Microbiota metabolites in bone: Shaping health and Confronting disease.

The intricate interplay between the gut microbiota and bone health has become increasingly recognized as a fundamental determinant of skeletal well-being. Microbiota-derived metabolites play a crucial role in dynamic interaction, specifically in bone homeostasis. In this sense, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, indirectly promote bone formation by regulating insulin-like growth factor-1 (IGF-1). Trimethylamine N-oxide (TMAO) has been found to increase the expression of osteoblast genes, such as Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein-2 (BMP2), thus enhancing osteogenic differentiation and bone quality through BMP/SMADs and Wnt signaling pathways. Remarkably, in the context of bone infections, the role of microbiota metabolites in immune modulation and host defense mechanisms potentially affects susceptibility to infections such as osteomyelitis. Furthermore, ongoing research elucidates the precise mechanisms through which microbiota-derived metabolites influence bone cells, such as osteoblasts and osteoclasts. Understanding the multifaceted influence of microbiota metabolites on bone, from regulating homeostasis to modulating susceptibility to infections, has the potential to revolutionize our approach to bone health and disease management. This review offers a comprehensive exploration of this evolving field, providing a holistic perspective on the impact of microbiota metabolites on bone health and diseases.

Leaf nitrogen and phosphorus resorption efficiencies are related to drought resistance across woody species in a Chinese savanna.

Leaf nutrient resorption and drought resistance are crucial for the growth and survival of plants. However, our understanding of the relationships between leaf nutrient resorption and plant drought resistance is still limited. In this study, we investigated the nitrogen and phosphorus resorption efficiencies (NRE and PRE), leaf structural traits, leaf osmotic potential at full hydration (Ψosm), xylem water potential at 50% loss of xylem-specific hydraulic conductivity (P50) and seasonal minimum water potential (Ψmin) for 18 shrub and tree species in a semiarid savanna ecosystem, in Southwest China. Our results showed that NRE and PRE exhibited trade-off against drought resistance traits (Ψosm and P50) across woody species. Moreover, this relationship was modulated by leaf structural investment. Species with low structural investment (e.g., leaf mass per area, leaf dry mass content and leaf construction cost [LCC]) tend to have high NRE and PRE, while those with high LCCs show high drought resistance, showing more negative Ψosm and P50.These results indicate that species with a lower leaf structural investment may have a greater need to recycle their nutrients, thus exhibiting higher nutrient resorption efficiencies, and vice versa. In conclusion, nutrient resorption efficiency may be a crucial adaptation strategy for coexisting plants in semiarid ecosystems, highlighting the importance of understanding the complex relationships between nutrient cycling and plant survival strategies.

Prognostic role of body composition in peritoneal carcinomatosis patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Bioelectric impedance analysis (BIA)-measured body composition and nutritional status have been used as prognostic indicators in various cancer cohorts. This study investigated whether BIA could provide information on prognosis in peritoneal carcinomatosis patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We retrospectively analyzed the data of 99 patients with preoperative BIA data among those who underwent CRS and HIPEC. The association between BIA-derived parameters and intraoperative peritoneal cancer index (PCI) score was assessed. Predictive analysis for the occurrence of postoperative morbidities including major complications (Clavien-Dindo classification 3-4) and re-admission within 30 days after surgery as well as 1 year mortality was also performed. RESULTS: BIA-derived mineral (r = 0.224, p = 0.027), fat (r = - 0.202, p = 0.048), and total body water (TBW)/fat-free mass (FFM) (r = - 0.280, p = 0.005) showed significant associations with intraoperative PCI score. Lower TBW/FFM was an independent predictor of major postoperative complications (OR 0.047, 95% CI 0.003-0.749, p = 0.031) and re-admission (OR 0.094, 95% CI 0.014-0.657, p = 0.017) within 30 days after surgery. Higher fat mass was also independently associated with a higher risk of major postoperative complications (OR 1.120, 95% CI 1.006-1.248, p = 0.039) and re-admission (OR 1.123, 95% CI 1.024-1.230, p = 0.013). Intraoperative PCI score > 20 (OR 4.489, 95% CI 1.191-16.917, p = 0.027) and re-admission within 30 days after surgery (OR 5.269, 95% CI 1.288-21.547, p = 0.021) independently predicted postoperative 1-year mortality. CONCLUSIONS: We demonstrate that preoperative BIA-derived TBW/FFM and fat mass were significantly correlated with metastatic extent, assessed by PCI score, in patients with peritoneal carcinomatosis. In addition, BIA-derived TBW/FFM and fat mass showed independent predictability for postoperative 30-day major complications and re-admission in patients undergoing CRS and HIPEC. Our findings suggest that assessment of BIA may improve discrete risk stratification in patients who are planned to receive CRS and HIPEC.

A new insight on copper: Promotion of collagen synthesis and myofiber growth and development in juvenile grass carp (Ctenopharyngodon idella).

Copper (Cu) is a trace element, essential for fish growth. In the current study, in addition to growth performance, we first explored the effects of Cu on collagen synthesis and myofiber growth and development in juvenile grass carp (Ctenopharyngodon idella). A total of 1080 fish (11.16 ± 0.01 g) were randomly divided into 6 treatments (3 replicates per treatment) to receive five doses of organic Cu, which were Cu citrate (CuCit) at 0.99 (basal diet), 2.19, 4.06, 6.15, and 8.07 mg/kg, and one dose of inorganic Cu (CuSO4·5H2O at 3.15 mg/kg), for 9 weeks. The results showed appropriate Cu level (4.06 mg/kg) enhanced growth performance, improved nutritional Cu status, and downregulated Cu-transporting ATPase 1 mRNA levels in the hepatopancreas, intestine, and muscle of juvenile grass carp. Meanwhile, collagen content in fish muscle was increased after Cu intake, which was probably due to the following pathways: (1) activating CTGF/TGF-ß1/Smads signaling pathway to regulate collagen transcription; (2) upregulating of La ribonucleoprotein domain family 6 (LARP6) mRNA levels to regulate translation initiation; (3) increasing proline hydroxylase, lysine hydroxylase, and lysine oxidase activities to regulate posttranslational modifications. In addition, optimal Cu group increased myofiber diameters and the frequency of myofibers with diameter >50 µm, which might be associated with upregulation of cyclin B, cyclin D, cyclin E, proliferating cell nuclear antigen, myogenic determining factor (MyoD), myogenic factor 5, myogenin (MyoG), myogenic regulatory factor 4 and myosin heavy chain (MyHC) and downregulation of myostatin mRNA levels, increasing protein levels of MyoD, MyoG and MyHC in fish muscle. Finally, based on percentage weight gain (PWG), serum ceruloplasmin (Cp) activity and collagen content in fish muscle, Cu requirements were determined as 4.74, 4.37 and 4.62 mg/kg diet (CuCit as Cu source) of juvenile grass carp, respectively. Based on PWG and Cp activity, compared to CuSO4·5H2O, the efficacy of CuCit were 131.80% and 115.38%, respectively. Our findings provide new insights into Cu supplementation to promote muscle growth in fish, and help improve the overall productivity of aquaculture.

Effects of Different Dietary Selenium Sources on the Meat Quality and Antioxidant Capacity of Yellow Catfish (Pelteobagrus fulvidraco).

To assess the effect of dietary selenium (Se) sources on the meat quality and antioxidant capacity of yellow catfish (Pelteobagrus fulvidraco), sodium selenite (Na2SeO3), Se yeast, and selenium-enriched Spirulina platensis (Se-SP) were supplemented in the control diet at 0.30 mg Se/kg feed to formulate four diets. The experimental period lasted 50 days. The results showed that Se levels in the plasma, liver, muscle, and whole body were significantly increased by dietary Se yeast supplementation (P < 0.05) but showed no change in response to Na2SeO3 (P > 0.05). The three types of Se all increased the firmness and decreased the fracturability of the muscles (P < 0.05), but only Na2SeO3 resulted in higher springiness, flexibility, stringiness, and stickiness (P < 0.05). In addition, the muscle n-3 polyunsaturated fatty acid (PUFA) content was increased by Se yeast (P < 0.05). Regarding antioxidant capacity, dietary Se yeast and Se-SP supplementation improved hepatic glutathione peroxidase activity but decreased hepatic malondialdehyde content (P < 0.05). Given these results, Se yeast was found to be the optimal source of Se for yellow catfish for higher tissue retention, antioxidant capacity, and PUFA levels. Dietary Se is an effective way to regulate the meat quality and antioxidant capacity of yellow catfish.

Tiaogan Jiejiu Tongluo Formula attenuated alcohol-induced chronic liver injury by regulating lipid metabolism in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiaogan Jiejiu Tongluo Formula (TJTF), a traditional Chinese medicine formula, is modified from the well-known ancient prescription Danzhi-Xiaoyao Powder (DXP). Owing to its ability to regulate liver, strengthen spleen, detoxicating, and dredge collaterals in Chinese medicine, TJTF is usually used to treat anxiety, hypertension, alcoholic fatty liver disease in clinical application. However, the protective effect and potential molecular mechanism of TJTF on alcoholic liver injury has not fully been clarified. AIM OF THE STUDY: To explore the effect of TJTF on chronic alcoholic liver injury and figure out whether its effects were due to the regulation of lipid metabolism. MATERIAL AND METHODS: 75 male SD rats were divided into the following five groups, control group, EtOH group, TJTF high dose group, TJTF low dose group and silybin group. Then a chronic alcoholic liver injury model was established by increasing concentration of 56% ethanol in rats. The rats in each TJTF group were given the corresponding dose of TJTF, the rats in the silybin group were given silybin, the rats in the control group and the EtOH group were given distilled water by gavage, once a day for 8 consecutive weeks. The components of TJTF were analyzed by UPLC-Q-TOF-MS. Hematoxylin and Eosin (H&E) was used to assess the severity of liver injury. in the pathological examination. Periodic acid-Schiff (PAS) and oil red O staining were used to evaluate the degree of the liver glycogen accumulation and lipid deposition, respectively. The serum ALT, AST, T-CHO, TG, LDL-C, ADH, HDL-C, and ALDH levels as well as liver tissue GSH, MDA, and SOD levels were analyzed in rats. Immunohistochemistry and western blotting were used to detect lipid metabolism-related proteins expressed in rat liver. RESULTS: TJTF significantly alleviated the chronic liver injury caused by alcohol in rats, and enhanced liver function. TJTF significantly decreased AST, ALT, ADH levels and increased ALDH level of serum, and increased GSH, SOD levels and decreased MDA level of liver tissue. In addition, TJTF significantly decreased the serum T-CHO, TG and LDL-C levels and increased HDL-C level in chronic alcoholic liver injury rats by regulating the expression of lipid metabolism associated proteins including p-LKB1, p-AMPKα, p-ACC, FAS, HMGCR, SREBP-1c, PPARα and CPT-1A. The results of western blot and immunohistochemical staining confirmed that TJTF can inhibit lipid production and promote fatty acid oxidation in the liver tissue of chronic alcoholic liver injury rats by activating the LKB1-AMPKα axis and then downregulating the protein expressions of p-ACC, FAS, HMGCR and SREBP-1c, as well as promoting the protein expressions of PPARα and CPT-1A. Meanwhile, TJTF also increased the glycogen content of liver and alleviated the liver damage. CONCLUSION: According to current research, TJTF is effective in treating chronic liver damage induced by alcohol in rats. Additionally, TJTF exhibits the protective benefits by modulating LKB1-AMPKα signal axis, which in turn inhibits the synthesis of lipids and promotes the oxidation of fatty acids.

Dietary yeast glycoprotein supplementation improves the growth performance, intestinal health and disease resistance of largemouth bass (Micropterus salmoides) fed low-fishmeal diets.

The active ingredients extracted from yeast are important for regulating animal health. The aim of the current research was to explore the impacts of dietary yeast glycoprotein (YG) on the growth performance, intestinal morphology, antioxidant capacity, immunity and disease resistance of largemouth bass (Micropterus salmoides). A total of 375 juvenile fish (6.00 ± 0.03 g) were allocated into 15 fiberglass tanks. Triplicate tanks were assigned to each diet. The dietary YG inclusion was as follows: the first group was given a high fishmeal diet (40% fishmeal, 0% YG) (FM) and the second group was given a low fishmeal diet (30% fishmeal and 15% soybean meal, 0% YG) (LFM). The fish in the third, fourth and fifth groups were fed the LFM diet supplemented with 0.5% (LFM+YG0.5), 1.0% (LFM+YG1.0) and 2.0% (LFM+YG2.0) YG, respectively. After a 60- day feeding trial, a challenge test using A. hydrophila was carried out. The results showed that the final body weight (FBW) and weight gain rate (WGR) in the LFM+YG2.0 group were significantly higher than those in the LFM group and were no significantly different from those in the FM group. This may be partially related to the activation of the target of rapamycin (TOR) signaling pathway. Dietary YG supplementation enhanced intestinal physical barriers by upregulating the intestinal tight junction protein related genes (claudin1, occludin and zo2) and improving the structural integrity of the gut, which may be partially associated with AMPK signaling pathway. Moreover, dietary YG increased the antioxidant capacity in the gut, upregulated intestinal anti-inflammatory factors (il-10, il1-1ß and tgf-ß) and downregulated proinflammatory factors (il-1ß and il-8), which may be partially related to the Nrf2/Keap1 signaling pathways. The results of the challenge test indicated that dietary supplementation with 0.5 or 1.0% YG can increase the disease tolerance of largemouth bass against A. hydrophila. In conclusion, the present results indicated that dietary supplementation with YG promotes the growth performance, intestinal immunity, physical barriers and antioxidant capacity of largemouth bass. In addition, 1.0% of dietary YG is recommended for largemouth bass based on the present results.

Effects of Curcumin on Oxidative Stress and Ferroptosis in Acute Ammonia Stress-Induced Liver Injury in Gibel Carp (Carassius gibelio).

This study investigated the potential role of curcumin (CUR) in preventing oxidative stress and ferroptosis induced by ammonia exposure in gibel carp. Experimental fish (initial weight: 11.22 ± 0.10 g, n = 150) were fed diets supplemented with or without 0.5% CUR for 56 days, followed by a 24 h ammonia (32.5 mg/L) exposure. Liver damages (aspartate aminotransferase (AST), alanine aminotransferase (ALT), adenosine deaminase (ADA), and alkaline phosphatase (ALP)) and oxidative stress enzyme activities (reactive oxygen species (ROS), malondialdehyde (MDA); and the content of antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GPx)) were induced by ammonia stress. The antioxidant capacity was decreased, as indicated by inhibited gene expression of nuclear factor erythroid 2-related factor 2 (nrf2), heme oxygenase-1 (ho-1), catalase (cat), and sod. Ferroptosis was induced by ammonia stress, as suggested by upregulated mRNA levels of nuclear receptor coactivator 4 (ncoa4), transferrin receptor 1 (tfr1), and iron-responsive element-binding protein 2 (ireb2), and downregulated expression of glutathione peroxidase 4 (gpx4), ferroportin (fpn), and ferritin heavy chain 1 (fth1). In addition, both mRNA and protein levels of ferroptosis markers acyl-CoA synthetase long-chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (PTGS2) were upregulated, while cystine/glutamate antiporter (SLC7A11) was downregulated. However, liver injury and ferroptosis in fish induced by ammonia could be attenuated by CUR. Collectively, these findings demonstrate that CUR ameliorates oxidative stress and attenuates ammonia stress-induced ferroptosis. This study provides a new perspective on potential preventive strategies against ammonia stress in gibel carp by dietary CUR.

Monolithic integration of embedded III-V lasers on SOI.

Silicon photonic integration has gained great success in many application fields owing to the excellent optical device properties and complementary metal-oxide semiconductor (CMOS) compatibility. Realizing monolithic integration of III-V lasers and silicon photonic components on single silicon wafer is recognized as a long-standing obstacle for ultra-dense photonic integration, which can provide considerable economical, energy-efficient and foundry-scalable on-chip light sources, that has not been reported yet. Here, we demonstrate embedded InAs/GaAs quantum dot (QD) lasers directly grown on trenched silicon-on-insulator (SOI) substrate, enabling monolithic integration with butt-coupled silicon waveguides. By utilizing the patterned grating structures inside pre-defined SOI trenches and unique epitaxial method via hybrid molecular beam epitaxy (MBE), high-performance embedded InAs QD lasers with monolithically out-coupled silicon waveguide are achieved on such template. By resolving the epitaxy and fabrication challenges in such monolithic integrated architecture, embedded III-V lasers on SOI with continuous-wave lasing up to 85 °C are obtained. The maximum output power of 6.8 mW can be measured from the end tip of the butt-coupled silicon waveguides, with estimated coupling efficiency of approximately -6.7 dB. The results presented here provide a scalable and low-cost epitaxial method for the realization of on-chip light sources directly coupling to the silicon photonic components for future high-density photonic integration.

[Progression and reflection on the mechanism study of acupuncture and moxibustion in treatment of Crohn's disease].

Crohn's disease (CD) is a common chronic non-specific gastrointestinal inflammatory disease. Studies showed that acupuncture-moxibustion (A&M) can effectively relieve the symptoms of CD and its clinical efficacy has been confirmed in patients. In this paper, by reviewing the relevant articles for the mechanism studies on CD treated with A&M in recent years, it is discovered that the effect mechanism of A&M on CD includes two aspects, i.e. the local regulation inside the intestines and the neuromodulation outside intestines. The former one refers to the regulation of intestinal microflora, intestinal epithelial cell function and the regulation of intestinal local immune cells. The latter points to the modulation of brain function effect and the modulation of "brain-gut axis" related neurotransmitters. This paper also introduces the differences in intervention modes and acupoint selection between clinical trial and animal experiment, the suggestions on elucidating the nerve-immunity mechanism for CD treatment with A&M in view of "brain-gut axis" system, and its prospects. It is anticipated that this review may be conductive to the effect mechanism research of A&M for CD so that the evidences may be provided for optimizing the clinical regimen of A&M in treatment of this disease.

Calcium Phosphate Silicate Microspheres with Soybean Lecithin as a Sustained-Release Bone Morphogenetic Protein-Delivery System for Bone Tissue Regeneration.

Bone morphogenetic protein (BMP) is a growth factor that effectively promotes osteogenesis. Microsphere-based drug-delivery systems can facilitate an increase in the local concentration of BMP, thus promoting bone formation. In this study, calcium phosphate silicate (CPS) microspheres were used as drug-loading systems for BMP. Three groups─CPS, CPS + BMP, and CPS + BMP + soy lecithin (SL)─were set up, where SL was used to prolong the osteogenic effect of the microsphere system. Bone marrow mesenchymal stem cells and femoral defects in rats were used to compare the osteogenic ability of the three groups. The results indicated that CPS microspheres were good carriers of BMP, facilitating a smoother release into the cells and tissues. SL loading improved the loading rate of BMP, which promoted the osteogenic effect of the microspheres with BMP. We propose CPS microspheres as potential drug-delivery systems that can be effectively used in the treatment of bone defects.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor.

OBJECTIVE: This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR). METHODS: Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway. RESULTS: Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon. CONCLUSION: Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC-MS/MS method: In vitro, in situ, and in vivo evaluations.

Alizarin (1,2-dihydroxyanthraquinone) is an anthraquinone reddish dye widely used for painting and textile dyeing. As the biological activity of alizarin has recently attracted increasing attention from researchers, its therapeutic potential as complementary and alternative medicine is of interest. However, no systematic research has been conducted on the biopharmaceutical and pharmacokinetic aspects of alizarin. Therefore, this study aimed to comprehensively investigate the oral absorption and intestinal/hepatic metabolism of alizarin using a simple and sensitive tandem mass spectrometry method developed and validated in-house. The present method for the bioanalysis of alizarin has merits, including a simple pretreatment procedure, small sample volume, and adequate sensitivity. Alizarin exhibited pH-dependent moderate lipophilicity and low solubility with limited intestinal luminal stability. Based on the in vivo pharmacokinetic data, the hepatic extraction ratio of alizarin was estimated to be 0.165-0.264, classified as a low level of hepatic extraction. In an in situ loop study, considerable fractions (28.2%-56.4%) of the alizarin dose were significantly absorbed in gut segments from the duodenum to ileum, suggesting that alizarin may be classified as the Biopharmaceutical Classification System class II. An in vitro metabolism study using rat and human hepatic S9 fractions revealed that glucuronidation and sulfation, but not NADPH-mediated phase I reactions and methylation, are significantly involved in the hepatic metabolism of alizarin. Taken together, it can be estimated that the fractions of oral alizarin dose unabsorbed from the gut lumen and eliminated by the gut and liver before reaching the systemic circulation are 43.6%-76.7%, 0.474%-36.3%, and 3.77%-5.31% of the dose, respectively, resulting in a low oral bioavailability of 16.8%. Therefore, the oral bioavailability of alizarin depends primarily on its chemical degradation in the gut lumen and secondarily on first-pass metabolism.

Osthole: A potential AMPK agonist that inhibits NLRP3 inflammasome activation by regulating mitochondrial homeostasis for combating rheumatoid arthritis.

BACKGROUND: Osthole (OST), a characteristic coumarin compound in Angelicae pubescentis radix (APR), has shown potent efficacy in the treatment of rheumatoid arthritis (RA), but its specific targets and potential mechanism are limited. PURPOSE: This study aimed to explore the potential targets and molecular mechanisms of OST against RA using computer-assisted techniques in combination with RA fibroblast-like synoviocytes (FLS) inflammation model and CIA rat model. METHODS: Network pharmacology and molecular docking were applied to initially predict the potential targets of OST for the treatment of RA. Thereafter, TNFα was used to stimulate FLS to build an in vitro model of inflammation, combined with RNA-seq technology and molecular biology such as qPCR to investigate the anti-inflammatory effects and related mechanisms of OST. Finally, the anti-RA effect of OST was demonstrated by establishing a CIA rat model. RESULTS: The network model results showed that the anti-RA effect of OST was mainly related to its anti-inflammatory effect, and AMPK was identified as a potential target for the potency of OST. In the TNFα-induced FLS cells, OST inhibited the secretion of FLS inflammatory factors, which was attributed to the ability of OST to activate AMPK to inhibit the activation of the NLRP3 inflammasome. Further, it was observed that the activation of AMPK by OST facilitated mitochondrial biogenesis, and corrected abnormal mitochondrial dynamics in FLS, which was favoured to the restoration of mitochondrial homeostasis, and further promoted the occurrence of apoptosis and the decrease of ROS in FLS. Consistent with in vivo studies, administration of OST significantly improved joint deformity and toe erythema, reduced arthritis index scores and inhibited synovial inflammation in CIA rats. CONCLUSION: Our study proposed for the first time that AMPK, served as a potential target of OST, positively participated in the anti-RA therapeutic effect of OST. By regulating mitochondrial homeostasis and function, OST can effectively inhibit the activation of inflammasome and the secretion of inflammatory factors in vitro and in vivo, and finally achieve beneficial effects in the treatment of RA, which provides support and greater possibility to make further efforts on pharmacological research and clinical application of OST.

Acupuncture for Fibromyalgia: A Review Based on Multidimensional Evidence.

Fibromyalgia (FM) is a complicated syndrome characterized by widespread chronic pain, fatigue, sleep disturbances, cognitive dysfunction, and other complications. There is currently no specific treatment available. No comprehensive surveys have been published to summarize the mechanism of acupuncture in FM management. Although several studies have shown that acupuncture can benefit FM patients, their clinical findings are inconsistent. Here, we summarize the operation method of acupuncture for FM. For the first time, we conducted a comprehensive review of the mechanisms of acupuncture for FM, and integrated evidence-based scientific findings with the most comprehensive and updated literature. According to studies conducted using FM patients and animal models, acupuncture may improve symptoms in FM patients by regulating the afferent pain pathway and descending inhibitory pain pathways of various molecules, such as ASIC3, Nav1.7, Nav1.8, and TRPV1, as well as peripheral inflammation and the autonomic nervous system. Furthermore, we discussed the epidemiology, pathophysiology, diagnosis, and management of FM, and reviewed acupuncture-related clinical studies. This review fills a previously unknown gap in knowledge of the mechanism of acupuncture for FM. Although there is growing evidence that acupuncture may be a promising therapy for treating symptoms in FM patients, further investigation is needed.

Benefits of ozone on mortality in patients with COVID-19: A systematic review and meta-analysis.

BACKGROUND: The Coronavirus disease-2019 (COVID-19) pandemic continues, and the death toll continues to surge. Ozone therapy has long been used in the treatment of a variety of infectious diseases, probably through its antioxidant properties and the supply of oxygen to hypoxic tissues. This systematic review and meta-analysis aimed to determine the efficacy of ozone on mortality in patients with COVID-19. METHODS: A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Prospective controlled trials on treatment of COVID-19 with ozone, compared with placebo or blank, were reviewed. Studies were pooled to risk ratios (RRs) and weighted mean differences (WMDs), with 95% confidence intervals (CIs). RESULTS: Eight trials (enrolling 371 participants) met the inclusion criteria. Ozone therapy showed significant effects on mortality (RR 0.38, 95% CI 0.17-0.85; P = 0.02), length of hospital stay (WMD -1.63 days, 95% CI -3.05 to -0.22 days; P = 0.02), and polymerase chain reaction (PCR) positivity (RR 0.07, 95% CI 0.01-0.34; P = 0.001). CONCLUSIONS: Ozone therapy significantly reduced mortality, PCR positivity, and length of stay in hospitalized patients with COVID-19. Ozone therapy should be considered for COVID-19 patients.

Isolation and Bioinspired Total Synthesis of Rugosiformisin A, A Skeleton-Rearranged Abietane-Type Diterpenoid from Isodon rugosiformis.

Rugosiformisin A, a skeleton-rearranged abietane-type diterpenoid with a spiro[4.5]decane motif, was isolated from Isodon rugosiformis. Its structure was unambiguously established via NMR spectroscopic analysis and single-crystal X-ray diffraction. A bioinspired asymmetric synthesis of rugosiformisin A was achieved in 15 steps with 2.7% overall yield. The synthesis features an iridium-catalyzed asymmetric polyene cyclization and a semipinacol rearrangement.

Prototype-based Domain Generalization Framework for Subject-Independent Brain-Computer Interfaces.

Brain-computer interface (BCI) is challenging to use in practice due to the inter/intra-subject variability of electroencephalography (EEG). The BCI system, in general, necessitates a calibration technique to obtain subject/session-specific data in order to tune the model each time the system is utilized. This issue is acknowledged as a key hindrance to BCI, and a new strategy based on domain generalization has recently evolved to address it. In light of this, we've concentrated on developing an EEG classification framework that can be applied directly to data from unknown domains (i.e. subjects), using only data acquired from separate subjects previously. For this purpose, in this paper, we proposed a framework that employs the open-set recognition technique as an auxiliary task to learn subject-specific style features from the source dataset while helping the shared feature extractor with mapping the features of the unseen target dataset as a new unseen domain. Our aim is to impose cross-instance style in-variance in the same domain and reduce the open space risk on the potential unseen subject in order to improve the generalization ability of the shared feature extractor. Our experiments showed that using the domain information as an auxiliary network increases the generalization performance. Clinical relevance-This study suggests a strategy to improve the performance of the subject-independent BCI systems. Our framework can help to reduce the need for further calibration and can be utilized for a range of mental state monitoring tasks (e.g. neurofeedback, identification of epileptic seizures, and sleep disorders).

Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Taurine Alleviates Cadmium-Induced Toxicity via Genetically Specific Strategies in Two Strains of Gibel Carp (Carassius gibelio).

Our previous studies in gibel carp (Carassius gibelio) have shown that cadmium (Cd) exposure elicits deleterious effects depending on the genetic background, and thus we hypothesized that mitigation via nutritional intervention may vary between strains. Therefore, two gibel carp strains (the A and F strains) were fed diets supplemented with 0% or 1% taurine for 8 weeks prior to 96 h Cd exposure, and the responses of antioxidant pathways, endoplasmic reticulum (ER) stress, autophagy, and apoptosis were investigated. The results showed that taurine supplementation had no effect on the growth performance of gibel carp. After Cd exposure, histological damage to mitochondria and ER, induction of oxidative stress and antioxidant responses, occurrence of ER stress, and apoptotic signals were observed in the livers. Upon the diet effects, taurine supplementation alleviated the ER-stress-induced autophagy and apoptosis after Cd exposure and stimulated antioxidant pathways. Regarding the difference between strains, taurine played a protective role in alleviating Cd toxicity through the antioxidant response, ER stress, and autophagy in the F strain, whereas such effects were achieved by the attenuation of apoptosis in the A strain. Taken together, our results demonstrate the potential use of taurine in the mitigation of heavy metal toxicity in aquatic organisms.