Associations between resting heart rate and cognitive decline in Chinese oldest old individuals: a longitudinal cohort study.

BACKGROUND: The trajectories of cognitive function in the oldest old individuals is unclear, and the relationship between resting heart rate (RHR) and cognitive decline is controversial. METHODS: 3300 participants who had cognitive function repeatedly measured 4 ~ 8 times were included, and latent class growth mixed models were used to identified the cognitive function trajectories. Cognitive decline was defined by the trajectory shapes, considering level and slope. After excluding individuals with sinus rhythm abnormal, 3109 subjects were remained and were divided into five groups by their RHR. Logistic regression models were used to estimate the relationship between RHR and cognitive decline. RESULTS: Three distinct cognitive function trajectory groups were identified: high-stable (n = 1226), medium-decreasing (n = 1526), and rapid-decreasing (n = 357). Individuals of medium/rapid-decreasing group were defined as cognitive decline. Adjusting for covariates, the odds ratios (95% confidence intervals) of RHR sub-groups were 1.19 (0.69, 2.05), 1.27 (1.03, 1.56), 1.30 (1.01, 1.67) and 1.62 (1.07, 2.47) for those RHR < 60 bpm, 70 ~ 79 bpm, 80 ~ 89 bpm and > 90 bpm respectively, compared with those RHR 60 ~ 69 bpm. The interaction effect between RHR and physical activity (PA) on cognitive decline was found, and stratification analysis was presented that higher RHR would only show risk effects on cognitive decline in those with physical inactivity (P < 0.05 for all). CONCLUSIONS: Our study demonstrates RHR more than 70 bpm present significant risk effect on cognitive decline, and this relationship is modified by PA. Elder population with physical inactivity and higher RHR should be paid more attention to prevent cognitive decline.

Metabolic dynamics and prediction of sFGR and adverse fetal outcomes: a prospective longitudinal cohort study.

BACKGROUND: Selective fetal growth restriction (sFGR) is an extreme complication that significantly increases the risk of perinatal mortality and long-term adverse neurological outcomes in offspring, affecting approximately 15% of monochorionic diamniotic (MCDA) twin pregnancies. The lack of longitudinal cohort studies hinders the early prediction and intervention of sFGR. METHODS: We constructed a prospective longitudinal cohort study of sFGR, and quantified 25 key metabolites in 337 samples from maternal plasma in the first, second, and third trimester and from cord plasma. In particular, our study examined fetal growth and brain injury data from ultrasonography and used the Ages and Stages Questionnaire-third edition subscale (ASQ-3) to evaluate the long-term neurocognitive behavioral development of infants aged 2-3 years. Furthermore, we correlated metabolite levels with ultrasound data, including physical development and brain injury indicators, and ASQ-3 data using Spearman's-based correlation tests. In addition, special combinations of differential metabolites were used to construct predictive models for the occurrence of sFGR and fetal brain injury. RESULTS: Our findings revealed various dynamic patterns for these metabolites during pregnancy and a maximum of differential metabolites between sFGR and MCDA in the second trimester (n = 8). The combination of L-phenylalanine, L-leucine, and L-isoleucine in the second trimester, which were closely related to fetal growth indicators, was highly predictive of sFGR occurrence (area under the curve [AUC]: 0.878). The combination of L-serine, L-histidine, and L-arginine in the first trimester and creatinine in the second trimester was correlated with long-term neurocognitive behavioral development and showed the capacity to identify fetal brain injury with high accuracy (AUC: 0.94). CONCLUSIONS: The performance of maternal plasma metabolites from the first and second trimester is superior to those from the third trimester and cord plasma in discerning sFGR and fetal brain injury. These metabolites may serve as useful biomarkers for early prediction and promising targets for early intervention in clinical settings.

Unfavourable intrauterine environment contributes to abnormal gut microbiome and metabolome in twins.

OBJECTIVE: Fetal growth restriction (FGR) is a devastating pregnancy complication that increases the risk of perinatal mortality and morbidity. This study aims to determine the combined and relative effects of genetic and intrauterine environments on neonatal microbial communities and to explore selective FGR-induced gut microbiota disruption, metabolic profile disturbances and possible outcomes. DESIGN: We profiled and compared the gut microbial colonisation of 150 pairs of twin neonates who were classified into four groups based on their chorionicity and discordance of fetal birth weight. Gut microbiota dysbiosis and faecal metabolic alterations were determined by 16S ribosomal RNA and metagenomic sequencing and metabolomics, and the long-term effects were explored by surveys of physical and neurocognitive development conducted after 2~3 years of follow-up. RESULTS: Adverse intrauterine environmental factors related to selective FGR dominate genetics in their effects of elevating bacterial diversity and altering the composition of early-life gut microbiota, and this effect is positively related to the severity of selective FGR in twins. The influence of genetic factors on gut microbes diminishes in the context of selective FGR. Gut microbiota dysbiosis in twin neonates with selective FGR and faecal metabolic alterations features decreased abundances of Enterococcus and Acinetobacter and downregulated methionine and cysteine levels. Correlation analysis indicates that the faecal cysteine level in early life is positively correlated with the physical and neurocognitive development of infants. CONCLUSION: Dysbiotic microbiota profiles and pronounced metabolic alterations are associated with selective FGR affected by adverse intrauterine environments, emphasising the possible effects of dysbiosis on long-term neurobehavioural development.

Cross-reactive antibodies against dust mite-derived enolase induce neutrophilic airway inflammation.

BACKGROUND AND AIMS: Neutrophilic inflammation is a hallmark of some specific asthma phenotypes; its aetiology is not yet fully understood. House dust mite (HDM) is the most common factor in the pathogenesis of airway inflammation. This study aims to elucidate the role of cross-antibodies against HDM-derived factors in the development of neutrophilic inflammation in the airway. METHODS: Blood samples were collected from asthma patients with chronic neutrophilic asthma for analysis of HDM-specific cross-reactive antibodies. The role of an antibody against HDM-derived enolase (EnoAb) in the impairment of airway epithelial barrier function and induction of airway inflammation was assessed in a cell culture model and an animal model. RESULTS: High similarity (72%) of the enolase gene sequences was identified between HDM and human. Serum EnoAb was detected in patients with chronic neutrophilic asthma. The EnoAb bound to airway epithelial cells to form complexes with enolase, which activated complement, impaired airway epithelial barrier functions and induced neutrophilic inflammation in the airway tissues. CONCLUSIONS: HDM-derived enolase can induce specific cross-antibodies in humans, which induce neutrophilic inflammation in the airway.

Saikosaponin d contributed to cancer chemotherapy induced neutropenia therapy by promoting neutrophil differentiation via activation CBL-dependent ERK pathway.

Cancer chemotherapy induced neutropenia (CCIN) is one of the most common toxicity caused by cytotoxic anticancer agents. Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical practice, the infection and infection-related mortality rate is still high for lack of functionally mature neutrophils. Saikosaponin d (SSD) is one of the major bioactive constituents of Radix Bupleuri (RB), which exerts immune-modulatory properties. We explored the function of SSD in CCIN therapy, we found that SSD contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology was employed to explore the mechanism, 61 signal pathways might play an important role in CCIN treatment. Western Blot was employed to further confirm the potential pathway involved. We found CBL-ERK1/2 pathway was activated by SSD, followed by upregulating PU.1 and CEBPß expression and leading to neutrophil differentiation. Our findings suggest a natural regimen SSD which could regenerate microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2, providing a rationale for future therapeutic approaches.

Four new caffeoylgluconic acid positional isomers from the fruits of Evodia rutaecarpa.

Four new compounds, 4-O-trans-caffeoylgluconic acid (1), 2-O-trans-caffeoylgluconic acid (2), 3-O-trans-caffeoylgluconic acid (3), 5-O-trans-caffeoylgluconic acid (4), together with three known ones including 6-O-trans-caffeoylgluconic acid (5), neochlorogenic acid (6), chlorogenic acid (7) were obtained from the fruits of Evodia rutaecarpa. Their structure elucidation was achieved by the methods of spectroscopic analyses, including HR-ESI-MS, NMR, and by comparison with literatures. The hepatotoxicity of compounds 1-3 was evaluated by CCK-8 method. [Formula: see text].

[Current evaluation situation and research strategies on enhanced immune function of health food containing Chinese materia medica].

At present,the function evaluation of health food containing Chinese materia medica is in lack of theoretical support of Chinese medicine,which can't reflect the function characteristics,dose-effect relationship and mechanism of functional food. What' s more,the evaluation technology of health food containing Chinese materia medica is relatively lagging behind and has been abolished now,which seriously restricts the development of health food containing Chinese materia medica industry. The proportion of health food containing Chinese materia medica with enhancing immune function is the highest among approved products,which is up to 30.33%. By collecting,analyzing and digging the current evaluation situation of enhancing immune function of health food containing Chinese materia medica,this paper has shown that there is no difference between health food containing Chinese materia medica evaluation and other functional food evaluation. What's more,there is a lack of characteristics of traditional Chinese medicine(TCM). The technological means including evaluation of immune active substances is under-developed and the immune cell evaluation needs to be refined and improved urgently,restricting the development of health food containing Chinese materia medica industry. Therefore,the evaluation of the enhanced immune function of health food containing Chinese materia medica should be guided by health-preserving theory in TCM,and based on the identification of TCM constitution for its claim of health function. With TCM theory and modern scientific technological means,a new evaluation model for immune function enhancement of health food containing Chinese materia medica is put forward to distinguish it from other functional food and traditional medicines. Formulation of the evaluation technology and technical specifications suitable for health food containing Chinese materia medica can fundamentally ensure the healthy,orderly,fast and sustainable development of health food containing Chinese materia medica industry.

[Research,evaluation,industry status and development strategy of traditional Chinese medicine functional food].

With the development of social economy,people's demand for health services is growing rapidly. As health resource with Chinese characteristics,health food containing Chinese materia medica have broad prospect and great market space for development.However,at present,there are still many problems of health food containing Chinese materia media in the research,development,evaluation and market application. In addition,due to lack of theoretical support of traditional Chinese medicine(TCM) in the research and development of health food containing Chinese materia media,blurred boundaries between health food containing Chinese materia media and other health products as well as TCM are present,lacking of TCM characteristics. In the evaluation process of health food containing Chinese materia media,the construction of functional food laws,regulations and evaluation norms is relatively lagging behind,which can't meet the needs of health food containing Chinese materia media research and development,severely restricting the development of health food containing Chinese materia media. Based on the research and evaluation of health food containing Chinese materia media,the existing problems were reviewed and the reasons for the deficiencies were analyzed in this paper. Guided by the theory of TCM,based on the constitution identification in TCM,and combined with modern scientific and technological means,a new research and development mode of functional food was put forward in this paper to distinguish health food containing Chinese materia media from TCM as well as general health products. Nevertheless,we should ensure the vitality of Chinese medicine health products with original thinking and scientific and technological connotations,and accelerate the harmonious,rapid and sustainable development of Chinese medicine health industry.

Peel oils from three Citrus species: volatile constituents, antioxidant activities and related contributions of individual components.

In the present study, peel oils were extracted through hydrodistillation and cold pressing from three Citrus species (Valencia orange, Ponkan and Eureka lemon) to investigate their volatile constituents and antioxidant activities. A total of 47 volatile components were identified by GC-MS, and then grouped by principal component analysis. The extraction methods were found to have an obvious effect on the proportion of terpenes and oxygenated compounds in the six Citrus oils, especially for Eureka lemon oils. The major fractions in the Citrus oils were found to be monoterpenes (78.65-96.57%), with limonene occupying a dominant percentage (51.22-86.65%). Furthermore, γ-terpinene and terpinolene displayed strong DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging abilities and efficient inhibition of lipid peroxidation, while oxygenated compounds of α-terpineol and terpinen-4-ol showed poor DPPH radical-scavenging abilities. Therefore, hydrodistillated Eureka lemon oil with high levels of α-terpineol (9.11%) and terpinen-4-ol (4.69%) presented low radical scavenging capability. Citral displayed a high pro-oxidant ability against thiobarbituric acid reactive species formation, which might lead to the decreased ability of the Eureka lemon oils in inhibition of lipid peroxidation, since citral was significantly high in Eureka lemon oils. This study facilitated the understanding of volatile constituents and antioxidant activities in different Citrus peel oils.

Retinol-binding protein 4 is positively associated with bone mineral density in patients with type 2 diabetes and osteopenia or osteoporosis.

OBJECTIVE: This study intends to study the association between serum retinol binding protein 4 (RBP4), bone mineral density (BMD) and other bone metabolic-related parameters in type 2 diabetic patients older than 50 years, with or without osteopenia or osteoporosis. METHODS: Patients (n = 274 cases) with type 2 diabetes, hospitalized in the Endocrinology Department of Yantai Yuhuangding Hospital from December 2015 to March 2017, were enrolled in the study. The bone mineral density (BMD) was recorded by the dual-energy X-ray absorptiometer, and patients were divided into normal bone mineral density (148 cases), osteopenia (93 cases) and osteoporosis (33 cases) groups. The serum adipokine RBP4 and other biomarkers were determined accordingly. RESULTS: Serum RBP4, body weight, calcium and body mass index (BMI) demonstrated a positive correlation with BMD at all tested body sites in osteopenia and osteoporosis groups compared with normal bone mineral density group. In contrast, age, duration of diabetes and alkaline phosphatase (ALP) were inversely correlated with BMD at all tested body sites. In nonadjusted analyses, age, gender, duration of diabetes and ALP were inversely associated with BMD at the femoral neck, total hip and lumbar spine, while body weight, BMI and RBP4 were positively associated with BMD at all sites. In multiple regression analyses, adjusted for age, weight, BMI and other bone-related factors, a graded stepwise positive association between serum RBP4 and BMD was shown, at all sites. CONCLUSION: Serum RBP4 was positively associated with BMD at all sites after adjustments for other factors in osteopenia and osteoporosis groups compared with normal bone mineral density group of type 2 diabetic patients.

Elevated Tumor Necrosis Factor-a-induced Protein 8-like 2 mRNA from Peripheral Blood Mononuclear Cells in Patients with Acute Ischemic Stroke.

Background: Tumor necrosis factor-a-induced protein 8-like 2 (TIPE2) is a novel regulator of immunity and protects against experimental stroke. However, the expression and function of TIPE2 in patients with acute ischemic stroke has not been well demonstrated. Methods: A total of 182 consecutive patients with acute ischemic stroke and 40 healthy controls were included during November 2015 to June 2016. The mRNA levels of TIPE2, interleukin(IL)-1ß, IL-10, IL-6, nuclear factor(NF)-κß, activator protein(AP)-1, interferon(IFN)-γ and tumor necrosis factor(TNF)-α from peripheral blood mononuclear cells were determined using real time quantitative reverse transcriptase polymerase chain reaction. The severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. Results: The median mRNA levels of TIPE2, TNF-α, AP-1, IFN-γ and NF-κß in patients with acute ischemic stroke were significantly higher than healthy controls (all P<0.001, respectively). Of note, TIPE2 mRNA showed an increasing trend on a time-dependent manner after the onset of stroke. Furthermore, TIPE2 mRNA was negatively associated with lesion volumes (r=-0.23, P<0.01), NIHSS(r=-0.15, P<0.05), TNF-α(r=-0.33,P<0.001), AP-1(r=-0.28,P<0.001), IFN-γ (r=-0.16, P<0.05) and NF-κß (r=-0.13, P<0.05), but positively associated with IL-6(r=0.14, P<0.05) and IL-10(r=-0.31, P<0.001). Hierarchy cluster analysis showed that TIPE2 mRNA has nearest membership with TNF-α, followed by IL-6, NF-κß, AP-1, IL-10, IL-1ß and IFN-γ. In addition, TIPE2 mRNA in survivals (n=149) was significantly higher than nonsurvivals (n=33) (P<0.001), and showed a great odd ratio (0.52, 95% confidence interval: 0.349-0.760, P<0.001) on 3-month mortality. Conclusions: TIPE2 mRNA contributed to the immune response of stroke and might be a potential biomarker for the mortality of acute ischemic stroke.

[Research on rat models of acute liver injury with syndrome of liver depression and spleen deficiency].

This paper aimed to establish animal models which are suitable for the activity found, efficacy evaluation of herbs resistant to acute liver injury with syndrome of liver depression and spleen deficiency and new drug research and development based on corresponding of formula and syndrome. The symptoms that are suitable for evaluating the rat models of acute liver injury with syndrome of liver depression and spleen deficiency were extracted according to the evolution rule of the etiology and pathogenesis in traditional Chinese medicine and the modern pathological mechanism. Xiaoyao pill and silibin meglumine tablets were used as drug counter evidence for models in accordence with the principle of consistence of prescription and syndrome. Rats model were fed with high-lipid and low-protein fodder of different proportion and induced by intraperitoneal injection with pig serum, intragastric administration with edible alcohol once a day for 7 days. Daily record of body weight, daily food intake and daily water intake were conducted day after day in experimental session. Symptoms were also observed and evaluated by score at the same time. The contents of ALT, AST, PA, TBIL and TBA in serum were detected and histopathological changes of liver were checked at the ending of experiment. Obvious acute liver injury occurred to all rats in model groups at 1 week following model induction. Both main symptoms and secondary symptoms were consistent with syndrome manifestation of liver depression and spleen deficiency. Compared with normal control group, the activity of ALT,AST and contents of TBIL,TBA in serum increased and the content of PA decreased. Liver tissue pathological morphology showed inflammatory cells infiltration, eosinophilic or eosinophilic adipose change in hepatocytes of rats in model groups. All the above lesions manifestation could be improved by drug counterevidence. By the disproof of medicine, rat models of acute liver injury with syndrome of liver depression and spleen deficiency could be induced by fed with high-lipid and low-protein fodder which contained 89.5% cornstarch, 10% lard and 0.5% cholesterol, intraperitoneal injected with pig serum, intragastric administrated with edible alcohol for 7 days. The rat models with a low mortality could be induced in a short time and animal status were similar to syndrome performance of patients. So the rats models are suitable for the activity found, efficacy evaluation and drug discovery of herbs resistant to acute liver injury with syndrome of liver depression and spleen deficiency, and also can be used in the research of correlation between prescription and syndrome and its mechanism.

[Tidal breathing pulmonary function after treatment in neonates with respiratory distress syndrome].

OBJECTIVE: To investigate the pulmonary function after treatment in neonates with respiratory distress syndrome (RDS) at varying disease severity levels and different gestational ages. METHODS: A total of 107 neonates with RDS were divided into <34 weeks group (65 neonates), late preterm group (21 neonates), full-term group (21 neonates). Another 121 non-RDS children were enrolled as the control group. According to the severity of RDS, the RDS neonates were divided into mild RDS group (grades 1 and 2; 76 neonates), and severe RDS (grades 3 and 4; 21 neonates). The tidal breathing pulmonary function was measured at a corrected gestational age of 44weeks. RESULTS: The pulmonary function parameters showed no significant differences across the groups of RDS neonates of different gestational ages; the tidal volume per kilogram of body weight (VT/kg) showed no significant difference between the RDS and non-RDS groups, while the RDS group had significantly higher ratio of time to peak tidal expiratory flow to total expiratory time (tPTEF/tE) and ratio of volume to peak tidal expiratory flow to total expiratory volume (vPTEF/vE) than the non-RDS group of the same gestational age (P<0.05). At a corrected gestational age of 44 weeks, the two groups of neonates with varying severity levels of RDS had significantly lower tPTEF/tE and vPTEF/vE than the control group (P<0.05), and tPTEF/tE and vPTEF/vE tended to decrease with the increasing severity level of RDS. CONCLUSIONS: Neonates with RDS have significantly decreased pulmonary function than those without RDS. At a corrected gestational age of 44 weeks, the tidal breathing pulmonary function in neonates with RDS is not associated with gestational age, but is associated with the severity of RDS.

[Measurement of tidal breathing pulmonary function in premature infants with different gestational ages].

OBJECTIVE: To investigate the characteristics of the tidal breathing pulmonary function in premature infants with different gestational ages. METHODS: A total of 75 premature infants were classified into three groups according to their gestational ages: <32 weeks, 32-33(+6) weeks and 34-36(+6) weeks. Fifty-five full-term infants (39-40 weeks group) were selected as the control group. All infants were given the tidal breathing pulmonary function test at 3-5 days after birth. Moreover, all infants were given the tidal breathing pulmonary function test again at 40 weeks of the corrected gestational age. RESULTS: At 3-5 days after birth, the three groups of premature infants had significantly lower inspiratory time, time to peak tidal expiratory flow (tPTEF), and ratio of tPTEF to total expiratory time (tPTEF/tE) than the control group (P<0.05). The parameter values of the tidal breathing pulmonary function were lower when the gestational age was lower. Even at 40 weeks of the corrected gestational age, the three groups of premature infants still had significantly lower tPTEF and tPTEF/tE than the control group (P<0.05). CONCLUSIONS: The tidal breathing pulmonary function of neonates is influenced by the gestational age. The tidal breathing pulmonary function of premature infants is obviously impaired, and the lower the gestational age, the more obvious the impairment.

Case report: Successful treatment of advanced pulmonary sarcomatoid carcinoma with BUBIB-ALK rearrangement and KRAS G12C mutation by sintilimab combined with anlotinib.

Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC) that is characterized by poor differentiation and invasiveness. According to the World Health Organization, PSC exhibits sarcoma or sarcomatoid differentiation and typically presents with an insidious onset, lacking specific symptoms and signs. It is associated with high malignancy, early metastasis, short survival time, and a poor prognosis. Treatment for PSC follows a similar approach to NSCLC; however, it presents significant challenges due to its high resistance to chemotherapy. Previous research has demonstrated the coexistence of two or more target mutations in PSC, and the presence of multiple mutations is correlated with higher mortality rates compared to single mutations. This is supported by our case study of a male patient with advanced BUBIB-ALK rearrangement and KRAS G12C missense mutation. There is currently no standard treatment protocol available for patients with this condition. The patient showed rapid progression after 1 month of alectinib treatment and was intolerant to paclitaxel + cisplatin chemotherapy. Following this, successful disease control was achieved with a combination therapy of sintilimab and anlotinib. The patient achieved a progression-free survival (PFS) of over 20 months, and long-term follow-up is still ongoing for the patient. Based on our clinical experience, the combination of anlotinib and programmed death-1 (PD-1) inhibitors may be a promising strategy for PSC patients, particularly those with multi-target mutations who do not respond to ALK-TKI and are resistant to chemotherapy.

Heterogeneity of diabetic dyslipidemia, data from the NHANES (2011-2016).

Epidemiologic studies have demonstrated that diabetes amplifies the effects of dyslipidemia as a risk factor for cardiovascular disease (CVD). A better understanding of lipid profiles is important for lipid-lowering treatment and reducing cardiovascular risk in populations with diabetes. To describe the dyslipidemia patterns in patient with and without diabetes in the adult US population. Data from National Health and Nutrition Examination Survey (NHANES) 2011 to 2016 was analyzed. Surprisingly, 49.9% of the people with diabetes have both normal triglycerides (TGs) and normal high-density lipoprotein cholesterol (HDL-C). 33.4% of the people with diabetes have elevated TGs and 36.1% of them have low HDL-C. Only 19.3% of them have both elevated TGs and low HDL-C. Among people without diabetes, 67.5% have normal TGs and normal HDL-C, 28.0% have elevated TGs, 23.9% have low HDL-C and 8.8% have both elevated TGs and low HDL-C. The differences in the proportions of individuals with both elevated TGs and low HDL-C between the diabetic group and the nondiabetic group were more obvious in females: 7.7% in women without diabetes and 22.7% in women with diabetes. The proportion of individuals in the TG↑HDL-C↓group in the population with diabetes exhibited a decreasing trend in age groups > 30 years old, and the 30 to 40 years group of individuals with diabetes had the highest proportion of atherogenic dyslipidemia. The low-density lipoprotein cholesterol (LDL-C) to apoB ratio is generally lower in people with diabetes, with the lowest level in the TG↑HDL-C↓group. Dyslipidemia patterns in diabetes patients are highly heterogeneous. Deep phenotyping sub-groups of dyslipidemia is warranted to identify higher-risk patients for evaluation of non-LDL-C therapies. This explained at least partially of the difficult search for novel therapies in the post-LDL-C era.

A comprehensive review of bupleuri radix and its bioactive components： with a major focus on treating chronic liver diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Bupleuri Radix (BR) has been recognized as an essential herbal medicine for relieving liver depression for thousands of years. Contemporary research has provided compelling evidence of its pharmacological effects, including anti-inflammatory, immunomodulatory, metabolic regulation, and anticancer properties, positioning it as a promising treatment option for various liver diseases. Hepatitis, steatohepatitis, cirrhosis, and liver cancer are among the prevalent and impactful liver diseases worldwide. However, there remains a lack of comprehensive systematic reviews that explore the prescription, bio-active components, and underlying mechanisms of BR in treating liver diseases. AIM OF THE REVIEW: To summarize the BR classical Chinese medical prescription and ingredients in treating liver diseases and their mechanisms to inform reference for further development and research. MATERIALS AND METHODS: Literature in the last three decades of BR and its classical Chinese medical prescription and ingredients were collated and summarized by searching PubMed, Wiley, Springer, Google Scholar, Web of Science, CNKI, etc. RESULTS: BR and its classical prescriptions, such as Xiao Chai Hu decoction, Da Chai Hu decoction, Si Ni San, and Chai Hu Shu Gan San, have been utilized for centuries as effective therapies for liver diseases, including hepatitis, steatohepatitis, cirrhosis, and liver cancer. BR is a rich source of active ingredients, such as saikosaponins, polysaccharides, flavonoids, sterols, organic acids, and so on. These bioactive compounds exhibit a wide range of beneficial effects, including anti-inflammatory, antioxidant, immunomodulatory, and lipid metabolism regulation. However, it is important to acknowledge that BR and its constituents can also possess hepatotoxicity, which is associated with cytochrome P450 (CYP450) enzymes and oxidative stress. Therefore, caution should be exercised when using BR in therapeutic applications to ensure the safe and appropriate utilization of its potential benefits while minimizing any potential risks. CONCLUSIONS: To sum up, BR, its compounds, and its based traditional Chinese medicine are effective in liver diseases through multiple targets, multiple pathways, and multiple effects. Advances in pharmacological and toxicological investigations of BR and its bio-active components in the future will provide further contributions to the discovery of novel therapeutics for liver diseases.

Amniotic fluid metabolic fingerprinting contributes to shaping the unfavourable intrauterine environment in monochorionic diamniotic twins.

BACKGROUND & AIMS: Amniotic fluid (AF) is the primary intrauterine environment for fetal growth throughout gestation. Selective fetal growth restriction (sFGR) is an adverse complication characterized by unequal growth in twins with nearly identical genetic makeup. However, the influence of AF-mediated intrauterine environment on the development and progression of sFGR remains unexplored. METHODS: High-throughput targeted metabolomics analysis (G350) was performed on AF samples collected from sFGR (n = 18) and MCDA twins with birth weight concordance (MCDA-C, n = 20) cases. Weighted correlation network analysis (WGCNA) was used to identify clinical features that may influence the metabolite composition in AF. Subsequently, partial least-squares discriminant analysis (PLS-DA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to compare the different types of sFGR and MCDA-C twins. Receiver operating characteristic (ROC) and multivariate ROC curves were utilized to explore potential AF markers in twins with sFGR. RESULTS: In our study, 182 metabolites were quantified in 76 AF samples. WGCNA indicated that the metabolite composition in late AF may not be influenced by gestational age. PLSDA demonstrated distinct variations between the metabolite profiles of AF in the sFGR and MCDA-C twins, with a significant emphasis on amino acids as the primary differential metabolite. The dissimilarities observed in sFGR twins were predominantly attributed to lipid metabolism-related metabolites. In particular, the KEGG enrichment metabolic pathway analysis revealed significant associations of both types of sFGR twins with central carbon metabolism in cancer. The multivariate ROC curves indicated that the combination of carnosine, sarcosine, l-alanine, beta-alanine, and alpha-n-phenylacetylglutamine significantly improved the AUC to 0.928. Notably, the ROC curves highlighted creatine (AUC:0.934) may be a potential biomarker for severe sFGR. CONCLUSION: The data presented in this study offer a comprehensive metabolic map of the AF in cases of sFGR, shedding light on potential biomarkers associated with fetal growth and development in MCDA twins.

Inhibition of JNK transcription via the Nrf2/Keap1a pathway to resist microcystin-induced oxidative stress and apoptosis in freshwater mussels Cristaria plicata.

With global warming and increasing eutrophication of water bodies, a variety of algal toxins, including microcystin (MC), released into water by cyanobacterial blooms pose a serious threat to the survival of aquatic organisms. To investigate the mechanism of the Nrf2/Keap1a pathway on resisting MC-induced oxidative stress and apoptosis in Cristata plicata, we cloned the full-length cDNA of CpBcl-2. The cDNA full-length of CpBcl-2 was 760 bp, encoded a 177 amino acid peptide, and contained a highly conserved Bcl-2-like superfamily domain. MC stimulation increased the expression and activity levels of related antioxidant enzymes. After CpNrf2 knockdown, the transcription levels of NAD(P)H quinone redox Enzyme-1 (NQO1) and related antioxidant enzymes activity in the gills and kidney of C. plicata were significantly down-regulated upon MC stress, but that was significantly upregulated after knockdown of CpKeap1a. Additionally, Upon MC stress, the mRNA levels of CpBcl-2 were increased in the gills and kidney after knockdown of CpNrf2 at 24 h, and that of CpBcl-2 were decreased at 72 and 96 h in the CpKeap1a-siRNA+MC group. Moreover, MC stimulation significantly inhibited CpJNK expression in the gills and kidney, but which regulated the Nrf2/Keap1a pathway in C. plicata. However, the JNK inhibitor SP600125 promoted the expression of CpNrf2 and related enzymes with antioxidant response element (ARE-driven enzyme) in the gills and kidney. Then, we speculated that CpKeap1a was a negative regulator of CpNrf2, and C. plicata resisted MC-induced oxidative damage and apoptosis by inhibiting JNK transcription via the Nrf2/Keap1a pathway.

Therapeutic application of nicotinamide: As a potential target for inhibiting fibrotic scar formation following spinal cord injury.

AIM: We aimed to confirm the inhibitory effect of nicotinamide on fibrotic scar formation following spinal cord injury in mice using functional metabolomics. METHODS: We proposed a novel functional metabolomics strategy to establish correlations between gene expression changes and metabolic phenotypes using integrated multi-omics analysis. Through the integration of quantitative metabolites analysis and assessments of differential gene expression, we identified nicotinamide as a functional metabolite capable of inhibiting fibrotic scar formation and confirmed the effect in vivo using a mouse model of spinal cord injury. Furthermore, to mimic fibrosis models in vitro, primary mouse embryonic fibroblasts and spinal cord fibroblasts were stimulated by TGFß, and the influence of nicotinamide on TGFß-induced fibrosis-associated genes and its underlying mechanism were examined. RESULTS: Administration of nicotinamide led to a reduction in fibrotic lesion area and promoted functional rehabilitation following spinal cord injury. Nicotinamide effectively downregulated the expression of fibrosis genes, including Col1α1, Vimentin, Col4α1, Col1α2, Fn1, and Acta2, by repressing the TGFß/SMADs pathway. CONCLUSION: Our functional metabolomics strategy identified nicotinamide as a metabolite with the potential to inhibit fibrotic scar formation following SCI by suppressing the TGFß/SMADs signaling. This finding provides new therapeutic strategies and new ideas for clinical treatment.