Loureirin A is a narrow-spectrum antimicrobial agent against Helicobacter pylori.

Currently, Helicobacter pylori eradication by antibiotic therapy faces various challenges, including antibiotic resistance, side effects on intestinal commensal bacteria, and patient compliance. In this study, loureirin A (LrA), a traditional Chinese medicine monomer extracted from Sanguis Draconis flavones, was found to possess specific antibacterial activity against H. pylori without the bacteria displaying a tendency to develop resistance in vitro. LrA demonstrated a synergistic or additive effect when combined with omeprazole (a proton pump inhibitor) against H. pylori. The combination of LrA and omeprazole showed promising anti-H. pylori potential, exhibiting notable in vivo efficacy comparable to standard triple therapy in mouse models infected with both drug-sensitive and drug-resistant H. pylori strains. Moreover, the narrow-spectrum antibacterial profile of LrA is reflected in its minimal effect on the diversity and composition of the mouse gut microbiota. The underlying mechanism of action of LrA against H. pylori involves the generation of bactericidal levels of reactive oxygen species, resulting in apoptosis-like cell death. These findings indicate that LrA is a promising lead compound targeting H. pylori without harming the commensal bacteria.

Initial diet shapes resistance-gene composition and fecal microbiome dynamics in young ruminants during nursing.

This study was conducted to examine how colostrum pasteurization affects resistance genes and microbial communities in calf feces. Forty female Holstein calves were randomly assigned to either the control (CON) group, which received unheated colostrum, or the pasteurized colostrum (PAT) group. The calves body weight was measured weekly before morning feeding. Calf starter intake were measured and recorded daily before morning feeding. Samples of colostrum were collected before feeding. Blood was collected on d 1 and 70 before morning feeding. Ten calves were randomly selected from each group (n = 20 calves total) for fecal sampling on d 3, 28, 56 and 70 for subsequent DNA extraction and metagenomic sequencing. Total bacterial counts in the colostrum were markedly higher in the CON group than in the PAT group. Pasteurized colostrum administration substantially reduced the ARO diversity and diminishes the abundance of Enterobacteriaceae, thereby decreasing their contribution to resistance genes. Pasteurization also reduced glucoside hydrolase-66 activity in 3-day-old calves which led to an increase in the activity of aminoglycoside antibiotics, resulting in 52.63 % of PAT-enriched bacteria acquiring aminoglycoside resistance genes. However, from the perspective of overall microbial community, the proportion of aminoglycoside, beta-lactam and tetracycline resistance genes carried by microbial community in PAT group was lower than CON group (P < 0.05). Fecal samples from the PAT group contained greater abundances of Subdoligranulum (P < 0.05) and Lachnospiraceae_NK4A136_group (P < 0.05) on days 28 and 70 compared to CON. Network analysis and abundance variations of the different bacteria obtained by linear discriminant analysis effect size analysis showed that pasteurized colostrum feeding reduced the interactions among related bacteria and maintained stability of the hind-gut microbiome. In conclusion, these findings underscore the intricate interactions between early diet, calf resistance-gene transmission and microbial dynamics, which should be carefully considered in calf-rearing practices.

Green Synthesis of Narrow-Size Silver Nanoparticles Using Ginkgo biloba Leaves: Condition Optimization, Characterization, and Antibacterial and Cytotoxic Activities.

Natural products derived from medicinal plants offer convenience and therapeutic potential and have inspired the development of antimicrobial agents. Thus, it is worth exploring the combination of nanotechnology and natural products. In this study, silver nanoparticles (AgNPs) were synthesized from the leaf extract of Ginkgo biloba (Gb), having abundant flavonoid compounds. The reaction conditions and the colloidal stability were assessed using ultraviolet-visible spectroscopy. X-ray diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy (FTIR) were used to characterize the AgNPs. AgNPs exhibited a spherical morphology, uniform dispersion, and diameter ranging from ~8 to 9 nm. The FTIR data indicated that phytoconstituents, such as polyphenols, flavonoids, and terpenoids, could potentially serve as reducing and capping agents. The antibacterial activity of the synthesized AgNPs was assessed using broth dilution and agar well diffusion assays. The results demonstrate antibacterial effects against both Gram-positive and Gram-negative strains at low AgNP concentrations. The cytotoxicity of AgNPs was examined in vitro using the CCK-8 method, which showed that low concentrations of AgNPs are noncytotoxic to normal cells and promote cell growth. In conclusion, an environmentally friendly approach for synthesizing AgNPs from Gb leaves yielded antibacterial AgNPs with minimal toxicity, holding promise for future applications in the field of biomedicine.

A study on the anti-osteoporosis mechanism of isopsoralen based on network pharmacology and molecular experiments.

OBJECTIVE: Osteoporosis (OP) is a disease caused by multiple factors. Studies have pointed out that isopsoralen (IPRN) is one of the most effective drugs for the treatment of OP. Based on network pharmacological and molecular experimental analysis, the molecular mechanism of IPRN in osteoporosis is clarified. METHODS: IPRN target genes and OP-related genes were predicted from the databases. Intersections were obtained and visualized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on target genes, which was confirmed by experiments internal and external experiments. Molecular docking was used to verify the binding between IPRN and target proteins. Molecular dynamics (MD) simulates the binding affinity of protein targets and active compounds. RESULTS: 87 IPRN target genes and 242 disease-related targets were predicted. The protein-protein interaction (PPI) network identified 18 IPRN target proteins for the treatment of OP. GO analysis indicated that target genes were involved in biological processes. KEGG analysis showed that pathways such as PI3K/AKT/mTOR were associated with OP. Cell experiments (qPCR and WB) found that the expressions of PI3K, AKT, and mTOR in MC3T3-E1 cells at 10 µM, 20 µM, and 50 µM IPRN concentrations, especially at 20 µM IPRN treatment, were higher than those in the control group at 48 h. Animal experiments also showed that compared with the control group, 40 mg/kg/time IPRN could promote the expression of the PI3K gene in chondrocytes of SD rats. CONCLUSIONS: This study predicted the target genes of IPRN in the treatment of OP and preliminarily verified that IPRN plays an anti-OP role through the PI3K/AKT/mTOR pathway, which provides a new drug for the treatment of OP.

Paraffin-embedded Sample Test Promotes the Diagnosis of Tuberculous Pleurisy.

Context: Tuberculous pleurisy (TP) is the most common manifestation of extrapulmonary tuberculosis and the most frequent cause of pleural effusion (PE). Clinicians make a definitive diagnosis of TP based on the isolation of the mycobacterium tuberculosis (MTB) from PE or a pleural biopsy. Since the currently available tests for TP all have limitations in making a definitive diagnosis, clinicians urgently need new diagnostic tests. Objective: The study intended to compare the value in clinically diagnosing TP of the paraffin-embedded sample test (PEST), using pleural-effusion samples; an adenosine deaminase assay (ADA) using pleural fluid; and the T cell enzyme-linked immunospot test (T-SPOT), using peripheral-blood. Design: The research team performed a retrospective observational study. Setting: The study took place at the Sir Run Run Hospital, Nanjing Medical University in Nanjing, Jiangsu, China. Participants: Participants were 37 patients with suspected TP who had been admitted to the hospital between September 2018 and December 2022. Outcome Measures: The research team assessed the diagnostic performance of PEST, ADA, and T-SPOT in the TP group, calculating the positive rate, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the tests. Results: Among the 37 participants, the testing confirmed that 24 had TP (64.86%), with 13 not having TP (35.14%). The PEST test produced a sensitivity of 83.3% for TP, with 20 out of 24 participants in the TP group testing positive (95% CI: 61.8 to 94.5), which was superior to the ADA, with only 9 out of the 24 participants (37.5%) in the TP group testing positive (95% CI: 19.6 to 59.2), with P < .001. Conclusions: The PEST test possesses a high diagnostic value, and clinicians can use it as a time-saving, noninvasive, and highly sensitive method for TP diagnosis. It can be adjunct method to the currently used tests for diagnosing TP. A combination of several detection methods could promote effective treatment.

[Ten-year Trend Analysis of Eutrophication Status and the Related Causes in Lake Hongze].

In order to propose pertinent suggestions regarding eutrophication control for Lake Hongze, we used monthly monitoring data from 2011 to 2020 to elucidate the spatiotemporal changing characteristics of eutrophic status and the relevant driving factors. As the main river entering Lake Hongze, River Huaihe experienced an increase in permanganate index and a decrease in TN in the last 10 years. Meanwhile, Secchi depth, TP, and permanganate index increased, whereas TN and Chl-a concentration decreased significantly in Lake Hongze. As a result, the eutrophic status TLI index of Lake Hongze declined over the past 10 years. The change trend of TLI in Lake Hongze differed spatially. As the main water passage of River Huaihe, the algal biomass was lower in the eastern region than that in the other two lake regions, regardless of the relatively high nutrient concentration, due to the short water retention time. Furthermore, the water quality of River Huaihe improved; thus, the TLI index decreased significantly in the eastern lake region. The northern region had a high coverage of aquatic vegetation, which not only reduced the concentration of water nutrients but also provided a habitat for zooplankton and fish, effectively inhibiting algal growth. Thus, the TLI index was lowest among the three lake areas and showed a downward trend over the last 10 years. In the western region, the algal biomass was the highest due to the intensification of phosphorus release from sediment in summer. Thus, the TLI index was the highest and had not improved in the past 10 years. There were also significant seasonal differences in the TLI of Lake Hongze, which was highest in summer, due to the relatively high algal biomass. Moreover, the algal biomass in summer was mainly affected by the concentration of nitrate. According to the spatiotemporal distribution characteristics of eutrophic status and the impacting factors in Lake Hongze, corresponding measures for eutrophication control should be taken for different seasons and lake areas.

Role of Selenium and Vitamins E and B9 in the Alleviation of Bovine Mastitis during the Periparturient Period.

Mastitis (inflammation of the mammary gland) commonly occurs in dairy cattle during the periparturient period (transition period), in which dairy cattle experience physiological and hormonal changes and severe negative energy balance, followed by oxidative stress. To maintain successful lactation and combat negative energy balance (NEB), excessive fat mobilization occurs, leading to overproduction of reactive oxygen species (ROS). Excessive fat mobilization also increases the concentrations of nonesterified fatty acids (NEFA) and ß-hydroxybutyric acid (BHB) during the periparturient period. In addition, the excessive utilization of oxygen by cellular respiration in the mammary causes abnormal production of oxidative stress (OS). OS impairs the immunity and anti-inflammatory efficiency of periparturient dairy cattle, increasing their susceptibility to mastitis. To alleviate oxidative stress and subsequent mastitis, antioxidants are supplemented to dairy cattle from an external source. Extensive studies have been conducted on the supplementation of selenium (Se) and vitamins E and B9 to mitigate mastitis during the transition period in dairy cattle. Altogether, in the current review, we discuss the research development on bovine mastitis and its major causes, with special emphasis on oxidative stress during the transition period. Moreover, we discuss the antioxidant, immunoregulatory, and anti-inflammatory properties of Se and vitamins E and B9 and their role in the control of bovine mastitis in periparturient dairy cattle.

Overview of the effect of rumen-protected limiting amino acids (methionine and lysine) and choline on the immunity, antioxidative, and inflammatory status of periparturient ruminants.

Overproduction of reactive oxygen species (ROS) is a well-known phenomenon experienced by ruminants, especially during the transition from late gestation to successful lactation. This overproduction of ROS may lead to oxidative stress (OS), which compromises the immune and anti-inflammatory systems of animals, thus predisposing them to health issues. Besides, during the periparturient period, metabolic stress is developed due to a negative energy balance, which is followed by excessive fat mobilization and poor production performance. Excessive lipolysis causes immune suppression, abnormal regulation of inflammation, and enhanced oxidative stress. Indeed, OS plays a key role in regulating the metabolic activity of various organs and the productivity of farm animals. For example, rapid fetal growth and the production of large amounts of colostrum and milk, as well as an increase in both maternal and fetal metabolism, result in increased ROS production and an increased need for micronutrients, including antioxidants, during the last trimester of pregnancy and at the start of lactation. Oxidative stress is generally neutralized by the natural antioxidant system in the body. However, in some special phases, such as the periparturient period, the animal's natural antioxidant system is unable to cope with the situation. The effect of rumen-protected limiting amino acids and choline on the regulation of immunity, antioxidative, and anti-inflammatory status and milk production performance, has been widely studied in ruminants. Thus, in the current review, we gathered and interpreted the data on this topic, especially during the perinatal and lactational stages.

The Antioxidant Properties of Selenium and Vitamin E; Their Role in Periparturient Dairy Cattle Health Regulation.

Dairy cattle experience health risks during the periparturient period. The continuous overproduction of reactive oxygen species (ROS) during the transition from late gestation to peak lactation leads to the development of oxidative stress. Oxidative stress is usually considered the main contributor to several diseases such as retained placenta, fatty liver, ketosis, mastitis and metritis in periparturient dairy cattle. The oxidative stress is generally balanced by the naturally available antioxidant system in the body of dairy cattle. However, in some special conditions, such as the peripariparturient period, the natural antioxidant system of a body is not able to balance the ROS production. To cope with this situation, the antioxidants are supplied to the dairy cattle from external sources. Natural antioxidants such as selenium and vitamin E have been found to restore normal health by minimizing the harmful effects of excessive ROS production. The deficiencies of Se and vitamin E have been reported to be associated with various diseases in periparturient dairy cattle. Thus in the current review, we highlight the new insights into the Se and vitamin E supplementation as antioxidant agents in the health regulation of periparturient dairy cattle.

Thermo- and pH-responsive, Lipid-coated, Mesoporous Silica Nanoparticle-based Dual Drug Delivery System To Improve the Antitumor Effect of Hydrophobic Drugs.

Evodiamine (EVO) and Berberine (BBR), from Euodiae Fructus and Coptidis rhizoma, have been used as an herbal medicine pair in traditional Chinese medicine to exert synergistic antitumor effects against various types of tumor cells. However, their clinical use is limited by their poor solubility and adverse toxic side effects. Mesoporous silica nanoparticles (MSNs) possess excellent properties such as a readily functionalized surface, prominent biocompatibility, and huge specific surface area for loading with hydrophobic and hydrophilic drug. On this basis, a novel temperature- and pH-responsive dual drug delivery platform has been developed, in which lipid-coated MSN@p(NIPAM- co-MA) codelivers EVO and BBR. The results indicate that the nanocarrier improves the efficacy and biocompatibility of the drug pair and maintain desirable drug profiles at the low pH and higher temperature of the tumor microenvironment. The dual drug-loaded MSNs showed excellent synergistic therapy effects in vitro (cytotoxicity, cell migration and invasion, angiogenesis) and in vivo (growth of tumor grafts in mice). Meanwhile, the dual drug-loaded nanoparticles showed lower systemic toxicity than either drug alone, the free drug combination, or Taxol. These results suggest that the temperature- and pH-sensitive lipid-coated MSNs are a promising novel carrier for both hydrophobic and hydrophilic drugs.

Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway.

Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4',5-trihydroxy-stilbene-3-ß-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition.

Effects of Pulsatile Cupping on Body Pain and Quality of Life in People with Suboptimal Health:A Randomized Controlled Exploratory Trial.

Objective: The curative effect of pneumatic pulsatile cupping on pain has been shown. This study was conducted to investigate effects of the pulsating frequency of pneumatic pulsatile cupping, compared with traditional cupping (TC), on body pain and quality of life (QoL) in people with suboptimal health status (SHS). Materials and Methods: Ninety-six participants with SHS were randomized to low-frequency (LF; n = 24) or high-frequency (HF; n = 24) pulsating cupping, traditional cupping (TC; n = 24), or wait-list (WL; n = 24) groups. The LF, HF, and TC groups received 4 sessions of cupping over 2 weeks. Visual analogue scale (VAS; 0-100 mm) pain level and Short-Form-36 (SF-36) QoL measurements were taken before and after the intervention. Results: Both LF and HF reduced pain significantly (VAS: -28.26; 95% confidence interval [CI] -36.18 to -20.34; and -31.88, 95% CI -39.81 to -23.96; both P = 0.000) and improved QoL more than WL (SF-36, Bodily Pain dimension: 1.46, 95% CI: 0.85 to 2.07; and 1.75, 95% CI: 1.14 to 2.36, both P = 0.000). Compared to TC, LF and HF significantly reduced pain (VAS: -7.92, 95% CI: -15.75 to -0.08, P LT = 0.048; and -11.54, 95% CI: -19.38 to -3.70, P HT = 0.004) and improved QoL (SF-36, Bodily Pain dimension: 0.61, 95% CI: 0.01 to 1.21, P LT = 0.046; and 0.90, 95% CI: 0.30 to 1.50, P HT = 0.004). There was no significant difference between LF and HF. Conclusions: This study showed that, in patients with SHS, pulsatile cupping therapy could have a more-favorable effect to relieve body pain, compared to TC. LF and HF pulsation produced equivalent pain relief. Further studies investigating the underlying mechanism are needed. Trial registration: This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-INR-16009345).

Application of Traditional Chinese Medicine Four-diagnostic auxiliary apparatus in evaluation of health status and clinical treatment.

OBJECTIVE: To evaluate the application of Traditional Chinese Medicine (TCM) Four-diagnostic Auxiliary Apparatus in disease diagnosis. METHODS: The liver cancer patients and healthy controls were recruited from Shanghai Integrated Chinese and Western Medicine Hospital and Beijing University of Traditional Chinese Medicine, respectively. Then, the included subjects were diagnosed by the Four-diagnostic auxiliary apparatus. RESULTS: Thirty liver cancer patients and 30 paired healthy controls were enrolled in this study. Based on the apparatus, the pulse wave velocity was significantly higher in patients compared with controls (P < 0.05). The number of patients with purple tongue and ecchymosis were more than controls (P < 0.05). The number of patients (10%) with yellow tongue coating were higher than the controls (0%). Patients were inclined to be with water type and fire type constitution. CONCLUSION: TCM Four-diagnostic auxiliary apparatus can be applied in clinical diagnosis of body constitution and health status of subjects. It promotes the accuracy and speed for disease diagnosis and TCM standardization.

An innovative method to evaluate the severe level of general Qi deficiency.

OBJECTIVE: The study aim was to use existing relevant indexes to establish an index series for the quantitative measurement of Qi deficiency pattern (QDP) in Traditional Chinese Medicine (TCM). METHODS: Seventeen indexes of arterial oxygen saturation (SaO2), TCM pulse diagnosis, heart rate, and blood pressure were integrated into an index series, and 94 selected subjects were divided into a healthy control group, a mild QDP group, and a typical QDP group. All three groups were then synchronously given a breath-holding (BH) test and index detections using TCM apparatus for auxiliary diagnosis and treatment and a photoplethysmograph. The detections were carried out repeatedly until there was no monotonic change in the value of the minimal SaO2 during a BH measurement (SaO2min) or in the duration of BH during a BH measurement (TBH). RESULTS: BH measurement and index detection data from 380 eligible cases were analyzed and a significant intergroup difference was found for 12 indexes. CONCLUSION: An index series for quantitative QDP measurement could comprise the 12 effective indexes: RSaO2d (rate of decline of SaO2 during a BH measurement), RSaO2r (recovery rate of SaO2 after a BH measurement), SaO2min, BFV (blood flow velocity), TSaO2d (the time at which SaO2 started declining during a BH measurement), TBH, TSaO2min (the time of occurrence of the minimal SaO2 during a BH measurement), TSaO2max (the time of occurrence of the maximal SaO2 after a BH measurement), PTP (pulse-touching pressure), SBP (systolic blood pressure), PWV (pulse wave velocity), and DBP (diastolic blood pressure). Of the indexes, RSaO2d could play a key role in quantitative QDP measurement; RSaO2r and SaO2min could be used to differentiate the QDP symptom of shortness of breath and as early-warning indexes for chronic obstructive pulmonary disease. BFV, TSaO2d, and TBH could be used to quantitatively assess the QDP symptoms of spontaneous perspiration and shortness of breath.

Synchronous centennial abrupt events in the ocean and atmosphere during the last deglaciation.

Antarctic ice-core data reveal that the atmosphere experienced abrupt centennial increases in CO2 concentration during the last deglaciation (~18 thousand to 11 thousand years ago). Establishing the role of ocean circulation in these changes requires high-resolution, accurately dated marine records. Here, we report radiocarbon data from uranium-thorium-dated deep-sea corals in the Equatorial Atlantic and Drake Passage over the past 25,000 years. Two major deglacial radiocarbon shifts occurred in phase with centennial atmospheric CO2 rises at 14.8 thousand and 11.7 thousand years ago. We interpret these radiocarbon-enriched signals to represent two short-lived (less than 500 years) "overshoot" events, with Atlantic meridional overturning stronger than that of the modern era. These results provide compelling evidence for a close coupling of ocean circulation and centennial climate events during the last deglaciation.

Sodium Hydroxide Pinpoint Pressing Permeation Method for the Animal Modeling of Sick Sinus Syndrome.

Sodium hydroxide pinpoint pressing permeation (SHPPP) was investigated in order to build a rat model of sick sinus syndrome (SSS), which is easy to operate and control the degree of damage, with fewer complications and applicable for large and small animals.Thirty healthy Wistar rats (15 males and 15 females, weighing 250-350 g) were randomly divided into 3 groups, namely a formaldehyde thoracotomy wet compressing group (FTWC), formaldehyde pinpoint pressing permeation group (FPPP) group, and SHPPP group. The number of surviving rats, heart rate (HR), sinoatrial node recovery time (SNRT), corrected SNRT (CSNRT), and sinoatrial conduction time (SACT) were recorded 3 days, one week, and two weeks after modeling.The achievement ratio of modeling was 10% in the FTWC group, 40% in the FPPP group, and 70% in the SHPPP group, and the differences were statistically significant (χ(2) = 7.250, P = 0.007). Meanwhile, the HR was reduced by about 37% in these 3 groups 3 days after modeling, while the reduction was maintained only in SHPPP (P > 0.05) and the HR was re-elevated in the FTWC and FPPP groups 2 weeks after modeling (P < 0.05). Additionally, the SNRT, cS-NRT, and SACT were significantly prolonged compared with pre-modeling in all 3 groups (P < 0.01).SHPPP was the best method with which to build an SSS model with stable and lasting low HR and high success rate of modeling, which might be helpful for further studies on the SSS mechanisms and drugs.

Endogenous n-3 polyunsaturated fatty acids protect against imiquimod-induced psoriasis-like inflammation via the IL-17/IL-23 axis.

The beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on psoriasis have been reported in rats, mice and humans, but the specific mechanisms involved have not been well defined. The present study utilized the fat-1 mouse, a transgenic model that can endogenously convert n-6 FAs into n-3 PUFAs, to directly determine if the outcomes of psoriasis were correlated with n-3 PUFAs. Wild-type (WT) and fat-1 mice, which were treated daily with imiquimod (IMQ) cream or control cream on the shaved right ear and dorsal skin, were fed the same diet. The severity of inflammation of the ear and dorsal skin was scored according to the clinical Psoriasis Area and Severity Index (PASI) and epidermal hyperplasia was measured by H&E staining. The expression of inflammatory factors in the epidermis was analyzed by immunohistochemical analysis. Flow cytometry and an enzyme-linked immunosorbent assay were used to measure the differences in the content of inflammatory factors in the blood serum and to determine which of CD4+ T cells were present in the spleen between IMQ-induced fat-1 mice and WT mice. Fat-1 IMQ-induced mice exhibited significantly lower levels of inflammatory cell-like T helper 17 cells (Th17 cells) and higher levels of regulatory T cells (Treg cells) in the spleen as compared with the WT IMQ-induced mice. n-3 fatty acids stimulated Th17 cells to produce lower levels of inflammatory factors, including interleukin (IL)-17, IL-22, IL-23 and stimulated Treg cells to produce higher anti-inflammatory factors, such as Foxp3. In conclusion, the present study provides further insight into the mechanisms involved in preventing inflammation in psoriasis-like mice by n-3 PUFAs using a fat-1 transgenic mouse model.

Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice.

BACKGROUND: An exogenous supplement of n-3 polyunsaturated fatty acids (PUFAs) has been reported to prevent osteoarthritis (OA) through undefined mechanisms. OBJECTIVE: This study investigated the effect of alterations in the composition of endogenous PUFAs on OA, and associations of PUFAs with mammalian target of rapamycin complex 1 (mTORC1) signalling, a critical autophagy pathway in fat-1 transgenic (TG) mice. METHODS: fat-1 TG and wild-type mice were used to create an OA model by resecting the medial meniscus. The composition of the endogenous PUFAs in mouse tissues was analysed by gas chromatography, and the incidence of OA was evaluated by micro-computed tomography (micro-CT), scanning electron microscopy and histological methods. Additionally, primary chondrocytes were isolated and cultured. The effect of exogenous and endogenous PUFAs on mTORC1 activity and autophagy in chondrocytes was assessed. RESULTS: The composition of endogenous PUFAs of TG mice was optimised both by increased n-3 PUFAs and decreased n-6 PUFAs, which significantly alleviated the articular cartilage destruction and osteophytosis in the OA model (p<0.01), decreased protein expression of matrix metalloproteinase-13 (MMP-13) and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs) in the articular cartilage (p<0.01) and reduced chondrocyte number and loss of cartilage extracellular matrix. Both exogenous and endogenous n-3 PUFAs downregulated mTORC1 activity and promoted autophagy in articular chondrocytes. Conversely, mTORC1 pathway activation suppressed autophagy in articular chondrocytes. CONCLUSIONS: Enhancement of the synthesis of endogenous n-3 PUFAs from n-6 PUFAs can delay the incidence of OA, probably through inhibition of mTORC1, promotion of autophagy and cell survival in cartilage chondrocytes. Future investigation into the role of the endogenous n-6/n-3 PUFAs composition in OA prevention and treatment is warranted.

Endogenous n-3 polyunsaturated fatty acids (PUFAs) mitigate ovariectomy-induced bone loss by attenuating bone marrow adipogenesis in FAT1 transgenic mice.

AIM: To investigate the effect of endogenous n-3 polyunsaturated fatty acids (PUFAs) on bone marrow adipogenesis under osteoporosis conditions. METHODS: A mouse osteoporosis model overexpressing the FAT1 gene from Caenorhabditis elegans and converting n-6 PUFAs to n-3 PUFAs endogenously was used. RESULTS: The mice presented significantly lower bone marrow adiposity (adipocyte volume/tissue volume, mean adipocyte number) but increased the bone parameters (bone mineral density, bone mineral content, bone volume/total volume) in the distal femoral metaphysis. CONCLUSION: Endogenous n-3 PUFAs protect bone marrow adipogenesis, which provides a novel drug target.

Could heterotopic ossification be prevented by varying dietary n-3/n-6 polyunsaturated fatty acid ratio: a novel perspective to its treatment?

Heterotopic ossification (HO) is a common complication following with musculoskeletal trauma and surgical procedures. It usually decreases joint mobility and eventually causes loss of joint function. Despite nonsteroidal anti-inflammatory drugs (NSAIDs), the inhibitor of cyclooxygenase(COX), have been proven to prevent HO effectively via prostaglandin E2 synthesis regulation and modulation of tissue responsiveness to pro-inflammatory signaling, HO prevention is still a matter of debate for clinicians to avoid the side effect of NSAIDs. Interestingly, it is suggested that PGE2 production and pro-inflammatory microenvironment in body could be modified by varying the ratio of the precursor fatty acids in the diet. On account of the effect of dietary (n-6)/(n-3) PUFAs ratio on both COX metabolism and pro-inflammatory cytokines mediated biological responsiveness, we hypothesized lowering dietary (n-6)/(n-3) PUFAs ratio may not only directly reduce the substrate of COX-2 and COX-2 activity, but also partially ameliorate tissue inflammatory responsiveness to cytokines correlated with HO development,exerting an inhibitory effect on PGE2 synthesis to prevent HO formation. The negative role of lowering dietary (n-6)/(n-3) PUFAs ratio on angiogenesis, cytokines-induced apoptosis, inflammatory responsiveness and osteogenesis could also contribute to its action on HO development. If our hypothesis is proved to be corrected, it could be an innovative method to treat HO.