Perioperative Transcutaneous Electrical Acupoint Stimulation Reduces Postoperative Pain in Patients Undergoing Thoracoscopic Surgery: A Randomized Controlled Trial.

Objectives: This study aimed to determine the effects of perioperative transcutaneous electrical acupoint stimulation (TEAS) on postoperative pain management in patients undergoing thoracic surgery. Methods: In the prospective, randomized, controlled study, a total of 84 patients undergoing video-assisted thoracoscopic surgery (VATS) were randomly allocated to the TEAS group (Group T) or control group (Group C). Patients in the Group T received TEAS at Neiguan (PC6) and Hegu (LI4) acupoints for 30 min before anesthesia induction and 30 min after thoracoscopic surgery. Patients in the Group C received the same placement of electrodes but without electrical stimulation. The numeric rating scale (NRS) pain score, remifentanil consumption, demand for rescue analgesics and incidence of postoperative nausea and vomiting (PONV), patient satisfaction, and the levels of plasma ß-endorphin (EP) and IL-6 were recorded. Results: Patients in the Group T had significantly lower NRS pain scores at 6 h, 12 h, 24 h, and 48 h after surgery than those in the Group C. Compared with Group C, patients in Group T had lower remifentanil consumption during operation, lower demand for rescue analgesics and lower rate of PONV within 24 h after surgery. Patients in Group T also had lower IL-6 content, higher ß-EP content and higher satisfaction degree than those in the Group C. Conclusions: Perioperative TEAS significantly decreased postoperative pain and rescued analgesia requirements and the incidence of PONV in patients undergoing thoracoscopic surgery, with a higher patient satisfaction. This trial is registered with ChiCTR2100051841.

miR-200a-3p-enriched MSC-derived extracellular vesicles reverse erectile function in diabetic rats by targeting Keap1.

BACKGROUND: The administration of mesenchymal stem cells (MSCs) through intracavernous injection is a potential therapeutic approach for managing diabetes mellitus-induced erectile dysfunction (DMED). However, pulmonary embolism and tumorigenicity are fatal adverse events that limit the clinical application of MSCs. In this study, we examined the therapeutic efficacy and potential mechanism of MSC-derived extracellular vesicles (MSC-EVs). METHODS: In this study, forty 8-week-old male SpragueDawley (SD) rats were utilised. In the control group, ten rats were administered an intraperitoneal injection of PBS. STZ (60 mg/kg) was intraperitoneally injected into the remaining rats to establish a diabetes mellitus (DM) model. Afterwards, the diabetic rats were divided into three groups at random: the DM group (intracavernosal injection of PBS), the EVs group (intracavernosal injection of MSC-EVs), and the EVs-200a group (intracavernosal injection of miR-200a-3p-enriched extracellular vesicles). Erectile function was determined by measuring intracavernous pressure in real time and utilising electrical stimulation of the cavernous nerves. The smooth muscle content was evaluated through the investigation of penile tissue using immunofluorescence staining, Masson's trichrome staining, and western blotting after euthanasia. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in the corpus cavernosum were measured via ELISA. In vitro, hydrogen peroxide (H2O2) was used to induce oxidative stress. The viability of corpus cavernosum smooth muscle cells (ccSMCs) incubated with or without H2O2 was measured using a CCK8 assay. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) and apoptosis in ccSMCs. Furthermore, a dual-luciferase reporter assay was performed to validate the relationship between miR-200a-3p and Keap1. RESULTS: Reversal of erectile function was observed in the EVs groups, especially in the EVs-200a group. DM increased the MDA level and decreased the SOD and GSH levels. In the DM group, the expression of alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) was decreased, and the expression of osteopontin (OPN) was increased. Western blotting revealed decreased Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase3 expression in the cavernous tissue. miR-200a-3p-enriched extracellular vesicles (EVs-200a) reversed these changes and inhibited the loss of smooth muscle content and cavernous fibrosis. In vitro, H2O2 induced high ROS levels in ccSMCs and increased apoptosis, and these effects reversed by EVs-200a. H2O2 reduced Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase-3 expression, and these effects were reversed by MSC-EVs, especially EVs-200a. The of dual-luciferase reporter assay results indicated that miR-200a-3p directly targeted Keap1 in a negative manner. CONCLUSION: MSC-EVs, especially EVs-200a, alleviated erectile dysfunction in diabetic rats through the regulation of phenotypic switching, apoptosis and fibrosis. Mechanistically, miR-200a-3p targeted the Keap1/Nrf2 pathway to attenuate oxidative stress in diabetic rats.

Human mesenchymal stromal cells ameliorate cisplatin induced acute and chronic kidney injury via TSG-6.

Cisplatin is widely employed in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rhTSG-6), or PBS through tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. hBM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen (BUN), tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, knockdown of TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviate cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.

Boosting Sono-immunotherapy of Prostate Carcinoma through Amplifying Domino-Effect of Mitochondrial Oxidative Stress Using Biodegradable Cascade-Targeting Nanocomposites.

Sono-immunotherapy faces challenges from poor immunogenicity and low response rate due to complex biological barriers. Herein, we prepared MCTH nanocomposites (NCs) consisting of disulfide bonds (S-S) doped mesoporous organosilica (MONs), Cu-modified protoporphyrin (CuPpIX), mitochondria-targeting triphenylphosphine (TPP), and CD44-targeting hyaluronic acid (HA). MCTH NCs efficiently accumulate at the tumor site due to the overexpressed CD44 receptors on the membrane of the cancer cells. Under the function of HAase and glutathione (GSH), MCTH degrades and exposes TPP to deliver CuPpIX to the mitochondrial site and induce a reactive oxygen species (ROS) burst in situ under ultrasound irradiations, thereby causing severe mitochondria dysfunction. This cascade-targeting ability of MCTH NCs not only reinforces oxidative stress in cancer cells but also amplifies immunogenic cell death (ICD) to stimulate the body's immune response and alleviate the tumor immunosuppressive microenvironment. These NCs significantly enhance the infiltration of immune cells into the tumor, particularly CD8+ T cells, for a powerful antitumor sono-immunotherapy. The proposed cascade-targeting strategy holds promise for strengthening sono-immunotherapy for prostate cancer treatment and overcoming the limitations of traditional immunotherapy.

Phenolic composition, antioxidant, cytotoxic activities and cardioprotective effect of hydroalcoholic extract from aerial-parts of Hypericum attenuatum Fisch. ex Choisy.

This study investigated phenolic metabolites, antioxidant, cytotoxic and cardioprotective effects of the hydroalcoholic extract from the aerial parts of Hypericum attenuatum Fisch. ex Choisy. The total phenolic and flavonoid contents of the extract were 132.40 ± 2.06 mg GAE/g and 101.46 ± 1.47 mg QE/g respectively. The extract exhibited antioxidant activities with an EC50 value against DPPH radical of 0.099 ± 0.03 mg/mL and a FRAP value of 1.22 ± 0.086 mmol/L Fe2+. The extract could protect H9c2 cardiomyoblasts from the injury of H2O2, while it restored the H9c2 cell viability to 82.69 ± 2.33% at 100 µg/mL. The extract possessed cytotoxicity on MGC803, C666-1 and SW620 cells with IC50 values of 69.77 ± 2.43 µg/mL, 74.97 ± 1.08 µg/mL and 58.91 ± 1.81 µg/mL, respectively. Moreover, it could promote apoptosis of the tested cancer cells. This research provided useful information for the utilization of H. attenuatum as herbal medicine.

Root-knot nematode infections and soil characteristics significantly affected microbial community composition and assembly of tobacco soil microbiota: a large-scale comparison in tobacco-growing areas.

Introduction: Tobacco root-knot nematode (RKN) is a highly destructive soil-borne disease worldwide. However, there is a lack of research on the relationship between RKN and tobacco root microbial community composition under large-scale geographical conditions in China. Methods: In this study, we collected 65 samples from 28 main tobacco-growing areas across 10 provinces in China and conducted 16S rDNA sequencing to investigate the dynamic microbial changes in tobacco soil infected by RKN compared to healthy tobacco soil. Based on the analysis of rhizosphere soil bacterial communities, changes after RKN infection, and soil environmental factors. Results: We found the 28 tobacco-growing areas could be divided into two distinct groups with different microbial compositions and varying responses to RKN infection. In group1 of the provinces of Anhui, Henan, Shanxi, and Heilongjiang, Vicinamibacteria dominated the bacterial community, while Acidobacteriae was present in low abundance. In contrast, group2 of the other six provinces (Yunnan, Guizhou, Chongqing, Guangxi, Hubei, and Shandong) exhibited an opposite pattern. After infected by RKN, the genera Chitinophaga increased significant in group 1, while the genera Rhodococcus in group 2 exhibited a substantial increase. Alpha-diversity analysis revealed that RKN-infected tobacco exhibited a richer and more diverse rhizosphere soil bacterial community compared to healthy tobacco in most growing areas. A total of 12 kinds of soil environmental factors were measured in healthy and RKN-infected tobacco soil, and based on the co-occurrence and correlation analysis between environmental factors and microbial species, the pH level, calcium (Ca), magnesium (Mg), phosphorus (P), iron (Fe), and sodium (Na) were identified as key environmental factors influencing the population composition of rhizosphere microorganisms during RKN infection. We observed that RKN infection further increased the pH in weakly alkaline group 1 soil, while weakly acidic group 2 soil experienced a further decrease in pH. Furthermore, we identified three genera as potential biocontrol or plant growth-promoting bacteria for tobacco. Discussion: These findings provide valuable reference data for managing RKN disease in different tobacco-growing areas and contribute to the exploration of new and effective biological control methods.

Hollow polyester/kapok/hollow polyester fiber-based needle punched nonwoven composite materials for rapid and efficient oil sorption.

Nowadays oil pollution poses a serious threat to the environment and people's daily life. As reusable and environmentally friendly materials, fiber-based oil sorption materials can effectively alleviate this phenomenon. However, maintaining a high sorption rate along with improved mechanical properties remains a challenge for oil sorption materials. Herein, we report a novel hollow PET/kapok/hollow PET nonwoven with high porosity and oil retention, outstanding cyclic oil sorption rate and improved mechanical performance using kapok as the oil preserver and hollow PET as the conductor and structure enhancer. Benefiting from the three-layer composite structure fabricated by carding and needle punching reinforcement, the resulting oil sorption materials, with kapok proportion more than or equal to 60%, exhibited high oil sorption rate and oil sorption speed. The materials of 20HP/60K/20HP component content present a high initial oil sorption rate of 28.22 g g-1, a maximum oil sorption rate of 31.17 g g-1 and a sorption rate constant of the Quasi second-order kinetic equation of 0.067 in plant oil. On the other hand, when the proportion of kapok fiber in the material was below 60%, due to the introduction of hollow PET, the mechanical properties were significantly boosted, and its oil retention and reusability were distinguished, with a reuse rate stabilizing at a relatively high level (>93%) in plant oil after undergoing three oil sorption cycles. The successful fabrication of hollow PET/kapok/hollow PET nonwovens could provide a new approach for the design and development of oil sorption materials.

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury.

Background: Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED. Aim: To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI). Methods: In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups. Outcomes: Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured. Results: Two ratios-maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen-were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α-smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group. Clinical Translation: The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment. Strengths and Limitations: The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation. Conclusion: The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.

High-power green-light laser endoscopic submucosal dissection for non-muscle-invasive bladder cancer: A technical improvement and its initial application.

Background: The technique of laser en bloc resection of bladder tumor (ERBT) has been a valuable alternative technique to transurethral resection of bladder tumor (TURBT). However, the combination of laser ERBT and endoscopic submucosal dissection (ESD) technique has not been well studied. Here, a novel technique integrating a high-power green-light laser with ESD was presented. This study aimed to evaluate the safety and efficacy of high-power green-light laser endoscopic submucosal dissection (HPL-ESD) for the treatment of primary non-muscle-invasive bladder cancer (NMIBC). Materials and Methods: From January 2015 to December 2018, a total of 56 patients with NMIBC underwent HPL-ESD. All tumors were transurethral en bloc resected in the ESD technique. Perioperative clinical data were retrospectively collected and analyzed. Results: All operations were safely performed by the technique of HPL-ESD without blood transfusion. The mean tumor diameter was 2.04 ± 0.65 cm, ranging from 0.5 to 3.5 cm. The mean operative time was 28.39 ± 16.04 min. The average serum hemoglobin decrease was 0.88 ± 0.54 g/dL. The mean postoperative catheterization time was 2.88 ± 0.94 days. The pathologic stages included pTa (32 cases), and pT1 (24 cases). Double-J stent indwelling was not performed for four patients whose tumors were adjacent to the ureteral orifice and no postoperative hydronephrosis was observed. Only one case of ectopic bladder tumor recurred due to irregular bladder irrigation during the 36-month follow-up. Conclusion: HPL-ESD is a safe and effective alternative for the treatment of primary NMIBCs, especially for tumors adjacent to the ureteral orifice.

Transcutaneous electrical acupoint stimulation versus dexamethasone for prophylaxis of postoperative nausea and vomiting in breast surgery: A non-inferiority randomized controlled trial.

BACKGROUND: Transcutaneous electrical acupoint stimulation and dexamethasone can reduce postoperative nausea and/or vomiting. In this noninferiority study, we compared the effects of Neiguan acupoint (PC6) transcutaneous electrical acupoint stimulation with dexamethasone to prevent postoperative nausea and/or vomiting in female patients undergoing breast surgery. METHODS: In total, 280 patients were randomized into the following 2 groups: transcutaneous electrical acupoint stimulation (n = 140) and dexamethasone (n = 140). Transcutaneous electrical acupoint stimulation was performed 0.5 hours before anesthesia induction, immediately after entering the post-anesthesia care unit, and every 3 hours after leaving the post-anesthesia care unit. In the postoperative ward, the anesthetist instructed the patient's family members to assist the patient with PC6 patient-controlled transcutaneous electrical acupoint stimulation. Patients in the dexamethasone group were given 8 mg dexamethasone (intravenously) at 0.5 hours before induction of anesthesia. The incidence of nausea, vomiting, need for rescue antiemetics, patient satisfaction score, and the feasibility results of PC6 patient-controlled transcutaneous electrical acupoint stimulation were recorded 24 hours after surgery. RESULT: Within 0 to 24 hours after surgery, the incidence of postoperative nausea and/or vomiting in the transcutaneous electrical acupoint stimulation group was not inferior to the dexamethasone group (31.1% vs 27.9%, per protocol risk difference 3.2; 95% confidence interval -7.7 to 14.0). The results of the intention-to-treat analysis (30.7% vs 27.1%, risk difference 3.6; 95% confidence interval -7.0 to 14.2) agreed with the per protocol analysis. Patient satisfaction score in the transcutaneous electrical acupoint stimulation group was higher than that in the dexamethasone group (3.9 ± 0.1 vs 3.6 ± 0.1, P = .003). The scheme of preventing postoperative nausea and/or vomiting by PC6 patient-controlled transcutaneous electrical acupoint stimulation was feasible. CONCLUSION: Transcutaneous electrical acupoint stimulation was noninferior to dexamethasone in preventing postoperative nausea and/or vomiting within 24 hours after breast surgery. Neiguan acupoint patient-controlled transcutaneous electrical acupoint stimulation was feasible to prevent postoperative nausea and/or vomiting.

MicroRNA-376b is involved in the pathogenesis of thyroid-associated ophthalmopathy by regulating HAS2.

PURPOSE: The aim of this study was to investigate the microRNA (miRNA) expression profile in peripheral blood mononuclear cells (PBMC) of thyroid-associated ophthalmopathy (TAO) patients and to explore the molecular mechanisms of MicroRNA-376b (miR-376b) in the pathogenesis of TAO. METHODS: PBMCs from TAO patients and healthy controls were analyzed by miRNA microarray to screen for the significantly differentially expressed miRNAs. The miR-376b expression in PBMCs were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). The downstream target of miR-376b was screened by online bioinformatics, and detected by qRT-PCR and Western blotting. RESULTS: Compared with normal controls, 26 miRNAs were significantly different in PBMCs of TAO patients (14 miRNAs were down-regulated and 12 miRNAs were up-regulated). Among them, miR-376b expression was significantly decreased in PBMCs from TAO patients compared to healthy controls. Spearman correlation analysis revealed that miR-376b expression in PBMCs was significantly negatively correlated with free triiodothyronine (FT3), and positively correlated with thyroid-stimulating hormone (TSH). MiR-376b expression was obviously reduced in 6T-CEM cells after triiodothyronine (T3) stimulation compared to controls. MiR-376b mimics significantly decreased hyaluronan synthase 2 (HAS2) protein expression and the mRNA expression of intercellular cell adhesion molecule-1 (ICAM1) and tumor necrosis factor-α (TNF-α) in 6T-CEM cells, whereas miR-376b inhibitors markedly elevated HAS2 protein expression and gene expression of ICAM1 and TNF-α. CONCLUSIONS: MiR-376b expression in PBMCs was significantly decreased in PBMCs from TAO patients compared with the healthy controls. MiR-376b, regulated by T3, could modulate the expression of HAS2 and inflammatory factors. We speculate that miR-376b may be involved in the pathogenesis of TAO patients by regulating the expression of HAS2 and inflammatory factors.

Efficacy and Safety of 1470 nm Diode Laser Enucleation of the Prostate in Elderly Benign Prostatic Hyperplasia Patients.

Objective: The aim of this study was to evaluate efficacy and safety of 1470 nm diode laser enucleation of the prostate (DiLEP) and plasmakinetic resection of the prostate (PKRP) in elderly benign prostatic hyperplasia (BPH) patients with lower urinary tract symptoms. Methods: A total of 123 elderly patients with BPH were randomized to undergo either 1470 nm DiLEP or PKRP by means of a random number table from September 2020 to April 2022. The perioperative and postoperative data were studied during a 3- and 6-month follow-up. Results: The patients treated with 1470 nm DiLEP had significantly decreased operation time (74.6 ± 17.0 vs 98.8 ± 18.9 minutes, p < 0.001), hemoglobin loss (1.06 ± 0.49 vs 1.59 ± 0.60 g/dL, p < 0.001), bladder irrigation time (22.1 ± 8.1 vs 33.9 ± 10.0 hours, p < 0.001), catheter duration (3.2 ± 1.3 vs 5.8 ± 1.0 days, p < 0.001), and hospital stay (7.6 ± 1.4 vs 9.6 ± 1.3 days, p < 0.001) compared with the PKRP group. Besides, International Index of Erectile Function-5 score of 1470 nm DiLEP group at postoperative 3- and 6-month follow-up was significantly higher than PKRP group. No differences achieving statistical significance were identified in total prostate-specific antigen, maximum urinary flow rate, International Prostate Symptom Score, quality-of-life score, and the postvoid residual urine volume, transient incontinence, urethral stricture, bladder neck contracture, and retrograde ejaculation at 3- and 6-month follow-up. Conclusions: 1470 nm DiLEP is safer than PKRP, with a smaller effect on sexual function, and it is comparable with the efficacy of PKRP, thus making it more suitable for elderly BPH patients. Clinical Trial Registration number: S2021-463-01.

Nomograms Combining PHI and PI-RADS in Detecting Prostate Cancer: A Multicenter Prospective Study.

(1) Background: The study aimed to construct nomograms to improve the detection rates of prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) in the Asian population. (2) Methods: This multicenter prospective study included a group of 293 patients from three hospitals. Univariable and multivariable logistic regression analysis was performed to identify potential risk factors and construct nomograms. Discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. The web-based dynamic nomograms were subsequently built based on multivariable logistic analysis. (3) Results: A total of 293 patients were included in our study with 201 negative and 92 positive results in PCa. Four independent predictive factors (age, prostate health index (PHI), prostate volume, and prostate imaging reporting and data system score (PI-RADS)) for PCa were included, and four factors (age, PHI, PI-RADS, and Log PSA Density) for CSPCa were included. The area under the ROC curve (AUC) for PCa was 0.902 in the training cohort and 0.869 in the validation cohort. The AUC for CSPCa was 0.896 in the training cohort and 0.890 in the validation cohort. (4) Conclusions: The combined diagnosis of PHI and PI-RADS can avoid more unnecessary biopsies and improve the detection rate of PCa and CSPCa. The nomogram with the combination of age, PHI, PV, and PI-RADS could improve the detection of PCa, and the nomogram with the combination of age, PHI, PI-RADS, and Log PSAD could improve the detection of CSPCa.

Derepression of the USP22-FASN axis by p53 loss under oxidative stress drives lipogenesis and tumorigenesis.

Overproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancer; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancer (CRC) cells, hydrogen peroxide (H2O2)-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and tumor growth. In human CRC specimens, USP22 expression is positively correlated with FASN expression. Our study demonstrates that ROS critically regulates lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.

Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6.

Objective: Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. Methods: Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/ß hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. Results: Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. Conclusion: Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.

The cAMP-PKA signalling pathway regulates hyphal growth, conidiation, trap morphogenesis, stress tolerance, and autophagy in Arthrobotrys oligospora.

The cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signalling pathway is evolutionarily conserved in eukaryotes and plays a crucial role in defending against external environmental challenges, which can modulate the cellular response to external stimuli. Arthrobotrys oligospora is a typical nematode-trapping fungus that specializes in adhesive networks to kill nematodes. To elucidate the biological roles of the cAMP-PKA signalling pathway, we characterized the orthologous adenylate cyclase AoAcy, a regulatory subunit (AoPkaR), and two catalytic subunits (AoPkaC1 and AoPkaC2) of PKA in A. oligospora by gene disruption, transcriptome, and metabolome analyses. Deletion of Aoacy significantly reduced the levels of cAMP and arthrobotrisins. Results revealed that Aoacy, AopkaR, and AopkaC1 were involved in hyphal growth, trap morphogenesis, sporulation, stress resistance, and autophagy. In addition, Aoacy and AopkaC1 were involved in the regulation of mitochondrial morphology, thereby affecting energy metabolism, whereas AopkaC2 affected sporulation, nuclei, and autophagy. Multi-omics results showed that the cAMP-PKA signalling pathway regulated multiple metabolic and cellular processes. Collectively, these data highlight the indispensable role of cAMP-PKA signalling pathway in the growth, development, and pathogenicity of A. oligospora, and provide insights into the regulatory mechanisms of signalling pathways in sporulation, trap formation, and lifestyle transition.

Modulating Activity Evaluation of Gut Microbiota with Versatile Toluquinol.

Gut microbiota have important implications for health by affecting the metabolism of diet and drugs. However, the specific microbial mediators and their mechanisms in modulating specific key intermediate metabolites from fungal origins still remain largely unclear. Toluquinol, as a key versatile precursor metabolite, is commonly distributed in many fungi, including Penicillium species and their strains for food production. The common 17 gut microbes were cultivated and fed with and without toluquinol. Metabolic analysis revealed that four strains, including the predominant Enterococcus species, could metabolize toluquinol and produce different metabolites. Chemical investigation on large-scale cultures led to isolation of four targeted metabolites and their structures were characterized with NMR, MS, and X-ray diffraction analysis, as four toluquinol derivatives (1-4) through O1/O4-acetyl and C5/C6-methylsulfonyl substitutions, respectively. The four metabolites were first synthesized in living organisms. Further experiments suggested that the rare methylsulfonyl groups in 3-4 were donated from solvent DMSO through Fenton's reaction. Metabolite 1 displayed the strongest inhibitory effect on cancer cells A549, A2780, and G401 with IC50 values at 0.224, 0.204, and 0.597 µM, respectively, while metabolite 3 displayed no effect. Our results suggest that the dominant Enterococcus species could modulate potential precursors of fungal origin and change their biological activity.

Tegaserod maleate exhibits antileukemic activity by targeting TRPM8.

To identify therapeutic targets in acute myeloid leukemia (AML), we conducted growth inhibition screens of 2040 small molecules from a library of FDA-approved drugs using a panel of 12 AML cell lines. Tegaserod maleate, a 5-hydroxytryptamine 4 receptor partial agonist, elicits strong anti-AML effects in vitro and in vivo by targeting transient receptor potential melastatin subtype 8 (TRPM8), which plays critical roles in several important processes. However, the role of TRPM8 remains incompletely described in AML, whose treatment is based mostly on antimitotic chemotherapy. Here, we report an unexpected role of TRPM8 in leukemogenesis. Strikingly, TRPM8 knockout inhibits AML cell survival/proliferation by promoting apoptosis. Mechanistically, TRPM8 exerts its oncogenic effect by regulating the ERK-CREB/c-Fos signaling axis. Hyperactivation of ERK signaling can be reversed by TRPM8 inhibition. Importantly, TRPM8 is overexpressed in AML patients, indicating that it is a new prognostic factor in AML. Collectively, our work demonstrates the anti-AML effects of tegaserod maleate via targeting TRPM8 and indicates that TRPM8 is a regulator of leukemogenesis with therapeutic potential in AML.

Adrenal Gland Metastasis of Breast Invasive Mucinous Carcinoma: A Rare Case Report and Review of Literature.

The adrenal gland is a frequent site for metastasis, and the majority of the metastatic lesions of the adrenal gland normally originate from lung cancer, colon cancer, renal cell carcinoma, and melanoma. However, adrenal gland metastasis from breast invasive mucinous carcinoma is extremely rare. This report described a rare case of right adrenal gland metastasis in a 48-year-old female, who was diagnosed with breast invasive mucinous carcinoma and underwent right modified radical mastectomy with axillary lymph node dissection 5 years previously. A mass located on the right adrenal gland was detected during a routine examination 2 months ago. The patient was asymptomatic and adrenal gland MRI revealed a mass in the right adrenal gland. Definitive preoperative diagnosis failed to be established. Right adrenal gland laparoscopic adrenalectomy was performed and the diagnosis of adrenal gland metastasis of breast carcinoma was confirmed by pathological and immunohistochemical examination, especially ER, PR, GATA3, and HER-2. The patient remained in good condition by the time of writing.