ATOH8 binds SMAD3 to induce cellular senescence and prevent Ras-driven malignant transformation.

The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor ß1 (TGF-ß1)-activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle-promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor-controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-ß/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Ropivacaine synergizes with sorafenib to induce apoptosis of hepatocellular carcinoma cells via the IL-6/STAT3 pathway.

The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth in vivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.

Microvesicles-delivering Smad7 have advantages over microvesicles in suppressing fibroblast differentiation in a model of Peyronie's disease.

BACKGROUND: This study compared the differences of microvesicles (MVs) and microvesicles-delivering Smad7 (Smad7-MVs) on macrophage M1 polarization and fibroblast differentiation in a model of Peyronie's disease (PD). METHODS: Overexpression of Smad7 in rat BMSCs was obtained by pCMV5-Smad7 transfection. MVs were collected from rat BMSCs using ultracentrifugation. In cells, 100 µg/mL of MVs or Smad7-MVs were used to treat the 100 ng/mL of lipopolysaccharide (LPS)-induced RAW264.7 cells or 10 ng/mL of recombinant transforming growth factor-ß1 (TGF-ß1)-induced fibroblasts. The pro-inflammatory cytokines and markers of M1 macrophages were measured in RAW264.7 cells, and the migration and markers of fibroblast differentiation were measured in fibroblasts. In rats, 50 µg of MVs or Smad7-MVs were used to treat the TGF-ß1-induced animals. The pathology of tunica albuginea (TA), the markers of M1 macrophages and fibroblast differentiation in the TA were measured. RESULTS: The MVs or Smad7-MVs treatment suppressed the LPS-induced macrophage M1 polarization and TGF-ß1-induced fibroblast differentiation. Moreover, the Smad7-MVs treatment decreased the fibroblast differentiation compared with the MVs treatment. In the TGF-ß1-induced TA of rats, MVs or Smad7-MVs treatment ameliorated the TA fibrosis by suppressing the macrophage M1 polarization and fibroblast differentiation. There was no significance on the M1-polarized macrophages between the MVs treatment and the Smad7-MVs treatment. Meanwhile, the Smad7-MVs treatment had an edge in terms of suppressing the fibroblast differentiation in the TGF-ß1-induced PD model compared with the MVs treatment. CONCLUSIONS: This study demonstrated that Smad7-MVs treatment had advantages over MVs treatment in suppressing of fibroblast differentiation in a model of PD.

Oral-gut microbial transmission promotes diabetic coronary heart disease.

BACKGROUND: Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS: We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS: Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION: Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.

A comparative study of platelet storage lesion in platelet-rich plasma under cryopreservation.

Platelet-rich plasma (PRP) has significant potential for various applications and holds clinical value in regenerative medicine. Cryopreservation is used to extend the preservation period of PRP, facilitating its clinical application. However, the potential negative effects of long-term cryopreservation on platelet storage lesion are still uncertain. In this study, PRP was stored at - 30 °C or - 80 °C. Platelet count, apoptosis, reactive oxygen species (ROS) content, and CD62P expression were assessed on the 14th and 28th days. The study also evaluated platelet mitochondria morphology and function, serotonin (5-HT) secretion by platelets, and the inflammatory activating effect of cryopreserved platelets in PRP. The results showed that there were no significant differences in platelet count, the content of 5-HT, and inflammatory effects between fresh PRP and PRP cryopreserved at both - 30 °C and - 80 °C. However, there was an increase in ROS level, apoptosis, and CD62P level after cryopreservation at both temperatures. Additionally, the levels of ROS, apoptosis, and CD62P in platelets were similar after storage at - 30 °C and - 80 °C. The main difference observed was that the morphology and function of mitochondria were severely damaged after storage at - 30 °C, while they were less affected at - 80 °C. Based on these findings, it can be concluded that storing PRP at - 80 °C is more suitable for achieving a better therapeutic effect in clinical applications, but cryopreservation could not replace the current standard.

Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. METHODS: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. SIGNIFICANCE: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

Is it useful to wash stored red blood cells in cardiopulmonary bypass priming fluid for neonatal cardiac surgery? A single-centre retrospective study.

BACKGROUND AND OBJECTIVES: Neonatal cardiac surgery requires careful consideration of cardiopulmonary bypass (CPB) priming fluid composition due to small blood volume and immature physiology. This study investigated the impact of allogeneic stored red blood cells (RBCs) processed using an autotransfusion system in CPB priming fluid for neonates. MATERIALS AND METHODS: We compared perioperative parameters, inflammatory mediators, coagulation indicators, vasoactive-inotropic score (VIS) and clinical outcomes between neonates receiving unwashed (n = 56) and washed (n = 45) RBCs in CPB priming fluid. Regression models were used to assess the independent association between RBC washing and patient outcomes. RESULTS: The autotransfusion system improved stored RBC quality. The washed group showed higher peak haematocrit (p < 0.01) and haemoglobin levels (p = 0.04) during CPB, an increased oxygen delivery index during rewarming (p < 0.05) and lower postoperative lactate levels and VIS (p < 0.05). Inflammatory (IL-6, IL-8 and IL-10) and coagulation parameters (D-dimer, fibrinogen and fibrin degradation product) fluctuated compared with baseline but did not significantly differ between groups. The washed group had a lower incidence of hyperlactacidaemia and delayed sternal closure at CPB weaning. CONCLUSIONS: Adding washed allogeneic stored RBCs to neonatal CPB priming fluid reduced postoperative lactate elevation and VIS without early improvement in the inflammatory and coagulation systems.

Unveiling the Influence of Antimony Substitution on the Surface Properties and Adsorption Behavior of Ferrihydrite: From Molecular Mechanisms to Environmental Implications.

Antimony(V) substitution is common in secondary ferrihydrite, especially in mining areas and tailings. However, its impact on the adsorption behavior of ferrihydrite is still unclear. Therefore, this study investigated the influential mechanisms of Sb(V) substitution on the lattice structure and surface properties of Sb-substituted ferrihydrite (SbFh), and its adsorption of coexisting Sb(OH)6-. Antimony(V) is substituted at Fe1 sites and is primarily distributed on the surface. Substitution has opposing effects on the outer- and inner-sphere complexation of Sb(OH)6-. On one hand, substituted-Sb(V) transfers more positive charges to ≡FeOH, reducing the number of H bonds. Subsequently, the charge saturation of ≡FeOH decreases, surface charge increases, and outer-sphere complexation is promoted. On the other hand, the elevated bond valence of Sb-O increases charge saturation of ≡FeOH, reducing the charge capacity that ≡FeOH can accommodate from inner-sphere complexes. Thus, inner-sphere complexation is inhibited. Inner-sphere complexation plays a more important role, and Sb(OH)6- adsorption is inhibited. Additionally, the primary complexation modes of Sb(OH)6- transform from bidentate to monodentate complexation. This research has important implications for understanding the environmental behavior of ferrihydrite, as well as the fate and bioavailability of antimony in mining areas and tailings.

Comparative outcomes of cardioplegic arrest versus beating heart in pediatric undergoing extracardiac total cavopulmonary connection.

BACKGROUND: Total cavopulmonary connection (TCPC) is a definitive palliative procedure for functionally univentricular congenital heart disease. The study aims to compare the impact of on-pump cardioplegic arrest and on-pump beating heart cardiopulmonary bypass (CPB) on the prognosis of pediatric patients undergoing extracardiac TCPC. METHODS: The medical data of patients (< 18 years) who underwent extracardiac TCPC with CPB between January 2008 and December 2020 in the cardiac surgery center were retrospectively analyzed. Depending on CPB strategies, the patients were assigned to the beating-heart (BH) and cardioplegic arrest (CA) groups. Data including baseline characteristics, intra/postoperative variables, and clinical outcomes were collected for analysis with 1:1 propensity score matching and multivariable stepwise logistic regressions. RESULTS: Fifty-seven matched patient pairs were obtained. No significant difference existed between the two groups in the in-hospital mortality (3.5% vs. 1.8%, P = 1) and one-year survival rate (100% vs. 96.4%, P = 0.484). The BH group had significantly less intraoperative platelet transfusion (10 mL vs. 150 mL, P = 0.019) and blood loss (100 mL vs. 150 mL, P = 0.033) than the CA group. The CA group had significantly higher vasoactive-inotropic scores (P < 0.05) and longer postoperative ICU stays (2.0 d vs. 3.7 d, P = 0.017). No significant difference existed between the two groups in the incidence of postoperative adverse events. CONCLUSION: Although both CPB strategies are safe and feasible for extracardiac TCPC, the BH technique would cause less intraoperative platelet transfusion and blood loss, and achieve faster early-term postoperative recovery.

Effect of self-efficacy on self-management ability for colorectal cancer patients with stoma: a path analysis.

PURPOSE: Colorectal cancer threatens health and causes heavy social burdens. The purpose of this study is to analyze the pathway model for the effect of self-efficacy on self-management ability in colorectal cancer patients with stoma. METHODS: A cross-sectional study was conducted from December 2022 to April 2023, with a convenience sample of 422 colorectal cancer patients with stoma at six tertiary grade A hospitals in Shandong Province, China. Statistical analysis was undertaken using SPSS 26.0 and Amos 24.0 software. A pathway model based on individual and family self-management theories was developed and analyzed by collecting data through onsite survey and online survey. RESULTS: Chinese colorectal cancer patient's self-management ability score is 105.19 (17.19), which shows medium-level self-management ability. The self-efficacy of colorectal cancer patients with a stoma is influenced by social support, which ultimately leads to changes in their self-management ability. CONCLUSION: The findings may help healthcare professionals to identify the factors that influence self-management skills of colorectal cancer patients with stoma and provide a basis for developing interventions.

Quantification for photochemical loss of volatile organic compounds upon ozone formation chemistry at an industrial city (Zibo) in North China Plain.

Volatile organic compounds (VOCs) are consumed by photochemical reactions during transport, leading to inaccuracies in estimating the local ozone (O3) formation mechanism and its subsequent strategy for O3 attainment. To comprehensively quantify the deviations in O3 formation mechanism by consumed VOCs (C-VOCs), a 5-month field campaign was conducted in a typical industrial city in Northern China over incorporating a 0-D box model (implemented with MCMv3.3.1). The averaged C-VOCs concentration was 6.8 ppbv during entire period, and Alkenes accounted for 62% dominantly. Without considering C-VOCs, the relative incremental reactivity (RIR) of anthropogenic VOCs (AVOC, overestimated by 68%-75%) and NOx (underestimated by 137%-527%) demonstrated deviations at multiple scenarios, and the RIR deviations for precursors in High-O3-periods (HOP) were lower than Low-O3-periods (LOP). The RIR deviations from individual species involved C-VOCs calculation did not impact the identification for the high-ranking-RIR AVOC species but non-negligible. Monthly comparisons showed that higher C-VOCs concentrations would lead to higher RIR deviations. The daily maximum of net Ox production rate (P(Ox)) and the regional transport Ox (Trans(Ox)) without C-VOCs were underestimated by 56%-194% and 81%-243%, respectively. After considering C-VOCs, the contribution of HO2+NO for Ox gross production (G(Ox)) decreased by 7% (LOP) and 7% (HOP), but OH + NO2 for Ox destruction (D(Ox)) decreased by 16% (LOP) and 23% (HOP), and alkenes + O3 increased for D(Ox) by 12% (LOP) and 22% (HOP). This implies that VOCs-NOx-O3 sensitivity was deviated between with/without C-VOCs, and severe O3 pollution rendered deviations in O3 formation, especially via NOx-driving chemistry. Based on RIR(NOx)/RIR(AVOC) with/without C-VOCs, the sensitivity regime shifted from VOCs-limited (-0.93) to transition (1.38) at LOP, and from VOCs-limited (0.19) to NOx-limited (3.79) at HOP. Our results reflected that the NOx limitation degree was underestimated without constraint C-VOCs, especially HOP, and provided implication to more precise O3 pollution control strategies.

Effectiveness and pregnancy outcomes of ultrasound-indicated and physical examination-indicated cervical cerclage: a retrospective study from a single centre.

OBJECTIVE: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide, and cervical incompetence (CIC) is a significant contribution. Cervical cerclage (CC) is an effective obstetric intervention. However, many clinical factors affect the success rate of surgery. The objective was to investigate and compare the pregnancy and neonatal outcomes of patients who underwent ultrasound- and physical examination-indicated cervical cerclage and to explore the influencing factors of preterm delivery before 34 weeks. METHODS: The sociodemographic characteristics and clinical data of patients with a diagnosis of cervical incompetence who underwent ultrasound- and physical examination-indicated transvaginal cervical cerclage at Nanjing Maternal and Child Health Hospital from January 2020 to December 2022 were retrospectively analyzed. The pregnancy and neonatal outcomes of the patients were evaluated. Continuous variables were compared using Student's t test (for normally distributed data) or the Mann-Whitney U test (for nonnormally distributed data). Categorical variables were analysed using the chi-square test or Fisher's exact test. Additionally, logistic regression analyses and receiver operating characteristic curves were used to evaluate the associations of inflammatory markers with maternal and neonatal outcomes. RESULTS: This study included 141 participants who underwent cervical cerclage, including 71 with ultrasound-indicated cerclage and 70 with physical examination-indicated cerclage. Compared to those in the ultrasound-indicated cerclage group, the duration from cerclage to delivery, birth weight, and APGAR score in the physical examination-indicated cerclage group were significantly lower, and the rates of delivery at < 28 weeks, < 32 weeks, < 34 weeks, and < 37 weeks of gestation and neonatal mortality were significantly higher (all P < 0.05). Compared to those in the physical ultrasound-indicated cerclage group, in the physical examination-indicated cerclage group, maternal blood inflammatory markers, such as C-reactive protein (CRP), the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) were significantly higher (P < 0.05). Additionally, maternal blood inflammatory markers, such as the CRP, white blood cell count, platelet to lymphocyte ratio (PLR), SII, and SIRI were significantly higher in the group with delivery before 34 weeks of gestation. Furthermore, the results demonstrated that twin pregnancy had the highest OR for preterm delivery before 34 weeks of gestation (OR = 3.829; 95% CI 1.413-10.373; P = 0.008), as well as the following: the SII level (OR = 1.001; 95% CI 1.000-1.002; P = 0.003) and CRP level (OR = 1.083; 95% CI 1.038-1.131; P = 0.022). The risk factors for preterm delivery before 34 weeks of gestation were twin gestation, an increased SII level and an increased CRP level, which had good combined predictive value. CONCLUSION: In patients with cervical insufficiency, ultrasound-indicated cervical cerclage appears to lead to better pregnancy outcomes than physical examination-indicated cerclage. Twin pregnancy and maternal blood inflammatory markers, such as the CRP level and the SII, are associated with preterm delivery before 34 weeks of gestation.

miR-34b-3p-mediated regulation of STC2 and FN1 enhances chemosensitivity and inhibits proliferation in cervical cancer.

Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.

Novel Pathogenic Mutation of P209L in TRPC6 Gene Causes Adult Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 µmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.

Meta-analysis of Palliative Care on End-stage Quality of Life in Cancer Patients.

Objective: This study aimed to investigate the impact of palliative care on the quality of life, depressive state, and physical and psychological symptoms of patients with end-stage cancer. Methods: A systematic literature search of PubMed, Embase, and Scopus databases was conducted for randomized controlled trials (RCTs) published from May 2000 to June 2023, focusing on the impact of palliative care on end-stage cancer patients. The search utilized terms such as "palliative care," "cancer/tumor/malignancy," "terminal/end-stage/advanced," to identify studies meeting our inclusion criteria. Selected RCTs were evaluated for quality, and relevant data were extracted for meta-analysis. Results: Meta-analysis of 16 RCTs revealed that palliative care significantly improved depressive states [OR=-0.88, 95%CI (-1.55, -0.20), P = .01] and alleviated physical and psychological symptoms [OR=-2.38, 95%CI (-3.95, -0.81), P = .003] in end-stage cancer patients compared to conventional oncology care. However, the improvement in overall quality of life was not statistically significant (P > .05). Conclusion: Palliative care significantly enhances the mental and physical well-being of end-stage cancer patients by reducing depressive states and symptom burden, although its impact on overall quality of life requires further exploration.

Ropivacaine combined with sorafenib attenuates hepatocellular carcinoma cell proliferation and metastasis by inhibiting the miR-224/HOXD10 axis.

OBJECTIVE: The development of drug resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib (Sor). However, the regulatory mechanisms underlying the effects of the combination Sor and ropivacaine (Rop) on HCC cells remain unclear. METHODS: miR-224 and HOXD10 mRNA expression in HCC cells was analyzed using qRT-PCR. CCK-8, Transwell assays and tumor formation experiments in nude mice were used to assess HCC cell proliferation, migration, and invasion. Migration of HCC cells was also analyzed using a cell scratch assay. Hematoxylin and eosin staining was used to detect tumor area. RESULTS: miR-224 expression profoundly increased in HepG2 and Huh7 cells. Treatment with Rop and/or Sor blocked miR-244 expression, especially the combination treatment. Transfection of miR-224 mimic increased HCC cell proliferation and tumor size in nude mice, and migration and invasion in vitro in the presence of Rop and Sor compared to the negative control mimic. Dual-luciferase reporter assays showed that HOXD10 was targeted by miR-224. HOXD10 protein expression and was markedly reduced in HepG2 and Huh7 cells. Rop and/or Sor treatment increased HOXD10 protein expression, particularly the combination treatment. miR-224 negatively regulated HOXD10 expression in HCC cells treated with Rop and Sor. Transfection-mediated silencing of HOXD10 increased HCC cell proliferation, migration, and invasion in the presence of Rop and Sor compared with negative control transfection. CONCLUSION: The combination of Rop and Sor attenuates HCC cell proliferation and metastasis via the miR-224/HOXD10 axis.

Effects of different adzuki bean flour additions on structural and functional characteristics of extruded buckwheat noodles.

BACKGROUND: Understanding the effects of different additions of adzuki bean flour (ABF) on structural and functional characteristics of extruded buckwheat noodles is important in developing high-quality starchy foods with desirable glycemic indexes. This study explored how varying amounts of ABF in extruded buckwheat noodles influenced their structural and functional characteristics. RESULTS: The findings indicated that adding ABF substantially boosted the levels of protein and flavonoids, while decreasing the content of fat and starch. Adding ABF to the noodles extended the optimum cooking time and led to a reduction in both the stickiness of the cooked noodles and the pore size of the starch gel structure, compared with pure buckwheat noodles. Fourier transform infrared spectroscopy indicated that R1047/1022 increased with the content of ABF increased, while R1022/995 decreased. X-ray diffraction showed that the relative crystallinity of buckwheat noodles was enhanced with increasing ABF amount. Adding ABF notably significantly decreased the estimated glycemic index. The buckwheat noodles extruded with 20% ABF addition demonstrated notably stronger α-glucosidase inhibitory effects than those extruded with no ABF addition. CONCLUSION: The present study demonstrates that the additions of ABF improved the structure and hypoglycemic activity of extruded buckwheat noodles while decreasing starch digestibility, and the optimal value was reached at an ABF addition of 20%. The study might fill gaps in starch noodle research and provide a new strategy for the development of functional food in the food industry. © 2024 Society of Chemical Industry.

An underutilized bean: hyacinth bean [Lablab purpureus (L.) sweet]: bioactive compounds, functional activity, and future food prospect and applications.

Hyacinth bean [Lablab purpureus (L.) Sweet], a plant belonging to the leguminous family and traditionally used for medicinal purposes in China, is a valuable resource with a wide range of health benefits. This review examines the bioactive compounds, health-promoting properties and functional food potential of hyacinth bean, highlighting its role in protecting against metabolic diseases and the underlying molecular mechanisms. According to existing research, hyacinth bean contains a diverse array of bioactive compounds, Consumption of hyacinth beans and hyacinth bean-related processed food products, as well as their use in medicines, is associated with a variety of health benefits that are increasingly favoured by the scientific community. In light of these findings, we posit that hyacinth bean holds great promise for further research and food application. © 2024 Society of Chemical Industry.

Joint analysis of WES and RNA-Seq identify signature genes related to metastasis in prostate cancer.

Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.