RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation.

Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.

Exploration of genetic characterization in hyperprogressive disease after immunotherapy retreatment in a patient with LCNEC: A case report.

Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for large cell neuroendocrine carcinoma (LCNEC). However, various studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving ICI, which might be associated with gene alterations. Here, this is the first report on an unknown primary LCNEC patient who had achieved a long-term response from ICI treatment (atezolizumab), but developed HPD after tumor progression due to receiving another ICI agent (serplulimab). The mutation region of FAT4, SMARCA4, CYLD, CTNNB1, and KIT was altered prior to serplulimab treatment compared to before atezolizumab treatment. This case suggested a potential association between these mutated genes and HPD. Patients with the aforementioned genes should caution when selecting ICI treatment. These findings required further confirmation in a larger study cohort.

Clinical Experience of External Application of Clearing Heat and Removing Dampness in Relieving Grade 2 to 3 Rash Caused by Programed Cell Death Protein 1 (PD-1)/Programed Cell Death Ligand 1 (PD-L1) Inhibitors: A Single-Center Retrospective Study.

OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.

SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer.

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.

Analysis of clinical features and identification of risk factors in patients with non-alcoholic fatty liver disease based on FibroTouch.

Our aim was to explore the correlation between ultrasound attenuation parameter (UAP) and liver stiffness measurement (LSM) based on FibroTouch (China) and clinical features in patients with non-alcoholic fatty liver disease (NAFLD), so as to provide a certain basis for the clinical application of FibroTouch in NAFLD. Hepatic steatosis and fibrosis in patients with NAFLD were graded according to FibroTouch, and the relationship between steatosis and fibrosis levels and clinical characteristics was retrospectively analyzed. Hepatic steatosis was positively related with weight, BMI, waist, hyperlipidemia, hyperuricemia, FBG, UA, TG, ALT, AST, GGT, LSM and hepatic fibrosis grading, and was negatively related with gender (male), age and AST/ALT ratio. Hepatic fibrosis was positively related with age, BMI, waist, hypertension, FBG, ALT, AST, GGT, NFS, APRI, FIB-4, UAP and hepatic steatosis grading, and was negatively related with blood platelet (PLT) counts. Moreover, BMI, waist, TG, ALT and LSM were independent risk factors of hepatic steatosis, while decreased PLT counts, AST and UAP were independent risk factors of hepatic fibrosis. Body mass parameters, metabolic risk factors and liver function indicators increase the risk of hepatic steatosis and fibrosis in patients with NAFLD, and UAP and LSM can interact with each other.

Improved Stability and Catalytic Efficiency of ω-Transaminase in Aqueous Mixture of Deep Eutectic Solvents.

The efficient biosynthesis of chiral amines at an industrial scale to meet the high demand from industries that require chiral amines as precursors is challenging due to the poor stability and low catalytic efficiency of ω-transaminases (ω-TAs). Herein, this study adopted a green and efficient solvent engineering method to explore the effects of various aqueous solutions of deep eutectic solvents (DESs) as cosolvents on the catalytic efficiency and stability of ω-TA. Binary- and ternary-based DESs were used as cosolvents in enhancing the catalytic activity and stability of a ω-TA variant from Aspergillus terreus (E133A). The enzyme exhibited a higher catalytic activity in a ternary-based DES that was 2.4-fold higher than in conventional buffer. Moreover, the thermal stability was enhanced by a magnitude of 2.7, with an improvement in storage stability. Molecular docking studies illustrated that the most potent DES established strong hydrogen bond interactions with the enzyme's amino acid, which enhanced the catalytic efficiency and improved the stability of the ω-TA. Molecular docking is essential in designing DESs for a specific enzyme.

Preparation and Characterization of an Invasive Plant-Derived Biochar-Supported Nano-Sized Lanthanum Composite and Its Application in Phosphate Capture from Aqueous Media.

Invasive plants pose a great threat to natural ecosystems owing to their rapid propagation and spreading ability in nature. Herein, a typical invasive plant, Solidago canadensis, was chosen as a novel feedstock for the preparation of nano-sized lanthanum-loaded S. canadensis-derived biochar (SCBC-La), and its adsorption performance for phosphate removal was evaluated by batch adsorption experiment. The composite was characterized by multiple techniques. Effects of parameters, such as the initial concentration of phosphate, time, pH, coexisting ions, and ionic strength, were studied on the phosphate removal. Adsorption kinetics and isotherms showed that SCBC-La shows a faster adsorption rate at a low concentration and SCBC-La exhibits good La utilization efficiency than some of the reported La-modified adsorbents. Phosphate can be effectively removed over a relatively wide pH of 3-9 because of the high pH pzc of SCBC-La. Furthermore, the SCBC-La shows a strong anti-interference capability in terms of pH value, coexisting ions, and ionic strength, exhibiting a highly selective capacity for phosphate removal. Additionally, Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) measurements reveal that hydroxyl groups on the surface of SCBC-La were replaced by phosphate and manifest the reversible transformation between La(OH)3 and LaPO4. Considering its high adsorption capacity and excellent selectivity, SCBC-La is a promising material for preventing eutrophication. This work gives a new method of pollution control with waste treatment since the invasive plant (S. canadensis) is converted into biochar-based nanocomposite for effective removal of phosphate to mitigate eutrophication.

Titanium dioxide nanoparticles functionalized chitosan toward bio-based antibacterial adsorbent for enhanced phosphate capture.

Developing an eco-friendly, sustainable and antibacterial adsorbent is significant for actual water treatment. Herein, a bio-based antibacterial adsorbent based on titanium dioxide (TiO2) nanoparticles functionalized chitosan (CS) was prepared through an in-situ hydrolysis strategy using titanium oxysulfate as the source of TiO2. The as-obtained CS/TiO2 nanocomposite was characterized by a variety of analytical techniques. According to the Langmuir mode, the adsorption capacity of CS/TiO2 reached 23.64 mg P g-1, almost 8 times higher than that of CS. In addition, the normalized adsorption capacity (adsorption value per Ti) of CS/TiO2 was calculated to be 102.68 mg P g-1 Ti-1, much higher than pure TiO2 (60.11 mg P g-1 Ti-1). Moreover, CS/TiO2 exhibited a highly selective capacity for phosphate removal in the presence of competing anions, and showed high stability in a wide pH range of 3.0-8.0. When the phosphate concentration was 2.0 mg P L-1, the removal efficiency of phosphate reached 99.5 % and the residual concentration was only 10 µg P L-1, which meets the USEPA standards for eutrophication prevention and control. In addition, after treatment by CS/TiO2, the phosphate concentration of two sewage water samples decreased from 1.50 and 1.0 mg P L-1 to <0.10 mg P L-1, meeting the standard of level II water based on the Environmental Quality Standard of China (GB3838-2002). Ligand exchange and electrostatic interactions are mainly responsible for phosphate adsorption by CS/TiO2. Furthermore, the CS/TiO2 nanocomposites exhibited excellent antibacterial activity, which could avoid biofouling contamination caused by microorganisms. Benefiting from the above advantages, the as-designed CS/TiO2 nanocomposite has great potential as a bio-based antibacterial adsorbent for phosphate capture or removal from wastewater.

A Recyclable Magnetic Aminated Lignin Supported Zr-La Dual-Metal Hydroxide for Rapid Separation and Highly Efficient Sequestration of Phosphate.

The application of lignin-based adsorbents in the efficient removal of phosphate from wastewater has attracted much attention and been intensively studied in recent years. However, most currently reported lignin-based adsorbents are difficult to recover and recycle. Herein, we have developed a recyclable, nanostructured bio-adsorbent, poly(ethyleneimine) (PEI)-modified lignin (LG) integrated with Fe3O4 and Zr-La dual-metal hydroxide (LG-NH2@Fe3O4@Zr-La), by the Mannich reaction followed by the chemical coprecipitation method. Multilayer adsorption existed on the surface of LG-NH2@Fe3O4@Zr-La based on the isotherm fitting curve, and its adsorption capacity reached 57.8 mg P g-1, exhibiting a higher phosphate uptake than most reported metallic oxide-based composites. The adsorption process was dominated by inner-sphere complexation of ligand-exchange and electrostatic interactions. Moreover, LG-NH2@Fe3O4@Zr-La exhibited excellent selectivity against coexisting anions, and the adsorption was more efficient under acidic conditions. When the phosphate concentration was 2.0 mg P L-1, the removal efficiency of phosphate reached 99.5% and the residual concentration was only 10 µg P L-1, which meets the United States Environmental Protection Agency (USEPA) standard for eutrophication prevention. In addition, the LG-NH2@Fe3O4@Zr-La displayed excellent reusability, maintaining 91.8% of removal efficiency after five cycles. Importantly, owing to the magnetic properties of the loaded Fe3O4, the resulting composite could be separated within 30 s under an external magnetic field. Thus, the separable and recyclable biobased magnetic adsorbent developed in this work exhibited promising application in phosphate capture from real sewage. This research study provides a new perspective for lignin valorization in lignocellulose biorefineries and establishes an approach for developing an economical and efficient bio-adsorbent for phosphate removal from wastewater.

Rhein Exhibits Anti-Inflammatory Effects in Chronic Atrophic Gastritis via Nrf2 and MAPK Signaling.

BACKGROUND: Chronic atrophic gastritis is a premalignant lesion with a high risk of developing into gastric cancer. Rhein is a key active ingredient of several traditional Chinese medicines with multiple pharmacological effects. Nevertheless, the role of rhein in chronic atrophic gastritis is unclear. METHODS: Helicobacter pylori infection was used to establish chronic atrophic gastritis in a mouse model. Murine gastric mucosa treated with saline or rhein was used in experiments. Hematoxylin and eosin staining and Alcian blue-periodic acid-Schiff staining were utilized for histopathological observation of murine gastric mucosa. The levels of proinflammatory factors were detected by enzyme-linked immunosorbent assay, and oxidative stress-associated markers were detected by commercially available assay kits. Western blotting was used for measuring the levels of nuclear factor, erythroid 2-like bZIP transcription factor 2, and mitogen-activated protein kinase signaling-related proteins. RESULTS: Rhein mitigated the gastric mucosal injury and suppressed inflammation and oxidative stress in H. pylori-infected chronic atrophic gastritis mouse models. Rhein inactivated mitogen-activated protein kinase and activated erythroid 2-like bZIP transcription factor 2 signaling in gastric mucosa of mice with chronic atrophic gastritis. CONCLUSION: Rhein exhibits anti-inflammatory and antioxidant effects in chronic atrophic gastritis via erythroid 2-like bZIP transcription factor 2 and mitogen-activated protein kinase signaling.

A magnetically recyclable lignin-based bio-adsorbent for efficient removal of Congo red from aqueous solution.

It has been always attractive to design a sustainable bio-derived adsorbent based on industrial waste lignin for removing organic dyes from water. However, existing adsorbent strategies often lead to the difficulties in adsorbent separation and recycling. Herein, we report a novel magnetically recyclable bio-adsorbent of Mg(OH)2/Fe3O4/PEI functionalized enzymatic lignin (EL) composite (EL-PEI@Fe3O4-Mg) for removing Congo red (CR) by Mannish reaction and hydrolysis-precipitation. The Mg(OH)2 and PEI functionalized EL on the surface act as active sites for the removal of CR, while the Fe3O4 allows for the easy separation under the help of a magnet. As-obtained EL-PEI@Fe3O4-Mg forms flower-like spheres and has a relatively lager surface area of 24.8 m2 g-1 which is 6 times that of EL. The EL-PEI@Fe3O4-Mg exhibits a relatively high CR adsorption capacity of 74.7 mg g-1 which is 15 times that of EL when initial concentration is around 100 mg L-1. And it can be easily separated from water by applying an external magnetic field. Moreover, EL-PEI@Fe3O4-Mg shows an excellent anti-interference capability according to the results of pH values and salt ions influences. Importantly, EL-PEI@Fe3O4-Mg possesses a good reusability and a removal efficiency of 92 % for CR remains after five consecutive cycles. It is illustrated that electrostatic attraction, π-π interaction and hydrogen binding are primary mechanisms for the removal of CR onto EL-PEI@Fe3O4-Mg. This work provides a novel sustainable strategy for the development of highly efficient, easy separable, recyclability bio-derived adsorbents for removing organic dyes, boosting the efficient utilization of industrial waste lignin.

Fuzi-Lizhong Decoction Alleviates Nonalcoholic Fatty Liver Disease by Blocking TLR4/MyD88/TRAF6 Signaling.

Background: Fuzi-Lizhong decoction (FLD) derives from the ancient Chinese Pharmacopoeia and has been clinically used for years. The present study aimed to investigate the activities and underlying mechanisms of FLD against nonalcoholic fatty liver disease (NAFLD). Methods: In vivo studies were conducted by inducing NAFLD in rats with a high-fat diet, and in vitro studies were performed on HL-7702 cells treated with oleic and linoleic acids. Total cholesterol (TC), triglyceride (TG), and blood glucose (Glu) levels were detected using an automatic biochemical analyzer. The expression of IL-2, IL-6, and TNF-α in sera and cell culture supernatants was measured by ELISA. The mRNA and protein levels of TLR4, MyD88, and TRAF6 were measured in liver tissue and HL-7702 cells using reverse transcription-quantitative polymerase chain reaction and western blot. Results: FLD significantly reduced the TC, TG, Glu, FFA, IL-2, IL-6, and TNF-α levels in NAFLD rats and HL-7702 cells. Analysis of liver lipid content by Oil Red O staining revealed a significant increase in hepatic lipid accumulation in rats with NAFLD, but this lipid accumulation was reversed by FLD treatment. In addition, the mRNA expression levels of TLR4, MyD88, TRAF6, and NF-κB p65 as well as the protein levels of TLR4, MyD88, TRAF6, and NF-κB p65 were decreased after FLD treatment. FLD significantly reduced inflammation and improved collagen accumulation in vivo and in vitro by inhibiting the activation of the TLR4/MyD88/TRAF6 signaling pathway. Conclusions: FLD exerted potent protective effects against NAFLD via TLR4/MyD88/TRAF6 signaling. These findings provide novel insights into the mechanisms whereby this compound acts as an anti-inflammatory agent and highlight the potential application of FLD in the treatment of acute liver failure (ALF).

Regulation of carbon flux and NADH/NAD+ supply to enhance 2,3-butanediol production in Enterobacter aerogenes.

As a valuable platform chemical, 2,3-Butanediol (2,3-BDO) has a variety of industrial applications, and its microbial production is particularly attractive as an alternative to petroleum-based production. In this study, the regulation of intracellular carbon flux and NADH/NAD+ was used to increase the 2,3-BDO production of Enterobacter aerogenes. The genes encoding lactate dehydrogenase (ldh) and pyruvate formate lyase (pfl) were disrupted using the λ-Red recombination method and CRISPR-Cas9 to reduce the production of several byproducts and the consumption of NADH. Knockout of ldh or pfl increased intracellular NADH/NAD+ by 111 % and 113 %, respectively. Moreover, two important genes in the 2,3-BDO biosynthesis pathway, acetolactate synthase (budB) and acetoin reductase (budC), were overexpressed in E. aerogenes to further amply the metabolic flux toward 2,3-BDO production. And the overexpression of budB or budC increased intracellular NADH/NAD+ by 46 % and 57 %, respectively. In shake-flask cultivation with sucrose as carbon source, the 2,3-BDO titer of the IAM1183-LPBC was 3.55 times that of the wild type. In the 5-L fermenter, the maximal 2,3-BDO production produced by the IAM1183-LPBC was 2.88 times that of the original strain. This work offers new ideas for promoting the biosynthesis of 2,3-BDO for industrial applications.

A lignin-based epoxy/TiO2 hybrid nanoparticle for multifunctional bio-based epoxy with improved mechanical, UV absorption and antibacterial properties.

Lignin, as a natural polymer material, has the advantages of green safety, renewable, and pollution-free. It has a wide application prospect in the field of thermosetting. However, it has been attractive but a huge challenge to design high performance and high added-value lignin-based epoxy resin. Herein, lignin-based epoxy (LEP) was synthesized from moso bamboo-derived lignin, and then lignin-based epoxy/titanium dioxide (LEP/TiO2) hybrid nanoparticle was synthesized via liquid deposition method for modifying lignin-based epoxy resin to prepare multifunctional bio-based epoxy. The results show that the LEP/TiO2 hybrid nanoparticle exhibits a stable topological surface shape and good dispersion and uniformity. By adding 10 wt% LEP/TiO2 hybrid nanoparticles, the multifunctional bio-based epoxy exhibits good mechanical strength and toughness, and the tensile strength and fracture toughness reach 36 MPa and 1.26 MPa·m1/2, respectively. In addition, the thermal stability, UV absorption and antibacterial properties of the multifunctional bio-based epoxy are further improved. This study provides a facile and efficient method for the preparation of high-performance multifunctional bio-based epoxy composite and a novel solution for the utilization of lignin.

ATX/LPA axis regulates FAK activation, cell proliferation, apoptosis, and motility in human pancreatic cancer cells.

Previous studies implicated ATX/LPA axis as a potential driver of tumorigenesis and progression in pancreatic cancer. This study aimed to determine the existence of the autocrine pathway of ATX/LPA action in pancreatic cancer cells, and to elucidate its influence on focal adhesion kinase (FAK) activation, cellular proliferation, apoptosis, and migration. Firstly, we identified the lysophosphatidic acid (LPA) concentrations in cultured cell supernatant by ELISA and observed the effect of the autotaxin (ATX)-specific inhibitor S32826 on LPA concentrations. We found the existence of a certain concentration of LPA in cellular supernatant, which was significantly decreased by S32826 in a dose- and time-dependent manner. A maximum response was observed at 50 µM for 72 h. Secondly, the effect of S32826 on the protein expression and intracellular sublocalization of total FAK and phosphorylated FAK (pY397 FAK) was determined by Western blot and immunofluorescence staining. It was found that the expression of total FAK and pY397 FAK and their distribution along the cell membrane where adhesion structures are located were significantly decreased by S32826. Finally, we observed the influence of S32826 on cell proliferation, apoptosis, and migration by CCK-8 assay, flow cytometric analysis, and transwell migration assay. Results showed that cell viability and migration were significantly declined, and the proportions of apoptotic cells were significantly increased by S32826. This study verified the existence of autocrine regulation of LPA secretion via producing ATX by pancreatic cancer cells in vitro and the important role of LPA/ATX axis on FAK activation, cell proliferation, apoptosis, and motility.

Xiaoyao Powder in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide with alarming prevalence. Due to its complex pathogeneses and considerable individual heterogeneity in disease, there is no specific medication to NAFLD safely and effectively. Therefore, there is a great need to explore complementary and alternative therapies. Xiaoyao Powder (XYP), a classic Chinese formula, has been tremendously applied to gastrointestinal diseases, especially non-alcoholic fatty liver disease. However, the efficacy and safety of XYP have not been fully assessed. AIM OF THE STUDY: To assess the effectiveness and safety of XYP for NAFLD. MATERIALS AND METHODS: The assigned registration number on the PROSPERO platform of this meta-analysis is CRD42020192154, and we strictly followed the protocol. We searched eight primary databases from their inception to June 2020. Two authors independently identified random controlled trials (RCTs) of XYP for NAFLD and evaluated the quality of the retrieved articles by Cochrane accessing risk bias tool. At least one of the following indices was thoroughly documented for outcome measurement: total effective rate, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptidase (GGT), body mass index (BMI), and adiponectin. We calculated risk ratio (RR) and mean difference (MD) for dichotomous data and continuous variables with a 95% confidence interval (CI). R 4.0.5 software was employed for data synthesis. RESULTS: Consequently, we identified 12 studies with 1012 participants. XYP, whether individually or combined with essential treatment, ameliorated NAFLD regardless of the course of the disease or curative duration. This benefit was mainly driven by regulating levels of serum markers, involving TC, TG, ALT, AST, GGT, and adiponectin. Three studies where statins were concerned about drug safety reported several adverse events with clinical symptoms, varying from flatulence, constipation, and diarrhea to rash, whereas others did not. CONCLUSION: Our findings provided evidence that XYP is a therapeutic option to treat NAFLD effectively and safely. Notwithstanding, a precise and comprehensive conclusion calls for RCTs on a larger scale with more rigorous designs considering the inferior methodological quality and limited retrieved articles.

Network Pharmacology-Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells.

Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell-related genes were identified. The drug-herb-active compound-target gene-disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.

Metabolic Engineering of Enterobacter aerogenes for Improved 2,3-Butanediol Production by Manipulating NADH Levels and Overexpressing the Small RNA RyhB.

Biotechnological production of 2,3-butanediol (2,3-BD), a versatile platform bio-chemical and a potential biofuel, is limited due to by-product toxicity. In this study, we aimed to redirect the metabolic flux toward 2,3-BD in Enterobacter aerogenes (E. aerogenes) by increasing the intracellular NADH pool. Increasing the NADH/NAD+ ratio by knocking out the NADH dehydrogenase genes (nuoC/nuoD) enhanced 2,3-BD production by up to 67% compared with wild-type E. aerogenes. When lactate dehydrogenase (ldh) was knocked out, the yield of 2,3-BD was increased by 71.2% compared to the wild type. Metabolic flux analysis revealed that upregulated expression of the sRNA RyhB led to a noteworthy shift in metabolism. The 2,3-BD titer of the best mutant Ea-2 was almost seven times higher than that of the parent strain in a 5-L fermenter. In this study, an effective metabolic engineering strategy for improved 2,3-BD production was implemented by increasing the NADH/NAD+ ratio and blocking competing pathways.

m6 A transferase KIAA1429-stabilized LINC00958 accelerates gastric cancer aerobic glycolysis through targeting GLUT1.

Emerging evidence has demonstrated that N6 -methyladenosine (m6 A) and long noncoding RNAs (lncRNAs) are both crucial regulators in gastric cancer (GC) tumorigenesis. However, the interaction of m6 A and lncRNAs in GC progression are still unclear. Here, our team discovered that lncRNA LINC00958 expression up-regulated in GC tissue and cells. Clinically, high-expression of LINC00958 was clinically correlated to lower survival of GC patients. Functionally, in vitro assays demonstrated that LINC00958 promoted the GC cells' aerobic glycolysis. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) found that there were m6 A-modificated sites in LINC00958, and moreover m6 A methyltransferase KIAA1429 catalyzed the m6 A modification on LINC00958 loci. Moreover, LINC00958 interacted with GLUT1 mRNA via the m6 A-dependent manner to enhance GLUT1 mRNA transcript stability, thereby positively regulating the aerobic glycolysis of GC. In conclusion, our findings reveal the function and mechanism of KIAA1429-induced LINC00958 in GC, delineating novel understanding of m6 A-lncRNA in cancer biology.

Metabolic regulation and optimization of oxygen supply enhance the 2,3-butanediol yield of the novel Klebsiella sp. isolate FSoil 024.

BACKGROUND: Biogenic 2,3-butanediol (2,3-BDO) is a high-value-added compound that can be used as a liquid fuel and a platform chemical. Bioproduction of 2,3-BDO is an environmentally friendly choice. METHOD AND RESULTS: Three recombinant derivatives of the novel Klebsiella sp. isolate FSoil 024 (WT) were constructed via different strategies including deletion of lactate dehydrogenase by λ-Red homologous recombination technology, overexpression of the small-noncoding RNA RyhB and a combination of both. The 2,3-BDO productivity of the mutants increased by 61.3%-79%, and WT-Δldh/ryhB displayed the highest 2,3-BDO yield of 42.36 mM after 24 h of shake-flask fermentation. Glucose was shown as the best carbon source for 2,3-BDO production by WT-Δldh/ryhB. In addition, higher oxygenation was favorable for ideal product synthesis. The maximal 2,3-BDO yield of WT and WT-Δldh/ryhB were increased by 23.3% and 52.5% respectively compared to the control group in the presence of 70% oxygen (V:V' = O2 :(O2 + N2 )). CONCLUSION AND IMPLICATIONS: According to the present study, deletion of lactate dehydrogenase, RyhB overexpression, and manipulation of oxygen supply showed great impacts on cell growth, 2,3-BDO productivity and cellular metabolism of the novel isolated strain Klebsiella sp. FSoil 024. This work would also provide insights for promoting 2,3-BDO biosynthesis for industrial applications.