA-dep. In summary, HQC exerts its anti-inflammatory and antidepressant effects in the treatment of RA-dep by binding to Wnt1 and regulating the Wnt1/β-catenin signaling pathway. ConclusionsHQC improved the inflammatory reaction and depression-like behavior of RA-dep model rats by activating Wnt1/β-catenin signal pathway. This study revealed a new pathogenesis of RA-dep and contributes to the clinical promotion of HQC in the treatment of RA-dep.