One-step bioremediation of hypersaline and nutrient-rich food industry process water with a domestic microbial community containing diatom Halamphora coffeaeformis.

Proper treatment of hypersaline and nutrient-rich food industry process water (FIPW) is challenging in conventional wastewater plants. Insufficient treatment leads to serious environmental hazards. However, bioremediation of FIPW with an indigenous microbial community can not only recover nutrients but generate biomass of diverse applications. In this study, monoculture of Halamphora coffeaeformis, together with synthetic bacteria isolated from a local wastewater plant, successfully recovered 91% of NH4+-N, 78% of total nitrogen, 95% of total phosphorus as well as 82% of total organic carbon from medium enriched with 10% FIPW. All identified organic acids and amino acids, except oxalic acid, were completely removed after 14 days treatment. A significantly higher biomass concentration (1.74 g L-1) was achieved after 14 days treatment in the medium with 10% FIPW than that in a nutrient-replete lab medium as control. The harvested biomass could be a potential feedstock for high-value biochemicals and fertilizer production, due to fucoxanthin accumulation (3 mg g-1) and a fantastic performance in P assimilation. Metagenomic analysis revealed that bacteria community in the algal system, dominated by Psychrobacter and Halomonas, also contributed to the biomass accumulation and uptake of nutrients. Transcriptomic analysis further disclosed that multiple pathways, involved in translation, folding, sorting and degradation as well as transport and catabolism, were depressed in H. coffeaeformis grown in FIPW-enriched medium, as compared to the control. Collectively, the proposed one-step strategy in this work offers an opportunity to achieve sustainable wastewater management and a way towards circular economy.

Polyphenols from hickory nut reduce the occurrence of atherosclerosis in mice by improving intestinal microbiota and inhibiting trimethylamine N-oxide production.

BACKGROUND: Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal microbiota through metabolizing phosphatidylcholine, choline, l-carnitine and betaine in the diet, has been implicated in the pathogenesis of atherosclerosis (AS). Concurrently, dietary polyphenols have garnered attention for their potential to ameliorate obesity, diabetes and atherosclerosis primarily by modulating the intestinal microbial structure. Hickory (Carya cathayensis) nut, a polyphenol-rich food product favored for its palatability, emerges as a candidate for exploration. HYPOTHESIS/PURPOSE: The relationship between polyphenol of hickory nut and atherosclerosis prevention will be firstly clarified, providing theoretical basis for the discovery of natural products counteracting TMAO-induced AS process in hickory nut. STUDY DESIGN AND METHODS: Employing Enzyme-linked Immunosorbent Assay (ELISA) and histological examination of aortic samples, the effects of total polyphenol extract on obesity index, inflammatory index and pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high choline diet were evaluated. Further, the composition, abundance, and function of mouse gut microbiota were analyzed through 16srDNA sequencing. Concurrently, the levels of TMAO and the expression of key enzymes (CutC and FMO3) involved in its synthesis are quantified using ELISA, Western Blot and Real-Time Quantitative PCR (RT-qPCR). Additionally, targeted metabolomic profiling of the hickory nut polyphenol extract was conducted, accompanied by molecular docking simulations to predict interactions between candidate polyphenols and the CutC/FMO3 using Autodock Vina. Finally, the docking prediction were verified by microscale thermophoresis (MST) . RESULTS: Polyphenol extracts of hickory nut improved the index of obesity and inflammation, and alleviated the pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high-choline diet. Meanwhile, these polyphenol extracts also changed the composition and function of intestinal microbiota, and increased the abundance of microorganisms in mice. Notably, the abundance of intestinal microbiota endowed with CutC gene was significantly reduced, coherent with expression of CutC catalyzing TMA production. Moreover, polyphenol extracts also decreased the expression of FMO3 in the liver, contributing to the reduction of TMAO levels in serum. Furthermore, metabonomic profile analysis of these polyphenol extracts identified 647 kinds of polyphenols. Molecular docking predication further demonstrated that Casuariin and Cinnamtannin B2 had the most potential inhibition on the enzymatic activities of CutC or FMO3, respectively. Notably, MST analysis corroborated the potential for direct interaction between CutC enzyme and available polyphenols such as Corilagin, (-)-Gallocatechin gallate and Epigallocatechin gallate. CONCLUSION: Hickory polyphenol extract can mitigate HFD-induced AS by regulating intestinal microflora in murine models. In addition, TMA-FMO3-TMAO pathway may play a key role in this process. This research unveils, for the inaugural time, the complex interaction between hickory nut-derived polyphenols and gut microbial, providing novel insights into the role of dietary polyphenols in AS prevention.

A randomized controlled study investigating the efficacy of electro-acupuncture and exercise-based swallowing rehabilitation for post-stroke dysphagia: Impacts on brainstem auditory evoked potentials and cerebral blood flow.

BACKGROUND: Swallowing rehabilitation behavioral therapy and traditional Chinese acupuncture therapy are widely used in the treatment of post-stroke dysphagia (PSD). This study investigated the therapeutic effect of electro-acupuncture combined with exercise-based swallowing rehabilitation on PSD and its effect on brainstem auditory evoked potential (BAEP) and cerebral blood flow. METHODS: The 120 PSD patients were divided into 2 groups (n = 60 each) by simple random grouping method, that is, an experimental and control group, receiving routine swallowing training, or additional intervention with electro-acupuncture at a frequency of 5 times/week. Data in swallowing function, BAEP, and cerebrovascular color Doppler ultrasound parameters were collected before treatment, as well as after treatment. An intergroup comparison was conducted using an independent sample t-test, and an intra-group comparison was conducted among different time points using a paired t-test. The data were analyzed using the SPSS Statistics 22.0 software; P < .05 was considered statistically significant. RESULTS: The therapeutic effects were significantly better in the experimental group compared with the control group (P < .05). The standard swallowing function assessment scores were significantly lower in both groups after treatment (P < .05), and the score in the observation group was lower than in the control group (P < .05). The peak latency of BAEP waves III and IV, and the inter-peak latency between peaks III to V and I to V in the 2 groups changed significantly (P < .05). The peak systolic velocity (PSV), end-diastolic velocity (EDV), and mean velocity (MV) were significantly increased in both groups after treatment (P < .05). The pulsatility index decreased significantly in both groups (P < .05), and the PSV, EDV, and MV were higher in the experimental group than in the control group (P < .05). CONCLUSION: Electro-acupuncture, combined with swallowing training in the treatment of Post-stroke Dysphagia, effectively improved cerebral microcirculation and conduction velocity, enhanced the motor function of swallowing muscles, and promoted the recovery of swallowing function.

Sinomenine ameliorates fibroblast-like synoviocytes dysfunction by promoting phosphorylation and nuclear translocation of CRMP2.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and arthritic pain. Sinomenine (SIN), derived from the rhizome of Chinese medical herb Qing Teng (scientific name: Sinomenium acutum (Thunb.) Rehd. Et Wils), has a longstanding use in Chinese traditional medicine for treating rheumatoid arthritis. It has been shown to possess anti-inflammatory, analgesic, and immunosuppressive effects with minimal side-effects clinically. However, the mechanisms governing its effects in treatment of joint pathology, especially on fibroblast-like synoviocytes (FLSs) dysfunction, and arthritic pain remains unclear. AIM: This study aimed to investigate the effect and underlying mechanism of SIN on arthritic joint inflammation and joint FLSs dysfunctions. MATERIALS AND METHODS: Collagen-induced arthritis (CIA) was induced in rats and the therapeutic effects of SIN on joint pathology were evaluated histopathologically. Next, we conducted a series of experiments using LPS-induced FLSs, which were divided into five groups (Naïve, LPS, SIN 10, 20, 50 µg/ml). The expression of inflammatory factors was measured by qPCR and ELISA. The invasive ability of cells was detected by modified Transwell assay and qPCR. Transwell migration and cell scratch assays were used to assess the migration ability of cells. The distribution and content of relevant proteins were observed by immunofluorescence and laser confocal microscopy, as well as Western Blot and qPCR. FLSs were transfected with plasmids (CRMP2 T514A/D) to directly modulate the post-translational modification of CRMP2 protein and downstream effects on FLSs function was monitored. RESULTS: SIN alleviated joint inflammation in rats with CIA, as evidenced by improvement of synovial hyperplasia, inflammatory cell infiltration and cartilage damage, as well as inhibition of pro-inflammatory cytokines release from FLSs induced by LPS. In vitro studies revealed a concentration-dependent suppression of SIN on the invasion and migration of FLSs induced by LPS. In addition, SIN downregulated the expression of cellular CRMP2 that was induced by LPS in FLSs, but increased its phosphorylation at residue T514. Moreover, regulation of pCRMP2 T514 by plasmids transfection (CRMP2 T514A/D) significantly influenced the migration and invasion of FLSs. Finally, SIN promoted nuclear translocation of pCRMP2 T514 in FLSs. CONCLUSIONS: SIN may exert its anti-inflammatory and analgesic effects by modulating CRMP2 T514 phosphorylation and its nuclear translocation of FLSs, inhibiting pro-inflammatory cytokine release, and suppressing abnormal invasion and migration. Phosphorylation of CRMP2 at the T514 site in FLSs may present a new therapeutic target for treating inflammatory joint's destruction and arthritic pain in RA.

Phycoremediation and valorization of hypersaline pickled mustard wastewater via Chaetoceros muelleri and indigenous bacteria.

Hypersaline pickled mustard wastewater (PMW), a typical food wastewater with high nutrient content, was successfully bioremediated via the co-treatment of Chaetoceros muelleri and indigenous bacteria in this study. Chemical oxygen demand, ammonia nitrogen, total nitrogen and total phosphorus in 10 % PMW could be effectively reduced by 82 %, 90 %, 94 % and 96 %, respectively, after 12 days treatment. Oxygen species activities, malondialdehyde content, microalgal biomass, photosynthesis and extracellular polymeric substances were characterized during the treatment to determine the responses of the consortium when exposed to different concentration of PMW. Microbial community analysis demonstrated a significant increase in the relative abundance of Halomonas and Marinobacter in the 10 % PMW after 12 days treatment, which was beneficial for nutrients recycling by the diatoms. Meanwhile, C. muelleri was effective in reducing the relative abundance of potentially pathogenic bacteria Malaciobacter. In conclusion, the work here offers a promising and environmentally friendly approach for hypersaline wastewater treatment.

Brain network mechanism of acupuncture for chronic spontaneous urticaria: a functional magnetic resonance imaging study protocol.

Introduction: Chronic spontaneous urticaria (CSU) is a common skin condition that can significantly impact patients' quality of life. Although studies have demonstrated the efficacy of acupuncture in treating CSU, the underlying mechanisms remain unclear. Dysfunction within the brain's default mode network (DMN) represents a fundamental characteristic of central pathological changes associated with CSU. Therefore, it is hypothesized that improving brain network dysfunction could serve as a key mechanism through which acupuncture exerts its therapeutic effects. This study aims to provide evidence supporting this hypothesis. Methods and analysis: This study, a parallel, randomized, sham-controlled functional neuroimaging investigation will be conducted in China. We aim to enroll 50 patients with CSU and 25 healthy controls, distributing them evenly between the acupuncture and sham acupuncture groups in a 1:1 ratio. The total observation period will span 6 weeks, including 2 weeks designated for the baseline phase and 4 weeks allocated for the clinical treatment phase. Prior to treatment, all participants will undergo magnetic resonance scanning, clinical index detection, and microbiota collection. Following treatment, the patients with CSU will be retested for these indicators. Using resting-state functional connectivity (rsFC) analysis, dynamic Functional Connection (dFC) analysis, and brain microstate extraction technology combined with correlation analysis of microbiota and clinical indicators, the regulatory mechanism of acupuncture on the brain network of CSU will be evaluated from multiple dimensions. Ethics and dissemination: This trial was approved by the Biomedical Ethics Review Committee of the West China Hospital, Sichuan University (No. 2022-1255). Each participant will provide written informed consent to publish any potentially identifiable images or data.Clinical trial registrationhttps://www.chictr.org.cn/, identifier: ChiCTR2200064563.

The effects of astragaloside IV on gut microbiota and serum metabolism in a mice model of intracerebral hemorrhage.

BACKGROUND: Astragaloside IV (AS-IV) is the main active component of "Astragalus membranaceus (Fisch.) Bunge, a synonym of Astragalus propinquus Schischkin (Fabaceae)", which demonstrated to be useful for the treatment of intracerebral hemorrhage (ICH). However, due to the low bioavailability and barrier permeability of AS-IV, the gut microbiota may be an important key regulator for AS-IV to work. OBJECTIVE: To explore the influences of gut microbiota on the effects of AS-IV on ICH. METHODS: Mice were randomly divided into five groups: sham, ICH, and AS-IV-treated groups (25 mg/kg, 50 mg/kg, and 100 mg/kg). Behavioral tests, brain histopathology, and immunohistochemistry analysis were used to evaluate the degree of brain injury. Western blot was employed to verify peri­hematoma inflammation. The plasma lipopolysaccharide (LPS) leakage, the fluorescein isothiocyanate-dextran permeability, the colonic histopathology, and immunohistochemistry were detected to evaluate the barrier function of intestinal mucosal. Moreover, 16S rDNA sequencing and metabolomic analysis was applied to screen differential bacteria and metabolites, respectively. The correlation analysis was adopted to determine the potential relationship between differential bacteria and critical metabolites or neurological deficits. RESULTS: AS-IV alleviated neurological deficits, neuronal injury and apoptosis, and blood-brain barrier disruption. This compound reduced tumor necrosis factor (TNF)-α expression, increased arginase (Arg)-1 and interleukin (IL)-33 levels around the hematoma. Next, 16S rRNA sequencing indicated that AS-IV altered the gut microbiota, and inhibited the production of conditional pathogenic bacteria. Metabolomic analysis demonstrated that AS-IV regulated the serum metabolic profiles, especially the aminoacid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Additionally, AS-IV mitigated intestinal barrier damage and LPS leakage. CONCLUSION: This study provides a new perspective on the use of AS-IV for the treatment of ICH. Among them, gut microbiota and its metabolites may be the key regulator of AS-IV in treating ICH.

Wogonin Diminishes Radioresistance of Breast Cancer via Inhibition of the Nrf2/HIF-1[Formula: see text] Pathway.

Radiotherapy plays a crucial role in the multimodal treatment of breast cancer. However, radioresistance poses a significant challenge to its effectiveness, hindering successful cancer therapy. Emerging evidence indicates that Nrf2 and HIF-1[Formula: see text] are critical regulators of cellular anti-oxidant responses and that their overexpression significantly promotes radioresistance. Wogonin (WG), the primary component isolated from Scutellaria baicalensis, exhibits potential antitumor and reversal of multidrug resistance activities. Nevertheless, the role of WG in radioresistance remains unclear. This study aims to explore the effects of WG on the radioresistance of breast cancer. Our results indicate that Nrf2 and HIF-1[Formula: see text] overexpression was observed in breast cancer tissues and was correlated with the histological grading of the disease. Radiation further increased the levels of Nrf2 and HIF-1[Formula: see text] in breast cancer cells. However, WG demonstrated the ability to induce cell apoptosis and reverse radioresistance by inhibiting the Nrf2/HIF-1[Formula: see text] pathway. These effects were also confirmed in xenograft mice models. Mechanistically, WG enhanced the level of the Nrf2 inhibitor Keap1 through reducing CpG methylation in the promoter region of the Keap1 gene. Consequently, the Nrf2/HIF-1[Formula: see text] pathway, along with the Nrf2- and HIF-1[Formula: see text]-dependent protective responses, were suppressed. Taken together, our findings demonstrate that WG can epigenetically regulate the Keap1 gene, inhibit the Nrf2/HIF-1[Formula: see text] pathway, induce apoptosis in breast cancer cells, and diminish acquired radioresistance. This study offers potential strategies to overcome the limitations of current radiotherapy for breast cancer.

Regulation of main ncRNAs by polyphenols: A novel anticancer therapeutic approach.

BACKGROUND: Plant polyphenols have shown promising applications in oncotherapy. Increasing evidence reveals that polyphenols possess the antitumor potential for multiple cancers. Non-coding RNAs (ncRNAs), mainly including small ncRNAs (microRNA) and long ncRNAs (lncRNAs), play critical roles in cancer initiation and progression. PURPOSE: To establish the modulation of ncRNAs by polyphenols as a novel and promising approach in anticancer treatment. STUDY DESIGN: The present research employed ncRNA, miRNA, lncRNA, and regulatory mechanism as keywords to retrieve the literature from PubMed, Web of Science, Science direct, and Google Scholar, in a 20-year period from 2003 to 2023. This study critically reviewed the current literature and presented the regulation of prominent ncRNAs by polyphenols. A comprehensive total of 169 papers were retrieved on polyphenols and their related ncRNAs in cancers. RESULTS: NcRNAs, mainly including miRNA and lncRNA, play critical roles in cancer initiation and progression, which are potential modulatory targets of bioactive polyphenols, such as resveratrol, genistein, curcumin, EGCG, quercetin, in cancer management. The mechanism involved in polyphenol-mediated ncRNA regulation includes epigenetic and transcriptional modification, and post-transcriptional processing. CONCLUSION: Regulatory ncRNAs are potential therapeutic targets of bioactive polyphenols, and these phytochemicals could modulate the level of these ncRNAs directly and indirectly. A better comprehension of the ncRNA regulation by polyphenols in cancers, their functional outcomes on tumor pathophysiology and regulatory molecular mechanisms, may be helpful to develop effective strategies to fight the devastating disease.

[Effect of guarana on lipid metabolism in obese rats: a study based on lipidomics].

This study investigated the effect of guarana on plasma lipid metabolites in obese rats and analyzed its mechanism in the treatment of dyslipidemia in obesity. High-fat diet was used to establish obese rat models, and the therapeutic effect of guarana on obese rats was evaluated by measuring body weight, white fat, liver weight, and lipid content, as well as observing liver histomorphology. Lipid metabolites in plasma of rats in each group were detected by UHPLC-Q-TOF-MS lipidomics. The protein expressions of fatty acid synthase, acetyl-CoA carboxylase 1, triglyceride synthesis enzyme, carnitine palmitoyltransferase Ⅰ, and acetyl-coenzyme A acyltransferase 2 in rat liver were detected using Western blot. The results revealed that guarana significantly reduced body weight, white fat, and liver weight of obese rats due to high-fat diet, and alleviated dyslipidemia and liver steatosis. Lipidomics showed that some triglycerides and phospholipids were significantly elevated in the high-fat model group, and part of them was reduced after guarana treatment. Western blot found that guarana inhibited the expression of hepatic fatty acid and triglyceride synthesis-related proteins and increased the expression of fatty acid ß-oxidation-related proteins. Abnormalities in triglyceride and phospholipid metabolism are the main characteristics of plasma lipid metabolism in obese rats induced by high-fat diet. Guarana may regulate partial triglyceride and phospholipid metabolism by inhibiting hepatic fatty acid and triglyceride synthesis and increasing fatty acid ß-oxidation, thereby improving rat obesity and dyslipidemia.

Preparation of thrombin-loaded calcium alginate microspheres with dual-mode imaging and study on their embolic properties in vivo.

Transcatheter arterial embolization (TAE) has played a huge role in the interventional treatment of organ bleeding and accidental bleeding. Choosing bio-embolization materials with good biocompatibility is an important part of TAE. In this work, we prepared a calcium alginate embolic microsphere using high-voltage electrostatic droplet technology. The microsphere simultaneously encapsulated silver sulfide quantum dots (Ag2S QDs) and barium sulfate (BaSO4), and fixed thrombin on its surface. Thrombin can achieve an embolic effect while stopping bleeding. The embolic microsphere has good near-infrared two-zone (NIR-II) imaging and X-ray imaging effects, and the luminous effect of NIR-II is better than that of X-rays. This breaks the limitations of traditional embolic microspheres that only have X-ray imaging. And the microspheres have good biocompatibility and blood compatibility. Preliminary application results show that the microspheres can achieve a good embolization effect in the ear arteries of New Zealand white rabbits, and can be used as an effective material for arterial embolization and hemostasis. This work realizes the clinical embolization application of NIR-II combined with X-ray multimodal imaging technology in biomedical imaging, achieving complementary advantages and excellent results, more suitable for studying biological changes and clinical applications.

San Huang Xiao Yan recipe modulates the HMGB1-mediated abnormal inflammatory microenvironment and ameliorates diabetic foot by activating the AMPK/Nrf2 signalling pathway.

BACKGROUND: Diabetic foot (DF) is one of the serious complications of diabetes and lacks of therapeutic drugs. Abnormal and chronic inflammation promoting foot infection and wound healing delay are the main pathogenesis of DF. The traditional prescription San Huang Xiao Yan Recipe (SHXY) has been used in the clinical treatment of DF for several decades as approved hospital experience prescription and showed remarkable therapeutic effect, but the mechanisms by which SHXY treats DF are still unclear. PURPOSE: Objectives of this study were to investigate SHXY anti-inflammatory effect on DF and explore the molecular mechanism for SHXY. METHODS: We detected the effects of SHXY on DF in C57 mouse and SD rat DF models. Animal blood glucose, weight and wound area were detected every week. Serum inflammatory factors were detected by ELISA. H&E and Masson's trichrome were used to observe tissue pathology. Single-cell sequencing data reanalysis revealed the role of M1 macrophages in DF. Venn analysis showed the co-target genes between DF M1 macrophages and compound-disease network pharmacology. Western blotting was used to explored target protein expression. Meanwhile, RAW264.7 cells were treated with drug-containing serum of SHXY to further unravel the roles of target proteins during high glucose-induced inflammation in vitro. The Nrf2 inhibitor ML385 was used on RAW 264.7 cells to further explore the relationship between Nrf2, AMPK and HMGB1. The main components of SHXY were analysed by HPLC. Finally, the treatment effect of SHXY on DF were detected on rat DF model. RESULTS: In vivo, SHXY can ameliorate inflammatory, accelerate wound healing and upregulate expression of Nrf2, AMPK and downregulate of HMGB1. Bioinformatic analysis showed that M1 macrophages were the main inflammatory cell population in DF. Moreover, the Nrf2 downstream proteins HO-1 and HMGB1 were potential DF therapeutic targets for SHXY. In vitro, we also found that SHXY increased AMPK and Nrf2 protein levels and downregulated HMGB1 expression in RAW264.7 cells. Inhibiting the expression of Nrf2 impaired the inhibition effect of SHXY on HMGB1. SHXY promoted Nrf2 translocation into the nucleus and increased the phosphorylation of Nrf2. SHXY also inhibited HMGB1 extracelluar release under high glucose. In rat DF models, SHXY also exhibited significant anti-inflammatory effect. CONCLUSION: The SHXY activated AMPK/Nrf2 pathway to suppress abnormal inflammation on DF via inhibiting HMGB1 expression. These findings provide novel insight into the mechanisms by which SHXY treats DF.

Rescue therapy for refractory Helicobacter pylori infection: current status and future concepts.

Helicobacter pylori infection is an important issue worldwide, and several guidelines have been published for clinicians to achieve successful eradication. However, there are still some patients who remain infected with H. pylori after treatment. Clinicians should identify the reasons that caused treatment failure and find strategies to manage them. We have searched and organized the literature and developed methods to overcome factors that contribute to prior treatment failure, such as poor compliance, inadequate intragastric acid suppression, and antibiotic resistance. To improve compliance, telemedicine or smartphone applications might play a role in the modern world by increasing doctor-patient relationships, while concomitant probiotics could be administered to reduce adverse effects and enhance adherence. For better acid suppression, high-potency and high-dose proton-pump inhibitors or potassium-competitive acid blockers have preferable efficacy. To overcome antibiotic resistance, susceptibility tests either by culture or by genotyping are the most commonly used methods and have been suggested for antibiotic selection before rescue therapy, but empirical therapy according to detailed medical history could be an alternative. Eradication with a longer treatment period (14 days) has a better outcome than shorter period (7 or 10 days). Ultimately, clinicians should select antibiotics based on the patient's history of drug allergy, previous antibiotic exposure, local antibiotic resistance, available medications, and cost. In addition, identifying patients with a high risk of cancer and shared decision-making are also essential for those who have experienced eradication failure.

Magnesium Ascorbyl Phosphate Promotes Bone Formation Via CaMKII Signaling.

Dysregulation of bone homeostasis is closely related to the pathogenesis of osteoporosis. Suppressing bone resorption by osteoclasts to attenuate bone loss has been widely investigated, but far less effort has been poured toward promoting bone formation by osteoblasts. Here, we aimed to explore magnesium ascorbyl phosphate (MAP), a hydrophilic and stable ascorbic acid derivative, as a potential treatment option for bone loss disorder by boosting osteoblastogenesis and bone formation. We found that MAP could promote the proliferation and osteoblastic differentiation of human skeletal stem and progenitor cells (SSPCs) in vitro. Moreover, MAP supplementation by gavage could alleviate bone loss and accelerate bone defect healing through promoting bone formation. Mechanistically, we identified calcium/calmodulin-dependent serine/threonine kinase IIα (CaMKIIα) as the target of MAP, which was found to be directly bound and activated by MAP, then with a concomitant activation in the phosphorylation of ERK1/2 (extracellular regulated kinase 1/2) and CREB (cAMP-response element binding protein) as well as an elevation of C-FOS expression. Further, blocking CaMKII signaling notably abolished these effects of MAP on SSPCs and bone remodeling. Taken together, our data indicated that MAP played an important role in enhancing bone formation through the activation of CaMKII/ERK1/2/CREB/C-FOS signaling pathway and may be used as a novel therapeutic option for bone loss disorders such as osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).

Effect of megarectum on postoperative defecation of female patients with congenital rectovestibular fistula or rectoperineal fistula.

Background: To assess the effect of megarectum on postoperative defecation of female patients with congenital rectovestibular fistula or rectoperineal fistula. Methods: From March 2013 to February 2021, 74 female patients with congenital rectovestibular fistula or rectoperineal fistula were treated. The age of patients ranged from 3 months to 1 year. Barium enema and spinal cord MRI were performed in all children. 4 patients were removed from the study because of spinal cord and sacral agenesis. Finally, 70 patients underwent one-stage anterior sagittal anorectoplasty (ASARP). Anal endoscopy and anorectal pressure measurement were performed 1 year after surgery. All patients were divided into two groups depending on the presence of megarectum (+) and (-) and observed for constipation and anal sphincter function. Results: 16 patients (4 months to 1 year) were complicated with megarectum, and 5 patients (3 months to 9 months) were without megarectum. The incision infection was seen in 3 patients. All patients were followed up for 1 year to 5 years. Fecal soiling was seen in 2 patients and constipation in 14 patients. Among 16 patients with megarectum, soiling was seen in 1 patient and the constipation in 12 patients. Among 54 patients without megarectum, soiling was seen in 1 patient and constipation in 2 patients. There was a significant difference in the incidence of postoperative constipation between the two groups (megarectum (+) 75% vs. megarectum (-) 3.7% (P < 0.05)). However, there was no significant difference in the score of anal sphincters between the two groups (P < 0.05). And there was no significant difference in anal resting pressure (P = 0.49) and length of anal high pressure area (P = 0.76). 7 patients with constipation and megarectum acquired normal anal function after the dilated rectum was resected. Conclusion: Megarectum increases the possibility of difficult postoperative defecation in the patients with congenital rectovestibular fistula or rectoperineal fistula. However, constipation was not associated with ASARP postoperative effects on sphincter function. Resection of megarectum is helpful to the improvement of constipation.

WRINKLED1 Positively Regulates Oil Biosynthesis in Carya cathayensis.

Hickory (Carya cathayensis Sarg.) is a kind of important woody oil tree species, and its nut has high nutritional value. Previous gene coexpression analysis showed that WRINKLED1 (WRI1) may be a core regulator during embryo oil accumulation in hickory. However, its specific regulatory mechanism on hickory oil biosynthesis has not been investigated. Herein, two hickory orthologs of WRI1 (CcWRI1A and CcWRI1B) containing two AP2 domains with AW-box binding sites and three intrinsically disordered regions (IDRs) but lacking the PEST motif in the C-terminus were characterized. They are nucleus-located and have self-activated ability. The expression of these two genes was tissue-specific and relatively high in the developing embryo. Notably, CcWRI1A and CcWRI1B can restore the low oil content, shrinkage phenotype, composition of fatty acid, and expression of oil biosynthesis pathway genes of Arabidopsis wri1-1 mutant seeds. Additionally, CcWRI1A/B were shown to modulate the expression of some fatty acid biosynthesis genes in the transient expression system of nonseed tissues. Transcriptional activation analysis further indicated that CcWRI1s directly activated the expression of SUCROSE SYNTHASE2 (SUS2), PYRUVATE KINASE ß SUBUNIT 1 (PKP-ß1), and BIOTIN CARBOXYL CARRIER PROTEIN2 (BCCP2) involved in oil biosynthesis. These results suggest that CcWRI1s can promote oil synthesis by upregulating some late glycolysis- and fatty acid biosynthesis-related genes. This work reveals the positive function of CcWRI1s in oil accumulation and provides a potential target for improving plant oil by bioengineering technology.

Priming effects of nZVI on carbon sequestration and iron uptake are positively mediated by AM fungus in semiarid agricultural soils.

We investigated the priming effect of nanoscale zero-valent iron (nZVI) on carbon sink and iron uptake, and the possible mediation by AMF (arbuscular mycorrhizal fungi, Funneliformis mosseae) in semiarid agricultural soils. Maize seed dressings comprised of three nZVI concentrations of 0, 1, 2 g·kg-1 and was tested with and without AMF inoculation under high and low soil moistures, respectively. The ICP-OES observations indicated that both low dose of nZVI (1 g·kg-1) and high dose of nZVI (2 g·kg-1) significantly increased the iron concentrations in roots (L: 54.5-109.8 %; H: 119.1-245.4 %) and shoots (L: 40.8-78.9 %; H: 81.1-99.4 %). Importantly, the absorption and translocation rate of iron were substantially improved by AMF inoculation under the low-dose nZVI. Yet, the excess nanoparticles as a stress were efficiently relieved by rhizosphere hyphae, and the iron concentration in leaves and stems can maintain as high as about 300 mg·kg-1 while the iron translocation efficiency was reduced. Moreover, next-generation sequencing confirmed that appropriate amount of nZVI clearly improved the rhizosphere colonization of Funneliformis mosseae (p < 0.001) and the development of soil fungal community. Soil observations further showed that the hyphae development and GRSP (glomalin-related soil protein) secretion were significantly promoted (p < 0.05), with the increased R0.25 (< 0.25 mm) by 35.97-41.16 %. As a return, AMF and host plant turned to input more organic matter into soils for microbial growth and Fe uptake, and such interactions became more pronounced under drought stress. In contrast, high dose of nZVI (2 g·kg-1) tended to agglomerate on the surface of hyphae and spores, causing severe deformation and inactivation of AMF symbionts. Therefore, the priming effects of nZVI on carbon sequestration and Fe uptake in agricultural soils were positively mediated by AMF via the feedback loop of the plant-soil-microbe system for enhanced adaptation to global climate change.

Arctiin-encapsulated DSPE-PEG bubble-like nanoparticles inhibit alveolar epithelial type 2 cell senescence to alleviate pulmonary fibrosis via the p38/p53/p21 pathway.

Background: Idiopathic pulmonary fibrosis is a severe and deadly form of diffuse parenchymal lung disease and treatment options are few. Alveolar epithelial type 2 (AEC2) cell senescence is implicated in the pathogenies of IPF. A major bioactive compound from the traditional Chinese medicine Fructus arctii, arctiin (ARC) has robust anti-inflammatory, anti-senescence, and anti-fibrosis functions. However, the potential therapeutic effects of ARC on IPF and the underlying mechanisms involved are still unknown. Methods: First of all, ARC was identified as an active ingredient by network pharmacology analysis and enrichment analysis of F. arctii in treating IPF. We developed ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) to increase ARC hydrophilicity and achieve high pulmonary delivery efficiency. C57BL/6 mice were used to establish a bleomycin (BLM)-induced pulmonary fibrosis model for assessing the treatment effect of ARC@DPBNPs on lung fibrosis and the anti-senescence properties of AEC2. Meanwhile, p38/p53 signaling in AEC2 was detected in IPF lungs, BLM-induced mice, and an A549 senescence model. The effects of ARC@DPBNPs on p38/p53/p21 were assessed in vivo and in vitro. Results: Pulmonary route of administration of ARC@DPBNPs protected mice against BLM-induced pulmonary fibrosis without causing significant damage to the heart, liver, spleen, or kidney. ARC@DPBNPs blocked BLM-induced AEC2 senescence in vivo and in vitro. The p38/p53/p21 signaling axis was significantly activated in the lung tissues of patients with IPF, senescent AEC2, and BLM-induced lung fibrosis. ARC@DPBNPs attenuated AEC2 senescence and pulmonary fibrosis by inhibiting the p38/p53/p21 pathway. Conclusion: Our data suggest that the p38/p53/p21 signaling axis plays a pivotal role in AEC2 senescence in pulmonary fibrosis. The p38/p53/p21 signaling axis inhibition by ARC@DPBNPs provides an innovative approach to treating pulmonary fibrosis in clinical settings.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center.

BACKGROUND: Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS: Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS: The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS: This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

Research on the Material Basis and Mechanism of Kudzu Root in Preventing and Treating Cerebral Ischemia based on Network Pharmacology.

BACKGROUND: It has been shown that Kudzu root has significant pharmacological effects such as improving microcirculation, dilating coronary arteries, and increasing cerebral and coronary blood flow, but its material basis and mechanism of action are not clear. OBJECTIVE: The aim of this study was to investigate the mechanism of action of Kudzu root in the prevention and treatment of cerebral ischemia (CI) through network pharmacology combined with animal experiments. METHODS: The components of kudzu root were screened by using the Chemistry Database, Chinese Academy of Science. Linpinski's five rules were used to perform pharmacophore-like analysis to obtain the active ingredients of Kudzu root. The Swiss Target Prediction Service database was used to predict the potential protein targets of kudzu root components associated with CI. An active ingredient-target network was constructed by using Cytoscape 3.6.0. A rat model of middle cerebral artery occlusion (MCAO) was established, then the main targets and signaling pathways predicted were verified by observing the area of cerebral infarction and Western blot experiments. RESULTS: In total, 84 major active compounds and 34 targets included gerberoside, belonging to the isoflavone class, gallic acid, amino acid class, 4-Methylphenol, phenolic class, and quercetin, and flavonoid class (Flavonoids). The targets covered were proteins related to excitatory amino acids and calcium overload, including Excitatory amino acid transporter 2 (SLC1A2), Glutamate receptor ionotropic, kainate 1 (GRIK1), Glutamate receptor ionotropic, NMDA 1 (GRIN1), Glutamate receptor 2(GRIA2), Calcium/calmodulin-dependent protein kinase II (CaMKII), Neuronal nitric oxide synthase(nNOS). Glutamatergic energy is prominent, and calcium transport across the membrane is central to the network and occupies an important position. CONCLUSION: Kudzu root can significantly reduce neurological damage in rats with CI, and also significantly reduce the rate of cerebral infarction. It is worth noting that Kudzu root can prevent and treat CI by reducing excitatory amino acid toxicity and improving calcium overload.