Nickel-catalyzed regiodivergent sulfonylarylation of 1,3-enynes to access allenes and dienes.

The radical-mediated difunctionalization of 1,3-enynes facilitates rapid access to structurally diverse allenes and dienes. Whereas, owing to the existence of multiple active sites in conjugated 1,3-enynes, regulating selectivity in difunctionalized addition via a single transition-metal-catalyzed radical tandem process remains elusive. Herein, we disclose an intriguing protocol of substrate-controlled nickel-catalyzed regiodivergent sulfonylarylation of 1,3-enynes with the assistance of sulfonyl chlorides and arylboronic acids. This valuable synthetic utility respectively delivers a series of highly functionalized and synthetically challenging allenyl sulfones and dienyl sulfones from fine-tuned 1,3-enynes by one step, which provides a facile approach for complex sulfone-containing drug molecules synthesis.

New Progress on DNA Primase Subunit Enzymes Research and Link to Cancer Development and Treatment Approaches.

In eukaryotic cells, primases are the key polymerase during DNA replication and DNA damage repair, which includes primase subunit 1 (PRIM1) and primase subunit 2 (PRIM2). Recent studies reported that the aberrant expression and activity of PRIM enzymes are closely associated with the carcinogenesis and development of various cancers. PRIM1 is overexpressed in hepatocellular carcinoma, breast cancer, and other cancers, while PRIM2 is highly expressed in lung cancer, gastrointestinal cancer, and other cancers. Further studies revealed that the knockdown of PRIM1 promoted the apoptosis of liver cancer cells, while Dihydroartemisinin (DHA) can inhibit PRIM2 expression, suppress lung cancer cell proliferation, and result in ferroptosis. The present review summarized the recent advancements in the research of the aberrant expression of PRIM1 and PRIM2 and their activity in DNA replication, DNA damage repair, and carcinogenesis. Furthermore, the strategies targeting PRIM1 or/and PRIM2 become potential therapeutic approaches in cancer treatment.

The clinical efficacy of single-hole punch excision combined with intralesional steroid injection for nodular keloid treatment: a self-controlled trial.

There are many methods to treat keloid, including various excision operations, laser, injection and radiotherapy. However, few studies have explored the effectiveness of single-hole punch excision in keloid treatment. This study aimed to investigate the efficacy and safety of lateral punch excision combined with intralesional steroid injection for keloid treatment through self-control trial. In this self-controlled trial, 50 patients meet the diagnosis of nodular keloid, and try to choose left-right symmetrical control, one skin lesion in the control group (50 skin lesionsin total) and the other in the observation group (50 skin lesions in total).The keloids in the treatment group were initially treated with punch excision combined with intralesional steroid injection, followed by injection treatment alone. Keloids in the control group received intralesional steroid injection alone. The Vancouver Scar Scale (VSS) of the keloid before and after the punch excision was evaluated; the keloid scores at different time points and the number of injection treatments required in both groups were compared, and adverse reactions were observed. The effective rate of the observation group was 86.0%, which was significantly higher than that of the control group (66.0%), and the recurrence rate of 22% was lower than that of the control group (χ2 = 4.141,63417), all of which were statistically significant (all P < 0.05). At the end of treatment, the VSS and total injection times in the observation group were significantly lower than those in the control group (t = 5.900,3.361), with statistical significance (P < 0.01). The combination of single-hole punch excision and intralesional steroid injection is an effective method to treat multiple nodular keloids, shortening the treatment course of tralesional steroid injection without obvious adverse reactions.

Saccharomyces cerevisiae cellular engineering for the production of FAME biodiesel.

The unsustainable and widespread utilization of fossil fuels continues to drive the rapid depletion of global supplies. Biodiesel has emerged as one of the most promising alternatives to conventional diesel, leading to growing research interest in its production. Microbes can facilitate the de novo synthesis of a type of biodiesel in the form of fatty acid methyl esters (FAMEs). In this study, Saccharomyces cerevisiae metabolic activity was engineered to facilitate enhanced FAME production. Initially, free fatty acid concentrations were increased by deleting two acetyl-CoA synthetase genes (FAA1, FAA4) and an acyl-CoA oxidase gene (POX1). Intracellular S-adenosylmethionine (SAM) levels were then enhanced via the deletion of an adenosine kinase gene (ADO1) and the overexpression of a SAM synthetase gene (SAM2). Lastly, the S. cerevisiae strain overproducing free fatty acids and SAM were manipulated to express a plasmid encoding the Drosophila melanogaster Juvenile Hormone Acid O-Methyltransferase (DmJHAMT). Using this combination of engineering approaches, a FAME concentration of 5.79 ± 0.56 mg/L was achieved using these cells in the context of shaking flask fermentation. To the best of our knowledge, this is the first detailed study of FAME production in S. cerevisiae. These results will provide a valuable basis for future efforts to engineer S. cerevisiae strains for highly efficient production of biodiesel.

Intensifying separation of Pb and Sn from waste Pb-Sn alloy by ultrasound-assisted acid leaching: Selective dissolution and sonochemistry mechanism.

Clean and efficient extraction and separation of precious metals from discarded Pb-Sn alloy is critical to the sustainable utilization of solid waste resources. Dense oxide layer and compact alloy texture in the waste Pb-Sn alloy pose challenges to the effective leaching process. Ultrasonic waves are demonstrated to improve separation efficiency via the favorable physical and chemical effects in solution system. In this study, ultrasound-assisted leaching technology is attempted to rapidly and selectively extract Pb from the waste Pb-Sn alloy, and gives emphasis on ultrasonic electrochemical behaviors. The Eh-pH diagrams of Sn-H2O and Pb-H2O systems were firstly analyzed to lay the selective dissolution foundation. It's indicated that oxidizing HNO3 lixiviant is suitable to realize the selective separation of Pb. Both Sn and Pb can be dissolved to ionic Sn2+ and Pb2+ in the HNO3 solution. However, Sn2+ rapidly oxidizes to Sn4+ and Sn4+ further hydrolyzes to insoluble SnO2, which will agglomerate on unreacted materials to limit internal metal leaching in conventional leaching process. Due to the vibratory stripping of oxide layer by physical effect of ultrasound, the conventional acid leaching time for Pb extraction can be halved with the ultrasound assistance. About 99.12 % Pb and only 0.1 % Sn are dissolved in ultrasound-assisted leaching under the following optimal parameters: 0.5 mol/L HNO3, leaching temperature of 80 °C, time of 30 min, liquid-to-solid ratio of 20 mL/g, and ultrasound intensity of 0.52 W/cm2. Leaching kinetics of Pb, phase transition, microstructure evolution, Pb-Sn galvanic corrosion and dissolution polarization curve were studied to determine the ultrasonic enhanced dissolution mechanism. Notably, Pb and Sn form a microcorrosion galvanic cell in which Sn acts as a cathode and is protected while the Pb undergoes intensifying corrosion as the anode giving rise to the higher Pb dissolution efficiency. Eventually, it's suggested that Pb can be rapidly extracted and separated from the waste Pb-Sn alloy during the ultrasound-assisted HNO3 leaching process via the ultrasound physical and chemical effects, especially the sonochemistry aspect of intensified spot corrosion and galvanic corrosion. The proposed ultrasonic electrochemical corrosion in this work were applicable to the extraction of valuable metals from various waste alloys through leaching method.

Relationship between ideal cardiovascular health score and perioperative acute kidney injury: A case-control study.

BACKGROUND: Maintaining ideal cardiovascular health scores (CHS) may indirectly contribute to reducing the risk of perioperative acute kidney injury (AKI), which has never been explored previously. In this study, we aimed to explore the relationship between CHS and AKI and provide new ideas for AKI prevention and treatment. METHODS: We examined the effects of CHS on the occurrence of AKI among 2783 participants from the Kailuan study, who received general anesthesia during noncardiac surgery from 2016 to 2020. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for AKI were calculated by using the logistic regression. RESULTS: Among 2783 participants 187 were diagnosed with perioperative AKI. We found an inverse relationship between the CHS scores and the risk of AKI. Participants with CHS score ≥ 10 had 57% decreased risk of AKI (OR = 0.43, 95% CI = 0.23, 0.79), compared with participants with CHS score ≤ 7, especially in men (OR = 0.39, 95% CI: 0.20, 0.76). In addition, participants who never smoked, exercised frequently, and had normal blood pressure had decreased risk of AKI, with corresponding ORs (95% CIs) of 0.66 (0.47, 0.91), 0.73 (0.60, 0.92), and 0.46 (0.28, 0.75), respectively. CONCLUSIONS: CHS was strongly associated with the risk of perioperative AKI, and higher CHS scores were associated with a lower risk of AKI. Further research is needed to explore the long-term effects of achieving and maintaining an ideal CHS on AKI risk.

Metabolomics-based investigation of the chemical composition changes in Mongolian medicinal plant Euphorbia pekinensis before and after processing with Chebulae Fructus.

Euphorbia pekinensis (EP), known for its diuretic properties, is clinically utilized for treating conditions such as edema and malignant tumors. However, in its raw form, Euphorbia pekinensis is toxic, and oral administration of this crude medicine can lead to gastrointestinal stimulation, resulting in abdominal pain and diarrhea. In Mongolian medicine's ethnomedicinal system, a distinctive processing method called "Chebulae Fructus processing" is employed. Chebulae Fructus is used to mitigate the toxicity of EP and alleviate its purgative effects. Nevertheless, the detoxification mechanism associated with this processing method remains unexplored. It is hypothesized that processing with Chebulae Fructus may alter the chemical composition of EP, and the residual components of Chebulae Fructus within processed Chinese medicine might exhibit pharmacological antagonistic effects, thereby achieving the purpose of processing and reducing toxicity. To investigate this further, a combination of UPLC-QTOF-MS-based metabolomics technology and multivariate statistical analysis was employed to analyze and compare the chemical composition of raw and processed EP. Differential variables contributing to group separation were identified based on specific criteria, including VIP (Variable Importance in Projection) values of ≥ 1 in PLS-DA models, p-values < 0.05, and fold changes (FC) > 1.2 or < 0.8. The resulting differentially expressed features were then identified through database matching, literature review, or manual annotation. In total, 47 components were identified from the PEP samples in both positive and negative ionization modes, primarily belonging to flavonoids, terpenoids, organic acids, glycosides, and fatty acids. Among the raw EP group and PEP S4 group, 10 differential compounds were identified. Notably, one toxic terpene and one phenylpropanoid from EP were downregulated, while two bioactive components from Chebulae Fructus were upregulated in the processed group. The possible conversion reactions of these two processing Q-markers were also elucidated. The characteristic processing with Chebulae Fructus resulted in a change in the composition of this Mongolian medicine EP. Furthermore, this study provides a scientific foundation for optimizing the processing technology of EP and offers insights into the processing of other ethnomedicines with toxic properties.

Compression Degree of Trigeminal Nerve and Type of Conflicting Vessels Determine Short- and Long-Term Complete Pain Relief in Adult Patients with Primary Trigeminal Neuralgia After Microvascular Decompression: A Three-Year Retrospective Study of 200 Adult Patients with Primary Trigeminal Neuralgia.

Objective: In this study, we aimed to explore the demographic and clinical factors that could determine short- and long-term complete pain relief (CPR) in adult patients with primary trigeminal neuralgia (PTN) after microvascular decompression (MVD) to guide clinical practice. Methods: This single-center retrospective study included adult patients with PTN who underwent MVD as their initial neurosurgical procedure in the Department of Neurosurgery at the Second Affiliated Hospital of Harbin Medical University from January 2017 to December 2019 and completed a 3-year post-surgery follow-up. Demographic and clinical information was obtained from medical records. Pain relief of adult patients with PTN at various time points after sufficient decompression of trigeminal nerve (TN) during MVD was determined and classified by the patient's subjective response and medications use. Pain relief of local patients was evaluated by outpatient follow-up at various time points, whereas that of local cases who could not return to outpatient or non-local cases was assessed through telephone or WeChat. Results: In univariate analysis, compression degree of TN and type of conflicting vessels constantly showed significant differences between the two groups at 3 months, 6 months, 1 year, 2 years, and 3 years after MVD. Compression degree of TN and type of conflicting vessels at various time points after MVD were always the related factors to CPR in logistic regression analysis, with the former having the greatest impact. The areas under the receiver operating characteristic (ROC) curve of CPR at various time points after MVD were 0.937, 0.874, 0.879, 0.864, and 0.869, respectively. Conclusion: In summary, compression degree of TN and type of conflicting vessels can determine short- and long-term CPR in adult patients with PTN after MVD.

Antioxidant-Engineered Milk-Derived Extracellular Vesicles for Accelerating Wound Healing via Regulation of the PI3K-AKT Signaling Pathway.

Inspired by the experience of relieving inflammation in infants with milk, antioxidant-engineered milk-derived extracellular vesicles (MEVs) are developed to evaluate their potential for accelerating wound healing. In this work, MEVs with polydopamines (PDA) are engineered using the co-extrusion method. Subsequently, the authors incorporated them into a Schiff-based crosslink hydrogel, forming a skin dosage form that could facilitate the wound healing process. The antioxidant properties of PDA assist in the anti-inflammatory function of engineered MEVs, while the gel provides better skin residency. The PDA@MEVs+GEL formulation exhibits excellent biocompatibility, pro-angiogenic capacity, and antioxidant ability in vitro. Furthermore, in vivo experiments demonstrate its efficacy in wound repair and inflammation inhibition. Mechanistically, PDA@MEVs+GEL simultaneously promotes the growth, migration, and anti-inflammation of 3T3 cells by activating PI3K-AKT pathway. Moreover, PDA@MEVs+GEL exhibits enhanced functionality in promoting wound healing in vivo, attributed to its ability to inhibit inflammation, stimulate angiogenesis, and promote collagen synthesis. In conclusion, this study delves into the mechanism of MEVs and underscores the improved efficacy of engineered extracellular vesicles. Additionally, the feasibility and prospect of engineered MEVs in treating skin wounds are verified, suggesting that antioxidant-engineered MEVs could be a promising therapeutic agent for wound healing applications.

Tanshinone IIA inhibited intermittent hypoxia induced neuronal injury through promoting autophagy via AMPK-mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic intermittent hypoxia (CIH) is the primary pathophysiological process of obstructive sleep apnea (OSA) and is closely linked to neurocognitive dysfunction. Tanshinone IIA (Tan IIA) is extracted from Salvia miltiorrhiza Bunge and used in Traditional Chinese Medicine (TCM) to improve cognitive impairment. Studies have shown that Tan IIA has anti-inflammatory, anti-oxidant, and anti-apoptotic properties and provides protection in intermittent hypoxia (IH) conditions. However, the specific mechanism is still unclear. AIM OF THE STUDY: To assess the protective effect and mechanism of Tan IIA treatment on neuronal injury in HT22 cells exposed to IH. MATERIALS AND METHODS: The study established an HT22 cell model exposed to IH (0.1% O2 3 min/21% O2 7 min for six cycles/h). Cell viability was determined using the Cell Counting Kit-8, and cell injury was determined using the LDH release assay. Mitochondrial damage and cell apoptosis were observed using the Mitochondrial Membrane Potential and Apoptosis Detection Kit. Oxidative stress was assessed using DCFH-DA staining and flow cytometry. The level of autophagy was assessed using the Cell Autophagy Staining Test Kit and transmission electron microscopy (TEM). Western blot was used to detect the expressions of the AMPK-mTOR pathway, LC3, P62, Beclin-1, Nrf2, HO-1, SOD2, NOX2, Bcl-2/Bax, and caspase-3. RESULTS: The study showed that Tan IIA significantly improved HT22 cell viability under IH conditions. Tan IIA treatment improved mitochondrial membrane potential, decreased cell apoptosis, inhibited oxidative stress, and increased autophagy levels in HT22 cells under IH conditions. Furthermore, Tan IIA increased AMPK phosphorylation and LC3II/I, Beclin-1, Nrf2, HO-1, SOD2, and Bcl-2/Bax expressions, while decreasing mTOR phosphorylation and NOX2 and cleaved caspase-3/caspase-3 expressions. CONCLUSION: The study suggested that Tan IIA significantly ameliorated neuronal injury in HT22 cells exposed to IH. The neuroprotective mechanism of Tan IIA may mainly be related to inhibiting oxidative stress and neuronal apoptosis by activating the AMPK/mTOR autophagy pathway under IH conditions.

Clinical Features and Risk Factors of Rapidly Progressive Systemic Sclerosis in a Single Center in China: Anti-RNA Polymerase III Antibodies as a Predictor.

OBJECTIVES: Systemic sclerosis (SSc) have been classified in two clinical subsets (diffuse and limited) based on the extend of skin thickening. In this study, we classified a novel subset of SSc defined rapidly progressive systemic sclerosis (RPSSc), which based on the rate of skin thickening progression and the progressive of interstitial lung disease (ILD). We aimed to evaluate RPSSc clinical characteristics and predictive factors in a Chinese single center. METHOD: Overall, 75 patients diagnosed with SSc, classified into RPSSc (n = 14) and non-rapidly progressive SSc (non-RPSSc, n = 61) were retrospectively included in the study. Clinical characteristics, disease severity and autoantibodies were collected. Logistic regression, least absolute shrinkage, and selection operator (LASSO) regression analysis was used to identify RPSSc predictors. Receiver operating characteristic (ROC) analysis and Delong test was conducted to evaluate and compare different indexes. RESULTS: RPSSc rate was 18.7%. ILD (64.3%), cardiac involvement (42.9%) were the most common organ system involvement of RPSSc, while Raynaud's phenomenon incidence significantly decreased. Disease duration (12 vs 72, months), sex (42.9% vs 11.5%, male %), SSc subset (85.7% vs 27.9%, diffuse cutaneous SSc (dsSSc) %), modified Rodnan total skin score (mRSS) (20.5 vs 6), Raynaud's phenomenon (64.3% vs 98.4%), cardiac involvement (42.9% vs 18%), higher incidence with malignancy (28.6% vs 1.6%) and positive anti-RNA polymerase III antibodies (ARA) (64.3% vs 1.6%) were statistically significant differences among the RPSSc groups and non-RPSSc groups (p < 0.05). Univariate analysis showed that positive ARA, male, dsSSc and malignancy were RPSSc risk factors, while long-disease duration, Raynaud's phenomenon was RPSSc protective factors. ARA was the strongest factor associated to RPSSc (OR 108, 95% CI 11.287-1033.327, p < 0.001). LASSO logistic regression model identified six factors: Disease duration, dsSSc, malignancy, cardiac involvement, positivity of ARA were RPSSc risk factors, Raynaud's phenomenon was RPSSc protective factors. CONCLUSIONS: RPSSc is an SSc clinical category which should be accounted for early detection of organ involvement and close follow-up of malignancy. ARA might be used as a predictor for RPSSc and organ involvement.

CaCO3 powder-mediated biomineralization of antigen nanosponges synergize with PD-1 blockade to potentiate anti-tumor immunity.

Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of "antigen multi-copy display" and "calcium carbonate (CaCO3) biomineralization" to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4+ T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.

The Development of Drug Delivery Systems for Efficient Intracranial Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) is the most devastating form of stroke, which accounts for 10-15% of cases and causes high morbidity and mortality. With the continuous exploration of the pathological mechanism of ICH, extensive research focusing on ICH therapy has been conducted. However, the traditional treatment methods, such as surgery for removing the hematoma and pharmacotherapy for improving the clearance of the hematoma and neuroprotection, are greatly limited due to their poor practicality and treatment efficiency. The rapid development of drug delivery systems offers an important prospect for treating ICH as they exhibit great versatility, which can improve the pharmacokinetic behavior of drugs in vivo, increase the drug accumulation in specific cell types or tissues, and enhance the therapeutic effect with diminished toxic effect. In this review, the main molecular pathological mechanisms of ICH are comprehensively described and the limitation of traditional pharmacotherapy are also discussed. Then the development based on drug delivery systems for treating ICH is highlighted. Finally, based on these discussions the challenges of drug delivery systems with a view to providing a new feasible path for the treatment of ICH are summarized.

Labeling Assembly of Hydrophilic Methionine into Nanoparticle for Mild-Heat Mediated Immunometabolic Therapy.

Methionine metabolism has a significant impact on T cells' survival and activation even in comparison to arginine, a well-documented amino acid in metabolic therapy. However, hydrophilic methionine is hardly delivered into TME due to difficult loading and rapid diffusion. Herein, the labeling assembly of methionine into nanoparticle is developed to overcome high hydrophilicity for mild-heat mediated immunometabolic therapy. The strategy is to first label methionine with protocatechualdehyde (as the tag) via reversible Schiff-base bond, and then drive nanoassembly of methionine (MPC@Fe) mediated by iron ions. In this fashion, a loading efficiency of 40% and assembly induced photothermal characteristics can be achieved. MPC@Fe can accumulate persistently in tumor up to 36 h due to tumor-selective aggregation in acidic TME. A mild heat of 43 °C on tumor by light irradiation stimulated the immunogenic cell death and effectively generated CD8+ T cells. Notably, MPC@Fe assisted by mild heat promoted 4.2-fold of tumor-infiltrating INF-γ+ CD8+ T cells, leading to an inhibition ratio of 27.3-fold versus the free methionine. Such labeling assembly provides a promising methionine delivery platform to realize mild heat mediated immunometabolic therapy, and is potentially extensible to other amino acids.

Dexmedetomidine Attenuates Spinal Cord Ischemia-reperfusion Injury in Rabbits by Decreasing Oxidation and Apoptosis.

BACKGROUND: In brain ischemia, dexmedetomidine (DEX) prevents glutamate and norepinephrine changes, increases nerve conduction, and prevents apoptosis, but the mechanisms are poorly understood. OBJECTIVE: This study aimed at examining the protective effect and function of DEX on spinal cord ischemia-reperfusion injury (SCIRI) and whether the effect is mediated by oxidative stress and apoptosis (with the involvement of Bcl-2, Bax, mitochondria, and Caspase-3). METHODS: Rabbits were randomly divided into the sham group, infusion/reperfusion (I/R) group, and DEX+I/R group. SCIRI was induced by occluding the aorta just caudal to the left renal artery for 40 min, followed by reperfusion. DEX was continuously administered for 60 min before clamping. The animals were evaluated for neuronal functions. Spinal cord tissues were examined for SOD activity and MDA content. Bcl-2, Bax, and Caspase-3 expressions were detected by western blotting. TUNEL staining was used for apoptosis. RESULTS: With the extension of reperfusion time, the hind limbs' neurological function in the DEX+I/R group gradually improved, but it became worse in the I/R group (all P<0.05 vs. the other time points within the same groups). Compared with I/R, DEX decreased MDA and increased SOD (P<0.01), upregulated Bcl-2 protein expression (P<0.05), downregulated Bax expression (P<0.05), decreased caspase-3 expression (P<0.05), prevented histological changes in neurons, and decreased the apoptotic index of the TUNEL labeling (P<0.05). CONCLUSION: DEX could attenuate SCIRI in rabbits by improving the oxidative stress status, regulating the expression of apoptosis-related proteins, and decreasing neuronal apoptosis.

Overexpression of the FERONIA receptor kinase MdMRLK2 confers apple drought tolerance by regulating energy metabolism and free amino acids production.

Drought is a major abiotic stress limiting the growth and production of apple trees worldwide. The receptor-like kinase FERONIA is involved in plant growth, development and stress responses; however, the function of FERONIA in apple under drought stress remains unclear. Here, the FERONIA receptor kinase gene MdMRLK2 from apple (Malus domestica) was shown to encode a plasma membrane-localized transmembrane protein and was significantly induced by abscisic acid and drought treatments. 35S::MdMRLK2 apple plants showed less photosystem damage and higher photosynthetic rates compared with wild-type (WT) plants, after withholding water for 7 days. 35S::MdMRLK2 apple plants also had enhanced energy levels, activated caspase activity and more free amino acids, than the WT, under drought conditions. By performing yeast two-hybrid screening, glyceraldehyde-3-phosphate dehydrogenase and MdCYS4, a member of cystatin, were identified as MdMRLK2 interaction partners. Moreover, under drought conditions, the 35S::MdMRLK2 apple plants were characterized by higher abscisic acid (ABA) content. Overall, these findings demonstrated that MdMRLK2 regulates apple drought tolerance, probably via regulating levels of energetic matters, free amino acids and ABA.

Up-regulation of Dsg2 confered stem cells with malignancy through wnt/ß-catenin signaling pathway.

In the previous study, we originally developed cancer stem cells (CSCs) models from mouse induced pluripotent stem cells (miPSCs) by culturing miPSCs in the conditioned medium of cancer cell lines, which mimiced as carcinoma microenvironment. However, the molecular mechanism of conversion in detail remains to be uncovered. Microarray analysis of the CSCs models in this study revealed Dsg2, one of the members of the desmosomal cadherin family, was up-regulated when compared with the original miPSCs. Moreover, the expression of key factors in Wnt/ß-catenin signaling pathway were also found up-regulated in one of the CSCs models, named miPS-LLCcm. An autocrine loop was implied between Dsg2 and Wnt/ß-catenin signaling pathway when miPSCs were treated with Wnt/ß-catenin signaling pathway activators, Wnt3a and CHIR99021, and when the CSCs model were treated with inhibitors, IWR-1 and IWP-2. Furthermore, the ability of proliferation and self-renewal in the CSCs model was markedly decreased in vitro and in vivo when Dsg2 gene was knocked down by shRNA. Our results showed that the Wnt/ß-catenin signaling pathway is activated by the up-regulation of Dsg2 expresssion during the conversion of miPSCs into CSCs implying a potential mechanism of the tranformation of stem cells into malignant phenotype.

Prognostic value of T cell immunoglobulin and mucin-domain containing-3 expression in upper gastrointestinal tract tumors: A meta-analysis.

BACKGROUND: There is a lack of robust prognostic markers for upper gastrointestinal (GI) tract cancers, including esophageal, gastric, and esophagogastric junction cancers. T cell immunoglobulin and mucin-domain containing-3 (TIM3) plays a key immunomodulatory role and is linked to the prognosis of various cancers. However, the significance of TIM3 in upper GI tract tumors is still uncertain. AIM: To investigate the prognostic value of TIM3 expression in upper GI tract tumors. METHODS: A literature search was conducted on the PubMed, Embase, and Web of Science databases for relevant studies published until June 2023. After screening and quality assessment, studies that met the criteria were included in the meta-analysis. Statistical methods were used for the pooled analysis to assess the association of TIM3 expression in upper GI tract tumors with the prognosis and clinicopathological parameters. The results were reported with the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Nine studies involving 2556 patients with upper GI tract cancer were included. High TIM3 expression was associated with a worse prognosis in upper GI tract cancer (HR: 1.17, 95%CI: 1.01-1.36). Positive expression of TIM3 in gastric cancer was correlated with the T and N stage, but the difference was not statistically significant. However, TIM3 overexpression was significantly correlated with the TNM stage (odds ratio: 1.21, 95%CI: 0.63-2.33; P < 0.05). TIM3 expression showed no association with the other clinicopathological parameters. CONCLUSION: High expression of TIM3 in the upper GI tract cancer is associated with a worse prognosis and advanced T or N stages, indicating its potential value as a prognostic biomarker. These findings may provide a basis for the personalized treatment of upper GI tract cancers.

Adipose improves muscular atrophy caused by Sirtuin1 deficiency by promoting mitochondria synthesis.

Muscular dysplasia is a common muscle disease, but its pathological mechanism is still unclear. Adipose is originally identified as a highly conservative and widely expressed anti-obesity gene, and our previous study has reported that Adipose is also a positive regulator of myogenesis. Considering the vital role of during muscle development, this study was to demonstrate a potential relationship between Sirtuin1 and Adipose and clarified the mechanism by which Adipose regulated muscle development. Our results showed that the muscle fiber cross-sectional area and myosin heavy chain protein level were significantly reduced in Sirtuin1+/- mice. Moreover, the longitudinal section of muscle fibers was obviously irregular. Sirtuin1 knockdown significantly reduced the expression levels of Adipose and its upstream transcriptional regulator Kruppel like factor 15 and notably inhibited the AMP-activated protein kinase α-peroxisome proliferator-activated receptor gamma coactivator 1α signaling pathway in skeletal muscle. However, Adipose over-expression activated this signaling pathway and promoted mitochondrial biosynthesis in C2C12 myoblasts. Adipose over-expression also enhanced glucose absorption of C2C12 cells, suggesting the increased needs for cells for metabolic substrates. In C2C12 cells with hydrogen peroxide treatment, Adipose over-expression repressed hydrogen peroxide-elicited apoptosis and mitochondrial loss, while Sirtuin1-specific inhibitor dramatically weakened these roles of Adipose. Taken together, our findings reveal that Adipose rescues the adverse effects of Sirtuin1 deficiency or hydrogen peroxide on muscle development by activating the AMP-activated protein kinase α- peroxisome proliferator-activated receptor gamma coactivator 1α pathway to promote mitochondria synthesis, which provides theoretical basis for developing new therapeutic targets against some muscle diseases.

Dietary Selenium Alleviated Mouse Liver Oxidative Stress and NAFLD Induced by Obesity by Regulating the KEAP1/NRF2 Pathway.

Nonalcoholic fatty liver disease (NAFLD) occurs when excess fat is stored in the liver and it is strongly linked with metabolic syndrome and oxidative stress. Selenium (Se) is an essential micronutrient in animals, which has a variety of biological functions, including antioxidant and anti-inflammatory. However, the exact effect of dietary selenium on NAFLD and the underlying molecular mechanism are not yet clear. Herein, we fed a high-fat diet (HFD) to C57BL/6 mice to construct an in vivo NAFLD model, treated AML-12 cells with palmitic acid (PA) to construct an in vitro NAFLD model, and AML-12 cells were stimulated with H2O2 to induce hepatocyte oxidative stress and then treated with adequate selenium. We observed that adequate selenium significantly improved the hepatic injury and insulin resistance in HFD mice, and decreased the fat accumulation and the expression of lipogenic genes in PA-induced AML-12 cells. Meanwhile, selenium significantly inhibited the production of reactive oxygen species (ROS), inhibited apoptosis, and restored mitochondrial number and membrane potential in PA- induced AML-12 cells. In addition, selenium can promote selenoproteinP1 (SEPP1) synthesis to regulate the Kelch-like ECH-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) pathway, so as to defend against hepatocyte oxidative stress. These findings suggest that dietary selenium supplementation can effectively resist hepatic injury and insulin resistance during NAFLD development, and regulate the KEAP1/NRF2 pathway to resist oxidative stress by promoting SEPP1 synthesis.