Biogenic sulfur recovery from sulfate-laden antibiotic production wastewater using a single-chamber up-flow bioelectrochemical reactor.

The high-concentration sulfate (SO42-) in the antibiotic production wastewater hinders the anerobic methanogenic process and also proposes possible environmental risk. In this study, a novel single-chamber up-flow anaerobic bioelectrochemical reactor (UBER) was designed to realize simultaneous SO42- removal and elemental sulfur (S0) recovery. With the carbon felt, the cathode was installed underneath and the anode above to meet the different biological niches for sulfate reducing bacteria (SRB) and sulfur oxidizing bacteria (SOB). The bio-anode UBER (B-UBER) demonstrated a much higher average SO42- removal rate (SRR) of 113.2 ± 5.7 mg SO42--S L-1 d-1 coupled with a S0 production rate (SPR) of 54.4 ± 5.8 mg S0-S L-1 d-1 at the optimal voltage of 0.8 V than that in the abio-anode UBER (control reactor) (SRR = 86.6 ± 13.4 mg SO42--S L-1 d-1; SPR = 25.5 ± 9.7 mg S0-S L-1 d-1) under long-term operation. A large amount of biogenic S0 (about 72.2 mg g-1 VSS) was recovered in the B-UBER. The bio-anode, dominated by Thiovirga (SOB genus) and Acinetobacter (electrochemically active bacteria genus), exhibited a higher current density, lower overpotential, and lower internal resistance. C-type cytochromes mainly served as the crucial electron transfer mediator for both direct and indirect electron transfer, so that significantly increasing electron transfer capacity and biogenic S0 recovery. The reaction pathways of the sulfur transformation in the B-UBER were hypothesized that SRB utilized acetate as the main electron donor for SO42- reduction in the cathode zone and SOB transferred electrons to the anode or oxygen to produce biogenic S0 in the anode zone. This study proved a new pathway for biogenic S0 recovery and sulfate removal from sulfate-laden antibiotic production wastewater using a well-designed single-chamber bioelectrochemical reactor.

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products.

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.

Efficient sulfur atom-doped three-dimensional porous MXene-assisted sodium ion batteries.

Recently, it has been reported that MXene is a promising pseudocapacitive material for energy storage, primarily due to its intercalation mechanism. However, Ti3C2Tx MXenes face challenges, such as inadequate layer spacing and low specific capacity, which greatly hinder their potential as anode materials for sodium storage. In this study, MXene was doped with sulfur to create a three-dimensional porous structure that resulted in an increased layer spacing. The sulfur-doped porous MXene (SPM) demonstrated exceptional performance as sodium ion battery anodes, with a capacity of 335.2 mA h g-1 after 490 cycles at 2 A g-1 and a long-term cycling performance of 256.1 mA h g-1 even after 2480 cycles at 5 A g-1. It is worth noting that the porous structure formed after sulfur-doping exhibits superior sodium storage performance compared to previously reported MXene-based electrodes. This highlights the feasibility of the structural construction strategy, offering an effective solution for energy storage and conversion applications.

A microglial activation cascade across cortical regions underlies secondary mechanical hypersensitivity to amputation.

Neural mechanisms underlying amputation-related secondary pain are unclear. Using in vivo two-photon imaging, three-dimensional reconstruction, and fiber photometry recording, we show that a microglial activation cascade from the primary somatosensory cortex of forelimb (S1FL) to the primary somatosensory cortex of hindlimb (S1HL) mediates the disinhibition and subsequent hyperexcitation of glutamatergic neurons in the S1HL (S1HLGlu), which then drives secondary mechanical hypersensitivity development in ipsilateral hindpaws of mice with forepaw amputation. Forepaw amputation induces rapid S1FL microglial activation that further activates S1HL microglia via the CCL2-CCR2 signaling pathway. Increased engulfment of GABAergic presynapses by activated microglia stimulates S1HLGlu neuronal activity, ultimately leading to secondary mechanical hypersensitivity of hindpaws. It is widely believed direct neuronal projection drives interactions between distinct brain regions to prime specific behaviors. Our study reveals microglial interactions spanning different subregions of the somatosensory cortex to drive a maladaptive neuronal response underlying secondary mechanical hypersensitivity at non-injured sites.

Efficacy of Targeted Scapular Stabilization Exercise vs Conventional Exercise for Patients with Shoulder Pain: A Randomized Clinical Trial.

OBJECTIVE: To investigate the efficacy of targeted scapular stabilization exercise in shoulder pain. DESIGN: This is an evaluator-blinded, multicenter, randomized controlled trial. The scapular stabilization exercise group (n = 45) received scapular stabilization exercise based on the type of scapular dyskinesis (SD) for 6 weeks; the conventional exercise group (n = 45) received pendulum, wall climbing and stick exercises for 6 weeks. Constant-Murley score (CMS), were numerical rating scale (NRS), range of motion (ROM), type of SD, lateral scapular sliding test (LSST), pectoralis minor index (PMI), scapular index (SI) and satisfaction were assessed at baseline, two, four, six-week treatment and a 6-week follow-up. RESULTS: After a 6-week intervention, the improvement of CMS was greater in the scapular stabilization exercise group than in the conventional exercise group, and improvement continued at the 6-week follow-up (F = 15.39, P < 0.001, Partial η2 = 0.17). The Results were also significant for NRS during activity, LSST, PMI, type of SD and satisfaction in favor of the scapular stabilization exercise group (P < 0.05). CONCLUSION: Targeted scapular stabilization exercise is an effective intervention program that might be applied to the rehabilitation of shoulder pain.

Circ ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 increases the stability of G9a and ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 messenger RNA through recruiting eukaryotic translation initiation factor 4A3, transcriptionally inhibiting PDZ and homeobox protein domain protein 1, and promotes the metastasis of hepatocellular carcinoma.

BACKGROUND AND AIM: Circular ubiquitin-like, containing PHD and ring finger domains 1 (circUHRF1) is aberrantly upregulated in human hepatocellular carcinoma (HCC) tissues. However, the underlying molecular mechanisms remain obscure. The present study aimed at elucidating the interactive function of circUHRF1-G9a-ubiquitin-like, containing PHD and ring finger domains 1 (UHRF1) mRNA-eukaryotic translation initiation factor 4A3 (EIF4A3)-PDZ and LIM domain 1 (PDLIM1) network in HCC. METHODS: Expression of circUHRF1, mRNAs of G9a, UHRF1, PDLIM1, epithelial-mesenchymal transition (EMT)-related proteins, and Hippo-Yap pathway components was determined by quantitative polymerase chain reaction (Q-PCR), immunofluorescence, or Western blot analysis. Tumorigenic and metastatic capacities of HCC cells were examined by cellular assays including Cell Counting Kit-8, colony formation, wound healing, and transwell assays. Molecular interactions between EIF4A3 and UHRF1 mRNA were detected by RNA pull-down experiment. Complex formation between UHRF1 and PDLIM1 promoter was detected by chromatin immunoprecipitation assay. Co-immunoprecipitation was performed to examine the binding between UHRF1 and G9a. RESULTS: Circular ubiquitin-like, containing PHD and ring finger domains 1, G9a, and UHRF1 were upregulated, while PDLIM1 was downregulated in HCC tissue samples and cell lines. Cellular silencing of circUHRF1 repressed HCC proliferation, invasion, migration, and EMT. G9a formed a complex with UHRF1 and inhibited PDLIM1 transcription. CONCLUSION: Eukaryotic translation initiation factor 4A3 regulated circUHRF1 expression by binding to UHRF1 mRNA promoter. circUHRF1 increased the stability of G9a and UHRF1 mRNAs through recruiting EIF4A3. Overexpression of circUHRF1 aggravated HCC progression through Hippo-Yap pathway and PDLIM1 inhibition. By elucidating the molecular function of circUHRF1-G9a-UHRF1 mRNA-EIF4A3-PDLIM1 network, our data shed light on the HCC pathogenesis and suggest a novel therapeutic strategy for future HCC treatment.

Role and mechanism of MiR-542-3p in regulating TLR4 in nonylphenol-induced neuronal cell pyroptosis.

BACKGROUND: This study aimed to investigate the spatial learning/memory and motor abilities of rats and the alteration of miR-542-3p and pyroptosis in the midbrain nigrostriatal area in vivo after nonylphenol (NP) gavage and to explore the mechanism of miR-542-3p regulation of Toll-like receptor 4 (TLR4) in NP-induced pyroptosis in BV2 microglia in vitro. METHODS: In vivo: Thirty-six specific-pathogen-free-grade Sprague-Dawley rats were divided into three equal groups: blank control group (treated with pure corn oil), NP group (treated with NP, 80 mg/kg body weight per day for 90 days), and positive control group [treated with lipopolysaccharide (LPS), 2 mg/kg body weight for 7 days]. In vitro: The first part of the experiment was divided into blank group (control, saline), LPS group [1 µg/ml + 1 mM adenosine triphosphate (ATP)], and NP group (40 µmol/L). The second part was divided into mimics NC (negative control) group, miR-542-3p mimics group, mimics NC + NP group, and miR-542-3p mimics + NP group. RESULTS: In vivo: Behaviorally, the spatial learning/memory and motor abilities of rats after NP exposure declined, as detected via Y-maze, open field, and rotarod tests. Some microglia in the substantia nigra of the NP-treated rats were activated. The downregulation of miR-542-3p was observed in rat brain tissue after NP exposure. The mRNA/protein expression of pyroptosis-related indicators (TLR4), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), gasdermin-D (GSDMD), cysteinyl aspartate-specific proteinase-1 (caspase-1), and interleukin-1ß (IL-1ß) in the substantia nigra of the midbrain increased after NP exposure. In vitro: ASC fluorescence intensity increased in BV2 cells after NP exposure. The mRNA and/or protein expression of pyroptosis-related indicators (TLR4, NLRP3, GSDMD, caspase-1, and IL-1ß) in BV2 cells was upregulated after NP exposure. The transfection of miR-542-3p mimics inhibited NP-induced ASC expression in BV2 cells. The overexpression of miR-542-3p, followed by NP exposure, significantly reduced TLR4, NLRP3, ASC, caspase-1, and IL-1ß gene and/or protein expression. CONCLUSIONS: This study suggested that NP exposure caused a decline in spatial learning memory and whole-body motor ability in rats. Our study was novel in reporting that the upregulation of miR-542-3p targeting and regulating TLR4 could inhibit NLRP3 inflammatory activation and alleviate NP-induced microglia pyroptosis.

Rapid fluctuations in functional connectivity of cortical networks encode spontaneous behavior.

Experimental work across species has demonstrated that spontaneously generated behaviors are robustly coupled to variations in neural activity within the cerebral cortex. Functional magnetic resonance imaging data suggest that temporal correlations in cortical networks vary across distinct behavioral states, providing for the dynamic reorganization of patterned activity. However, these data generally lack the temporal resolution to establish links between cortical signals and the continuously varying fluctuations in spontaneous behavior observed in awake animals. Here, we used wide-field mesoscopic calcium imaging to monitor cortical dynamics in awake mice and developed an approach to quantify rapidly time-varying functional connectivity. We show that spontaneous behaviors are represented by fast changes in both the magnitude and correlational structure of cortical network activity. Combining mesoscopic imaging with simultaneous cellular-resolution two-photon microscopy demonstrated that correlations among neighboring neurons and between local and large-scale networks also encode behavior. Finally, the dynamic functional connectivity of mesoscale signals revealed subnetworks not predicted by traditional anatomical atlas-based parcellation of the cortex. These results provide new insights into how behavioral information is represented across the neocortex and demonstrate an analytical framework for investigating time-varying functional connectivity in neural networks.

An off-policy multi-agent stochastic policy gradient algorithm for cooperative continuous control.

Multi-agent reinforcement learning (MARL) algorithms based on trust regions (TR) have achieved significant success in numerous cooperative multi-agent tasks. These algorithms restrain the Kullback-Leibler (KL) divergence (i.e., TR constraint) between the current and new policies to avoid aggressive update steps and improve learning performance. However, the majority of existing TR-based MARL algorithms are on-policy, meaning that they require new data sampled by current policies for training and cannot utilize off-policy (or historical) data, leading to low sample efficiency. This study aims to enhance the data efficiency of TR-based learning methods. To achieve this, an approximation of the original objective function is designed. In addition, it is proven that as long as the update size of the policy (measured by the KL divergence) is restricted, optimizing the designed objective function using historical data can guarantee the monotonic improvement of the original target. Building on the designed objective, a practical off-policy multi-agent stochastic policy gradient algorithm is proposed within the framework of centralized training with decentralized execution (CTDE). Additionally, policy entropy is integrated into the reward to promote exploration, and consequently, improve stability. Comprehensive experiments are conducted on a representative benchmark for multi-agent MuJoCo (MAMuJoCo), which offers a range of challenging tasks in cooperative continuous multi-agent control. The results demonstrate that the proposed algorithm outperforms all other existing algorithms by a significant margin.

Discovery of a novel anti-osteoporotic agent from marine fungus-derived structurally diverse sirenins.

Thirteen new sirenin derivatives named eupenicisirenins C-O (1-13), along with a biosynthetically related known one (14), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data, quantum chemical calculations, and X-ray diffraction. Among them, eupenicisirenin C (1) exhibited the strongest NF-κB inhibitory activities, as well as suppressing effects on cGAS-STING pathway. Moreover, 1 showed the significant inhibitory effect on RANKL-induced osteoclast differentiation in bone marrow macrophages cells, and also displayed the therapeutic potential on prednisolone-induced zebrafish osteoporosis. Transcriptome analysis and the following verification tests suggested that its anti-osteoporotic mechanism is related to the extracellular matrix receptor interaction-related pathways. This study provided a promising marine-derived anti-osteoporotic agent for the treatment of skeletal disease.

The creative behavior of virtual idol fans: a psychological perspective based on MOA theory.

Breakthroughs in digital technology are accelerating the development and commercialization of virtual idols. They are overturning the traditional one-way communication between idols and fans, turning fans into producers and consumers. Therefore, identifying the motivations for fan creation can regulate and guide the creative behavior of fans and turn their creativity into productivity. This paper took "the factors influencing fans' spontaneous participation in creating virtual idols" as the primary research question, took the Motivation Opportunity Ability (MOA) theory as the research framework, used questionnaires as the primary research method, and combined the relevant research on motivation theory and self-determination theory to explore fans' creative behavior from the psychological perspective in depth. The empirical tests revealed that in the motivation dimension, interest motivation, achievement motivation, social motivation, and utility motivation all positively influenced fans' creative behavior; in the opportunity dimension, fans' perceived cost had a significant negative moderating effect on the influence of interest motivation, social motivation, and utility motivation on fans' creative behavior; fans' perceived community atmosphere was substantial. The moderating effect of knowledge and skills on the capability dimension was insignificant. For the virtual idol industry, the future development of the industry could not only focus on IP image creation and content production but also effectively stimulate fans' creative motivation through the creation of an excellent community atmosphere, the provision of targeted creator services, and the reduction of fans' perceived costs in the creation process.

Pulmonary mucoepidermoid carcinoma in children: two case reports and a review of the literature.

Pulmonary mucoepidermoid carcinoma (PMEC) is a rare tumor, particularly in children, and its clinical manifestations vary. When the tumor is small, it may be asymptomatic; however, with larger tumors, patients may present with symptoms such as recurring pneumonia, atelectasis, persistent cough, chest pain, and even hemoptysis. PMEC appears as an exophytic intrabronchial mass. This study aims to report on the clinical manifestations, imaging findings, treatment approaches, and prognosis of two children diagnosed with PMEC at our hospital between January 2018 and December 2022. The age of onset for both children was 9 years, and the masses were located in the right upper lobe bronchi. Following surgical treatment, both patients showed a good prognosis. In addition, we conducted a comprehensive review of the relevant literature to enhance the overall understanding of PMEC.

Occurrence, distribution, and behaviors of erythromycin A, production byproducts, transformation products, and resistance genes in a full-scale erythromycin A production wastewater treatment system.

Antibiotic production wastewater from pharmaceutical manufacturing is a significant source of antibiotic and resistance gene pollution in the environment. Given that Erythromycin A (Ery-A) is a widely used antibiotic in both human clinical and livestock breeding, it is imperative to ascertain its presence, along with related compounds, in the biological treatment processes of production wastewater. In this study, the occurrence and behavior of Ery-A, its production byproducts, transformation products, and resistance genes were first systematically investigated in a full-scale anaerobic-aerobic system for treating Ery-A production wastewater. Simultaneously, residual antibacterial activity in wastewater and sludge was evaluated throughout the wastewater treatment process. Ery-A contributes only 24.2 - 36.0% to the antibacterial activities. Ery-A-derived compounds including production byproducts (erythromycin B and erythromycin C) and transformation products (anhydro erythromycin A, N-demethyl-erythromycin A, and erythromycin A enol ether), are determined to contribute to the antibacterial activities of the wastewater treatment system. High concentrations of antibiotics with antibacterial activity (up to 1,258.9 mg/kg·TS for erythromycin A enol ether) adsorbed in the sludge result in near collapse of the first-stage anaerobic sludge system. Sludge biodegradation in second-stage anaerobic and anoxic-aerobic tanks is essential in removing Ery-A-related compounds from wastewater. The Ery-A-related compounds in the secondary effluent and excess sludge are determined to be 44.5 g/h and 1.5 g/h through the mass balance analysis, respectively. The discharge of MLS resistance genes from the secondary effluent and excess sludge is 1.0 × 1016 copies/h and 7.1 × 1015 copies/h, respectively. These findings highlight the significant concern over the release of Ery-A-related compounds and MLS resistance genes from the Ery-A production wastewater treatment system. As a result, it is crucial to implement strategies for the removal of Ery-A-related compounds from production wastewater before biological processes. This study is the first to report the occurrence and behavior of Ery-A-related compounds and resistance genes along the full-scale wastewater treatment processes. Additionally, it sheds light on the importance of byproducts and transformation products with antibacterial activity from Ery-A in the Ery-A production wastewater treatment system.

Identification of hub genes and therapeutic drugs in osteonecrosis of the femoral head through integrated bioinformatics analysis and literature mining.

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease leading to severely limited function. By far, the etiology and pathogenesis of ONFH are not fully understood, and surgery is the only effective way to treat ONFH. This study aims to identify hub genes and therapeutic drugs in ONFH. Two gene expression profiles were downloaded from the gene expression omnibus database, and the hub genes and candidate drugs for ONFH were identified through integrated bioinformatics analysis and cross-validated by literature mining. A total of 159 DEGs were identified. PTGS2, LRRK2, ANXA5, IGF1R, MCL1, TIMP2, LYN, CD68, CBL, and RUNX2 were validated as 10 hub genes, which has considerable implications for future genetic research and related research fields of ONFH. Our findings indicate that 85 drugs interact with ONFH, with most drugs exhibiting a positive impact on ONFH by promoting osteogenesis and angiogenesis or inhibiting microcirculation embolism, rather than being anti-inflammatory. Our study provides novel insights into the pathogenesis, prevention, and treatment of ONFH.

mRNA Turnover Protein 4 Is Vital for Fungal Pathogenicity and Response to Oxidative Stress in Sclerotinia sclerotiorum.

Ribosome assembly factors have been extensively studied in yeast, and their abnormalities may affect the assembly process of ribosomes and cause severe damage to cells. However, it is not clear whether mRNA turnover protein 4 (MRT4) functions in the fungal growth and pathogenicity in Sclerotinia sclerotiorum. Here, we identified the nucleus-located gene SsMRT4 using reverse genetics, and found that knockdown of SsMRT4 resulted in retard mycelia growth and complete loss of pathogenicity. Furthermore, mrt4 knockdown mutants showed almost no appressorium formation and oxalic acid production comparing to the wild-type and complementary strains. In addition, the abilities to ROS elimination and resistance to oxidative and osmotic stresses were also seriously compromised in mrt4 mutants. Overall, our study clarified the role of SsMRT4 in S. sclerotiorum, providing new insights into ribosome assembly in regulating pathogenicity and resistance to environmental stresses of fungi.

Exploring the binding effects and inhibiting mechanism of hyperoside to lipase using multi-spectroscopic approaches, isothermal titration calorimetry, inhibition kinetics and molecular dynamics.

Hyperoside (HYP) is a flavonoid with various physiological activities. The present study examined the interaction mechanism between HYP and lipase using multi-spectrum and computer-aided techniques. Results demonstrated that the force type of HYP on lipase was mainly hydrogen bond, hydrophobic interaction force, and van der Waals force, and HYP had an excellent binding affinity with lipase at 1.576 × 105 M-1. HYP dose-dependently inhibited lipase in the inhibition experiment, and its IC50 value was 1.92 × 10-3 M. Moreover, the results suggested that HYP could inhibit the activity by binding to essential groups. Conformational studies indicated that the conformation and microenvironment of lipase were slightly changed after the addition of HYP. Computational simulations further confirmed the structural relationships of HYP to lipase. The interaction between HYP and lipase can provide ideas for the development of functional foods related to weight loss. The results of this study help comprehend the pathological significance of HYP in biological systems, as well as its mechanism.

Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.

Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha (LXRα) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.

Exploration of the inhibition action of TPGS on tumor cells and its combined use with chemotherapy drugs.

D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a commonly used nonionic surfactant used as a pharmaceutical carrier in different drug delivery systems. TPGS can reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and also has anticancer activities. It suggests that when designing antitumor drug preparation, it's necessary to take into account the antitumor activity of TPGS. Our in vivo studies showed that TPGS exerted the strongest cytotoxicity in MCF-7-ADR cells when compared with seven other tumor cell lines. The further study revealed TPGS caused apoptosis and blocked MCF-7 cell growth in G2/M phase. Mechanistic insights suggested that TPGS increased intracellular calcium ion concentrations, leading to apoptosis via the mitochondrial pathway. Furthermore, two in vivo experiments were performed. One was TPGS, and DOX solution was administered by tail vein injection on MCF-7-ADR tumor bearing nude mice. The other was temperature sensitive TPGS gel (TPGS-TG) was administered by intratumoral injection on MCF-7-ADR tumor bearing nude mice combined with paclitaxel albumin nanoparticles (Abraxane®) administered by tail vein injection. The findings confirmed that TPGS could play its role in anti-tumor to reduce the toxicity of chemotherapeutic drugs and improve the efficiency of drug-resistant tumors, thereby enhancing the development of safe oncology therapeutics.

Construction of Bi-Enzyme Self-Assembly Clusters Based on SpyCatcher/SpyTag for the Efficient Biosynthesis of (R)-Ethyl 2-hydroxy-4-phenylbutyrate.

Cascade reactions catalyzed by multi-enzyme systems are important in science and industry and can be used to synthesize drugs and nutrients. In this study, two types of macromolecules of bi-enzyme self-assembly clusters (BESCs) consisting of carbonyl reductase (CpCR) and glucose dehydrogenase (GDH) were examined. Stereoselective CpCR and GDH were successfully fused with SpyCatcher and SpyTag, respectively, to obtain four enzyme modules, namely: SpyCatcher-CpCR, SpyCatcher-GDH, SpyTag-CpCR, and SpyTag-GDH, which were covalently coupled in vitro to form two types of hydrogel-like BESCs: CpCR-SpyCatcher-SpyTag-GDH and GDH-SpyCatcher-SpyTag-CpCR. CpCR-SpyCatcher-SpyTag-GDH showed a better activity and efficiently converted ethyl 2-oxo-4-phenylbutyrate (OPBE) to ethyl(R)2-hydroxy-4-phenylbutanoate ((R)-HPBE), while regenerating NADPH. At 30 °C and pH 7, the conversion rate of OPBE with CpCR-SpyCatcher-SpyTag-GDH as a catalyst reached 99.9%, with the ee% of (R)-HPBE reaching above 99.9%. This conversion rate was 2.4 times higher than that obtained with the free bi-enzyme. The pH tolerance and temperature stability of the BESCs were also improved compared with those of the free enzymes. In conclusion, bi-enzyme assemblies were docked using SpyCatcher/SpyTag to produce BESCs with a special structure and excellent catalytic activity, improving the catalytic efficiency of the enzyme.

Herbal formula Jiawei Xiaochengqi decoction prevents postoperative abdominal adhesion in a rat model through inhibition of CXCL2-CXCR2 pathway.

BACKGROUND: Postoperative abdominal adhesion (PAA) is the most common complication after abdominal surgeries, which can lead to intestinal obstruction, chronic abdominal pain or female infertility. Jiawei Xiaochengqi decoction (JWXCQ) is a hospital preparation widely used for PAA treatment in Nanfang Hospital of Southern Medical University for more than twenty years. PURPOSE: This study aimed to investigate the therapeutic effects and potential mechanism of JWXCQ against PAA and provide beneficial information for its clinical application. METHODS: The main active components of JWXCQ were identified using ultra high performance liquid chromatography (UHPLC) combined with standard substance comparison. The efficacy and underlying mechanism of JWXCQ were evaluated through in vivo experiments with a postsurgical-induced peritoneal adhesion rat model, and in vitro studies with LPS-stimulated Raw 264.7 macrophages and primary fibroblasts. H&E and Masson staining were performed to assess histopathological changes. The levels of cytokines/proteins-associated with inflammation and degradation of extracellular matrix as well as CXCL2-CXCR2 pathway-related proteins were determined by ELISA, qRT-PCR, western blot assays or immunohistochemistry, respectively. Furthermore, siCXCR2 transfection was used to validate the mechanism of action of JWXCQ. RESULTS: JWXCQ treatment significantly reduced the formation of PAA, inhibited the inflammation and collagen deposition, and facilitated the secretion of MMP9, decreased the levels of IL-1ß, IL-6, TIMP1, COL-1, and suppressed the CXCL2-CXCR2 pathway in PAA rats. Furthermore, JWXCQ inhibited its downstream pathways, the JAK2-STAT3 and PI3K-AKT signaling, as indicated by the suppression of the phosphorylation levels of STAT3 and AKT. In vitro cell experiments revealed that JWXCQ reduced IL-1ß and IL-6 secretion in Raw 264.7 macrophages and COL-1 in primary fibroblasts. The CXCL2-CXCR2, JAK2-STAT3 and PI3K-AKT pathways were also inhibited after JWXCQ treatment, which were consistent with the in vivo results. More importantly, silence of CXCR2 eliminated the regulatory effects of JWXCQ. CONCLUSION: JWXCQ could effectively prevent the PAA formation by alleviating inflammation and collagen deposition, which was associated with the inhibition of CXCL2-CXCR2 pathway. This study investigated the relevant pharmacological mechanisms of JWXCQ, providing further evidence for the application of JWXCQ in clinical PAA treatment.