Effect of Probiotics on Portal Hypertension (PH) with Cirrhosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: There are many options for the reduction of portal hypertension (pH) in cirrhotic patients, but all the current ones have side effects. Probiotics are a new approach for ameliorating the hyperdynamic circulation of cirrhotic patients. The aim of this study is to measure the effect of probiotics on pH in cirrhosis for the first time. METHODS: A search was conducted across four electronic databases (PubMed, Scopus, Web of Science, Cochrane) for English-language records evaluating probiotic effects on pH in cirrhotic patients. Quality assessment used the Cochrane Collaboration's tool, employing a random-effects model in statistical analysis with Stata software version 1. RESULTS: A search yielded 1,251 articles, which were narrowed down to 5 through screening. These studies, involving 158 participants across Canada, India, Spain, and Russia, focused on probiotic interventions in cirrhotic patients. Meta-analysis of two RCTs (66 participants) indicated a significant decrease in hepatic venous pressure gradient (HVPG) (SMD: -0.60 [-1.09, -0.12]). In single-arm analysis, four studies (58 participants) showed a substantial reduction in HVPG with probiotic use compared to the control (SMD: -2.55 [-3.42, -1.68]). CONCLUSION: In summary, it showcased a notable reduction in HVPG compared to the control group, indicating a potential advantage of probiotics in decreasing pH in cirrhotic patients. Further research with larger samples and robust designs is warranted.

Ethyl pyruvate alleviates pulmonary arterial hypertension via PI3K-Akt signaling.

Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome that is extremely difficult to manage, and there is currently no effective treatment. We want to elucidate the therapeutic effect of ethyl pyruvate (EP) on PAH and its possible mechanism. Pulmonary artery endothelial cells (PAECs) were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with EP. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 was detected by Western blot. After hyperkinetic PAH rabbits' models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 protein was also detected after using autophagy inhibitor and agonists. We found that EP could inhibit PAECs proliferation. After EP treatment, expression of p-PI3K/Akt was upregulated in vitro and in vivo. LC3-II and Beclin-1 were inhibited and their expression was lower after autophagy inhibitor was given, while after administration of autophagy agonists, their expression was higher than that in the EP alone group. Besides, EP attenuated PAH, and right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. EP can reduce PAH and reverse vascular remodeling which is associated with inhibition of autophagy in PAECs based on PI3K-Akt signaling pathway. The results of this study can provide surgical opportunities for patients with severe PAH caused by congenital heart disease in clinical cardiovascular surgery.

Ion Dynamics at the Intermediate Charging State of the Sodium Vanadium Fluorophosphate Cathode.

Na super ionic conductor (NASICON)-type polyanionic vanadium fluorophosphate Na3V2O2(PO4)2F (NVOPF) is a promising cathode material for high-energy sodium-ion batteries. The dynamic diffusion and exchange of sodium ions in the lattice of NVOPF are crucial for its electrochemical performance. However, standard characterizations are mostly focused on the as-synthesized material without cycling, which is different from the actual battery operation conditions. In this work, we investigated the hopping processes of sodium in NVOPF at the intermediate charging state with 23Na solid-state nuclear magnetic resonance (ssNMR) and density functional theory (DFT) calculations. Our experimental characterizations revealed six distinct sodium coordination sites in the intermediate structure and determined the exchange rates among these sites at variable temperatures. The theoretical calculations showed that these dynamic processes correspond to different ion transport pathways in the crystalline lattice. Our combined experimental and theoretical study uncovered the underlying mechanisms of the ion transport in cycled NVOPF and these understandings may help the optimization of cathode materials for sodium-ion batteries.

Research on Traditional Chinese Medicine as an effective drug for promoting wound healing.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of skin trauma is high and the repair process is complex, often leading to poor healing and other issues, which can result in significant economic and social burdens. Traditional Chinese medicine (TCM) is a valuable resource with proven effectiveness and safety in wound repair, widely utilized in clinical practice. A systematic analysis of wound healing with a focus on TCM research progress holds both academic and clinical importance. AIM OF THE REVIEW: This article reviews the research progress of TCM in promoting wound healing, and provides basic data for the development of innovative drugs that promote wound healing. MATERIALS AND METHODS: This article provides a review of the literature from the past decade and conducts a thorough analysis of various databases that contain reports on the use of TCM for wound repair. The data for this systematic research was gathered from electronic databases including CNKI, SciFinder, and PubMed. The study explores and summarizes the research findings and patterns by creating relevant charts. RESULTS: This study reviewed the mechanism of wound healing, experimental TCM methods to promote wound healing, the theory and mode of action of TCM to promote wound healing, the active ingredients of TCM that promote wound healing, the efficacy of TCM formulae to promote wound healing, and the potential toxicity of TCM and its antidotes. This study enriched the theory of TCM in promoting wound healing. CONCLUSION: Skin wound healing is a complex process that can be influenced by various internal and external factors. This article offers a theoretical foundation for exploring and utilizing TCM resources that enhance wound repair. By analyzing a range of TCM that promote wound healing, the article highlights the clinical importance and future potential of these medicines in promoting wound healing.

Microwave-assisted intralesional curettage combined with other adjuvant methods for treatment of Campanacci III giant cell tumor of bone in distal radius: a multicenter clinical study.

Objective: To compare the clinical outcomes of microwave-assisted intralesional curettage(MAIC) with those of en bloc resection and autogenous fibular reconstruction (EBR-AFR) for treating grade III giant cell tumor of the bone (GCTB) of the distal radius and to elucidate the indications for wrist preservation surgery. Materials and methods: In this retrospective study, 19 patients with grade III GCTB of the distal radius who underwent surgery at three medical institutions were included and categorized based on their surgical pattern. Seven patients underwent MAIC and internal fixation with bone cement (MAIC group) and 12 underwent EBR-AFR (EBR-AFR group). To evaluate the function of the affected limb postoperatively, wrist range of motion, grip strength, Musculoskeletal Tumor Society (MSTS) scores were recorded. Results: The follow-up time of the MAIC group was 73.57 ± 28.61 (36-116) months, with no recurrence or lung metastasis. In contrast, the follow-up time of the EBR-AFR group was 55.67 ± 28.74 (36-132) months, with 1 case of local recurrence (8.3%, 1/12) and 1 case of lung metastasis (8.3%, 1/12). The wrist flexion, extension, supination, pronation, grip strength were better in the MAIC group than in the EBR-AFR group. Although there was no statistically significant difference in the MSTS score between the two groups, it is noteworthy that the MAIC group exhibited significantly superior emotional acceptance and hand positioning compared to the EBR-AFR group(p < 0.05). Conclusion: The functional outcomes of the MAIC group are better. The treatment strategy for grade III GCTB of the distal radius should be determined based on the specific preoperative imaging findings. Nevertheless, MAIC can be the preferred surgical approach for most patients with grade III GCTB of the distal radius, particularly for young patients.

Modality-specific impacts of distractors on visual and auditory categorical decision-making: an evidence accumulation perspective.

Our brain constantly processes multisensory inputs to make decisions and guide behaviors, but how goal-relevant processes are influenced by irrelevant information is unclear. Here, we investigated the effects of intermodal and intramodal task-irrelevant information on visual and auditory categorical decision-making. In both visual and auditory tasks, we manipulated the modality of irrelevant inputs (visual vs. auditory vs. none) and used linear discrimination analysis of EEG and hierarchical drift-diffusion modeling (HDDM) to identify when and how task-irrelevant information affected decision-relevant processing. The results revealed modality-specific impacts of irrelevant inputs on visual and auditory categorical decision-making. The distinct effects on the visual task were shown on the neural components, with auditory distractors amplifying the sensory processing whereas visual distractors amplifying the post-sensory process. Conversely, the distinct effects on the auditory task were shown in behavioral performance and underlying cognitive processes. Visual distractors facilitate behavioral performance and affect both stages, but auditory distractors interfere with behavioral performance and impact on the sensory processing rather than the post-sensory decision stage. Overall, these findings suggested that auditory distractors affect the sensory processing stage of both tasks while visual distractors affect the post-sensory decision stage of visual categorical decision-making and both stages of auditory categorical decision-making. This study provides insights into how humans process information from multiple sensory modalities during decision-making by leveraging modality-specific impacts.

The effects of anti-lung cancer in nude mice by a fully human single-chain antibody against associated antigen Ts7TMR between A549 cells and Trichinella spiralis.

Lung cancer is a dangerous disease that is lacking in an ideal therapy. Here, we evaluated the anti-lung cancer effect in nude mice of a fully human single-chain antibody (scFv) against the associated antigen 7 transmembrane receptor (Ts7TMR), which is also called G protein-coupled receptor, between A549 cells and Trichinella spiralis (T. spiralis). Our data showed that anti-Ts7TMR scFv could inhibit lung cancer growth in a dose-dependent manner, with a tumour inhibition rate of 59.1%. HE staining did not reveal any obvious tissue damage. Mechanistically, immunohistochemical staining revealed that the scFv down-regulated the expression of PCNA and VEGF in tumour tissues. Overall, this study found that anti-Ts7TMR scFv could inhibit A549 lung cancer growth by suppressing cell proliferation and angiogenesis, which may provide a new strategy for treating lung cancer.

Low neutralization of SARS-CoV-2 Omicron BA.5.2.48 and XBB.1 sub-variants in response to breakthrough infection by booster.

To assess the levels of and neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its mutants in serum samples from patients with breakthrough infection. Sixty-four patients with breakthrough infections were recruited for this cross-sectional study. All samples were used to neutralizing antibodies (nAbs) against SARS-CoV-2 and its mutants using a focused reduction neutralization assay. A total of 512 serum samples were obtained from unvaccinated patients who received one dose of vaccine (n = 12), received two doses of vaccine (n = 15), and received three doses of vaccine (n = 37). The geometric mean titer (GMT) of neutralizing antibodies against the Omicron subvariant was significantly lower (GMT 66.8 and 56.1) compared to the original strain, regardless of whether two or three doses of vaccine were administered. This result highlights that sera from breakthrough infections induce broad neutralization, but Omicron XBB.1.16 exhibits high immune evasion potential.

Efficiency of therapeutic plasma exchange in critically ill systemic rheumatologic diseases: A single-center 9-year experience.

INTRODUCTION: Therapeutic plasma exchange (TPE), an effective method to eliminate harmful soluble mediators associated with tissue injury, serves as a crucial intervention for systemic rheumatologic diseases (SRDs). However, its value in critically ill SRDs remains uncertain. This retrospective study aims to evaluate the efficacy of TPE in SRDs. METHODS: Critically ill SRD patients admitted to the department of intensive care unit of a large tertiary hospital receiving TPE from January 2011 to December 2019 were included. RESULTS: A total of 91 critically ill SRD patients received TPE were enrolled. Their mean age was 47.67 ± 16.35 years with a female predominance (n = 68). Significant decrease in SOFA score post-TPE treatment was observed (p < 0.05). There were no TPE-related fatalities. Improvement was observed in 64 (70.32%) patients. CONCLUSION: This study shows favorable clinical outcomes. TPE may be an acceptable treatment option for critically ill SRD patients.

Case report: unprecedented case of infantile cerebral infarction following COVID-19 and favorable outcome.

The 2019 novel coronavirus, SARS-CoV-2, was highly prevalent in China as of December 2022, causing a range of symptoms, predominantly affecting the respiratory tract. While SARS-CoV-2 infection in children is generally mild, severe cases, especially in infants, are rare. We present a case of a previously healthy 7-month-old infant who developed cerebral infarction and coagulation dysfunction three days after COVID-19 onset. Clinically, the infant had weakness in the left limbs and pinpoint bleeding spots. A cranial magnetic resonance imaging showed ischemic strokes in the right basal ganglia and thalamus. Laboratory tests indicated thrombocytopenia and coagulation dysfunction. Inflammatory cytokines like interleukin-10 were elevated, with increased CD3+, CD4+, and CD8+ T lymphocytes but decreased CD3- CD16+ CD56+ natural killer cells. Treatment included mannitol, dexamethasone, oral aspirin, and vitamins B1 and B6 for reducing intracranial pressure, antiinflammation, anticoagulation, and nerve support, respectively. During the recovery phase, rehabilitation therapy focused on strength training, fine motor skills, and massage therapy. The infant gradually improved and successfully recovered. While rare, such cases can lead to severe complications. These combined efforts were instrumental in achieving significant functional recovery in the patient, demonstrating that even in severe instances of pediatric cerebral infarction due to COVID-19, positive outcomes are attainable with early and comprehensive medical response.

Causal relationship between feelings and cognitive decline: An univariable and multivariable Mendelian randomization study.

BACKGROUND: While the impact of depression on cognition is well-documented, the relationship between feelings and cognition has received limited attention. AIM: To explore the potential association between feelings and cognition with a two-sample Mendelian randomization (MR) analysis. METHODS: Our analysis utilized genome-wide association data on various feelings (fed-up feelings, n = 453071; worrier/anxious feelings, n = 450765; guilty feelings, n = 450704; nervous feelings, n = 450700; sensitivity/hurt feelings, n = 449419; miserableness, n = 454982; loneliness/isolation, n = 455364; happiness, n = 152348) in the European population and their impact on cognitive functions (intelligence, n = 269867). Conducting a univariable MR (UVMR) analysis to assess the relationship between feelings and cognition. In this analysis, we applied the inverse variance weighting (IVW), weighted median, and MR Egger methods. Additionally, we performed sensitivity analysis (leave-one-out analysis), assessed heterogeneity (using MR-PRESSO and Cochran's Q test), and conducted multiple validity test (employing MR-Egger regression). Subsequently, a multivariable MR (MVMR) analysis was employed to examine the impact of feelings on cognition. IVW served as the primary method in the multivariable analysis, complemented by median-based and MR-Egger methods. RESULTS: In this study, UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition (OR = 0.63, 95%CI: 0.43-0.92, P = 0.017). After adjustment of other feelings using MVMR, a direct adverse causal effect on cognition was observed (ORMVMR = 0.39, 95%CI: 0.17-0.90, PMVMR = 0.027). While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis (ORUVMR = 0.64, 95%CI: 0.42-0.97, PUVMR = 0.037), this effect disappeared after adjusting for other feelings (ORMVMR = 1.42, 95%CI: 0.43-4.74, PMVMR = 0.569). These findings were generally consistent across MV-IVW, median-based, and MR-Egger analyses. MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition, presenting a challenge in identifying the effect. Notably, this study did not demonstrate any significant impact of guilty feelings, nervous feelings, miserableness, or loneliness/isolation on cognition. Due to a limited number of instrumental variables for happiness, this study was unable to analyze the relationship between happiness and cognition. CONCLUSION: This MR study finds that sensitivity/hurt feelings are associated with cognitive decline, while the link between worrier/anxious feelings and cognition remains inconclusive. Insufficient evidence supports direct associations between happiness, guilty feelings, nervous feelings, miserableness, loneliness/isolation, and cognition.

Using Mendelian randomization provides genetic insights into potential targets for sepsis treatment.

Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20-1.45, p = 1.66E-08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.

Elevated Circulating Procathepsin L as a Potential Biomarker of Inflamm-aging.

Inflamm-aging is a condition of low-grade and chronic systemic inflammation characterized by a systemic increase in multiple inflammatory biomarkers such as tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), and CXCL9 (MIG) in experimental and clinical settings. However, despite the recent identification of extracellular procathepsin L (pCTS-L) as a novel mediator of inflammatory diseases such as sepsis, its possible role in inflamm-aging was previously not investigated. In the present study, we compared blood levels of pCTS-L and other 62 cytokines and chemokines between young and aged Balb/C mice by Western blotting and Cytokine Antibody Arrays. In light of the surprising finding of a marked increase in blood pCTS-L levels in aged mice, we propose that blood pCTS-L levels may serve as another biomarker of inflamm-aging. Given the capacity of pCTS-L in inducing various cytokines (e.g., TNF and IL-6), it will be important to test the hypothetic role of pCTS-L in inflamm-aging under experimental and clinical conditions.

Effects of ankle-foot orthoses on gait parameters in post-stroke patients with different Brunnstrom stages of the lower limb: a single-center crossover trial.

BACKGROUND: Ankle-foot orthoses (AFO) can improve gait posture and walking ability in post-stroke patients. However, the effect of AFO on gait parameters in post-stroke patients according to the Brunnstrom stage of stroke recovery of the lower limbs remains unclear. The study aimed to investigate whether stroke patients with different Brunnstrom stages benefit from wearing AFO. METHODS: Twenty-five post-stroke participants included 18 men (50 ± 13 years) and 7 women (60 ± 15 years). The patients were divided based on Brunnstrom stage III or IV of the lower limbs. All patients underwent the gait and timed up and go (TUG) test using a gait analysis system while walking barefoot or with an AFO. The spatiotemporal and asymmetric parameters were analyzed. RESULTS: All 25 patients completed the study. Significant differences were observed between barefoot and AFO use in TUG time (P < 0.001) but not walking velocity (P > 0.05). The main effect of the swing time ratio was significant in both groups (P < 0.05); however, the main effects of stride length, stance time, and gait asymmetry ratio were nonsignificant (P > 0.05). For barefoot versus AFO, the main effects of stride length (P < 0.05) and swing time (P < 0.01) ratios were significant, whereas those of stance time and gait asymmetry ratio were nonsignificant (P > 0.05). CONCLUSIONS: Post-stroke patients with lower Brunnstrom stages benefitted more from AFO, particularly in gait asymmetry.

Rapid visual detection of Giardia duodenalis in faecal samples using an RPA-CRISPR/Cas12a system.

Giardiasis is a common intestinal infection caused by Giardia duodenalis, which is a major economic and health burden for humans and livestock. Currently, a convenient and effective detection method is urgently needed. CRISPR/Cas12a-based diagnostic methods have been widely used for nucleic acid-based detection of pathogens due to their high efficiency and sensitivity. In this study, a technique combining CRISPR/Cas12a and RPA was established that allows the detection of G. duodenalis in faecal samples by the naked eye with high sensitivity (10-1 copies/µL) and specificity (no cross-reactivity with nine common pathogens). In clinical evaluations, the RPA-CRISPR/Cas12a-based detection assay detected Giardia positivity in 2% (1/50) of human faecal samples and 47% (33/70) of cattle faecal samples, respectively, which was consistent with the results of nested PCR. Our study demonstrated that the RPA-CRISPR/Cas12a technique for G. duodenalis is stable, efficient, sensitive, specific and has low equipment requirements. This technique offers new opportunities for on-site detection in remote and poor areas.

Phylogenomics and biogeographical diversification of Collabieae (Orchidaceae) and its implication in the reconstruction of the dynamic history of Asian evergreen broadleaved forests.

The tribe Collabieae (Epidendroideae, Orchidaceae) comprises approximately 500 species. Generic delimitation within Collabieae are confusing and phylogenetic interrelationships within the Collabieae have not been well resolved. Plastid genomes and nuclear internal transcribed spacer (ITS) sequences were used to estimate the phylogenetic relationships, ancestral ranges, and diversification rates of Collabieae. The results showed that Collabieae was subdivided into nine clades with high support. We proposed to combine Ancistrochilus and Pachystoma into Spathoglottis, merge Collabium and Chrysoglossum into Diglyphosa, and separate Pilophyllum and Hancockia as distinctive genera. The diversification of the nine clades of Collabieae might be associated with the uplift of the Himalayas during the Late Oligocene/Early Miocene. The enhanced East Asian summer monsoon in the Late Miocene may have promoted the rapid diversification of Collabieae at a sustained high diversification rate. The increased size of terrestrial pseudobulbs may be one of the drivers of Collabieae diversification. Our results suggest that the establishment and development of evergreen broadleaved forests facilitated the diversification of Collabieae.

Endothelial progenitor cells control remodeling of uterine spiral arteries for the establishment of utero-placental circulation.

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.

Biomass fuels related-PM2.5 promotes lung fibroblast-myofibroblast transition through PI3K/AKT/TRPC1 pathway.

Emerging evidence has suggested that exposure to PM2.5 is a significant contributing factor to the development of chronic obstructive pulmonary disease (COPD). However, the underlying biological effects and mechanisms of PM2.5 in COPD pathology remain elusive. In this study, we aimed to investigate the implication and regulatory effect of biomass fuels related-PM2.5 (BRPM2.5) concerning the pathological process of fibroblast-to-myofibroblast transition (FMT) in the context of COPD. In vivo experimentation revealed that exposure to biofuel smoke was associated with airway inflammation in rats. After 4 weeks of exposure, there was inflammation in the small airways, but no significant structural changes in the airway walls. However, after 24 weeks, airway remodeling occurred due to increased collagen deposition, myofibroblast proliferation, and tracheal wall thickness. In vitro, cellular immunofluorescence results showed that with stimulation of BRPM2.5 for 72 h, the cell morphology of fibroblasts changed significantly, most of the cells changed from spindle-shaped to star-shaped irregular, α-SMA stress fibers appeared in the cytoplasm and the synthesis of type I collagen increased. The collagen gel contraction experiment showed that the contractility of fibroblasts was enhanced. The expression level of TRPC1 in fibroblasts was increased. Specific siRNA-TRPC1 blocked BRPM2.5-induced FMT and reduced cell contractility. Additionally, specific siRNA-TRPC1 resulted in a decrease in the augment of intracellular Ca2+ concentration ([Ca2+]i) induced by BRPM2.5. Notably, it was found that the PI3K inhibitor, LY294002, inhibited enhancement of AKT phosphorylation level, FMT occurrence, and elevation of TRPC1 protein expression induced by BRPM2.5. The findings indicated that BRPM2.5 is capable of inducing the FMT, with the possibility of mediation by PI3K/AKT/TRPC1. These results hold potential implications for the understanding of the molecular mechanisms involved in BRPM2.5-induced COPD and may aid in the development of novel therapeutic strategies for pathological conditions characterized by fibrosis.

INHBA regulates Hippo signaling to confer 5-FU chemoresistance mediated by cellular senescence in colon cancer cells.

Colon cancer has become a global public health challenge, and 5-Fluorouracil (5-FU) chemoresistance is a major obstacle in its treatment. Chemoresistance can be mediated by therapy-induced cellular senescence. This study intended to investigate mechanisms of INHBA (inhibin A) in 5-FU resistance mediated by cellular senescence in colon cancer. Bioinformatics analysis of INHBA expression in colon cancer tissues, survival analysis, and correlation analysis of cellular senescence markers were performed. The effects of INHBA on the biological characteristics and 5-FU resistance of colon cancer cells were examined through loss/gain-of-function and molecular assays. Finally, a xenograft mouse model was built to validate the mechanism of INHBA in vivo. INHBA was upregulated in colon cancer and was significantly positively correlated with cellular senescence markers uncoupling protein 2 (UCP-2), matrix metalloproteinase-1 (MMP-1), dense and erect panicle 1 (DEP1), and p21. Cellular senescence in colon cancer mediated 5-FU resistance. Downregulation of INHBA expression enhanced 5-FU sensitivity in colon cancer cells, inhibited cell proliferation, promoted apoptosis, increased the proportion of cells in G0/G1 phase, and it resulted in a lower proportion of senescent cells and lower levels of the cellular senescence markers interleukin 6 (IL-6) and interleukin 8 (IL-8). Analysis of whether to use the pathway inhibitor Verteporfin proved that INHBA facilitated colon cancer cell senescence and enhanced 5-FU chemoresistance via inactivation of Hippo signaling pathway, and consistent results were obtained in vivo. Collectively, INHBA conferred 5-FU chemoresistance mediated by cellular senescence in colon cancer cells through negative regulation of Hippo signaling.