Flavonoid extracts of Citrus aurantium L. var. amara Engl. Promote browning of white adipose tissue in high-fat diet-induced mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Obesity has become a public burden worldwide due to its booming incidence and various complications, and browning of white adipose tissue (WAT) is recognized as a hopeful strategy to combat it. Blossom of Citrus aurantium L. var. amara Engl. (CAVA) is a popular folk medicine and dietary supplement used for relieving dyspepsia, which is recorded in the Chinese Materia Medica. Our previous study showed that blossom of CAVA had anti-obesity potential, while its role in browning of WAT was still unclear. AIM OF THE STUDY: This study aimed to characterize the constituents in flavonoids from blossom of CAVA (CAVAF) and to clarify the anti-obesity capacities especially the effects on browning of WAT. MATERIALS AND METHODS: Gradient ethanol eluents from blossom of CAVA were obtained by AB-8 macroporous resin. 3T3-L1 cells and pancreatic lipase inhibition assay were employed to investigate the potential anti-obesity effects in vitro. HPLC and UPLC/MS assays were performed to characterize the chemical profiles of different eluents. Network pharmacology and molecular docking assays were used to reveal potential anti-obesity targets. Furthermore, high-fat diet (HFD)-induced mice were constructed to explore the anti-obesity actions and mechanisms in vivo. RESULTS: 30% ethanol eluents with high flavonoid content and great inhibition on proliferation of 3T3-L1 preadipocytes and pancreatic lipase activity were regarded as CAVAF. 19 compounds were identified in CAVAF. Network pharmacology analysis demonstrated that AMPK and PPARα were potential targets for CAVAF in alleviating obesity. Animal studies demonstrated that CAVAF intervention significantly decreased the body weight, WAT weight, serum TG, TC and LDL-C levels in HFD-fed obese mice. HFD-induced insulin resistance and morphological changes in WAT and brown adipose tissue were also markedly attenuated by CAVAF treatment. CAVAF supplementation potently inhibited iWAT inflammation by regulating IL-6, IL-1ß, TNF-α and IL-10 mRNA expression in iWAT of mice. Furthermore, the gene expression levels of thermogenic markers including Cyto C, ATP synthesis, Cidea, Cox8b and especially UCP1 in iWAT of mice were significantly up-regulated by CAVAF administration. CAVAF intervention also markedly increased the expression levels of PRDM16, PGC-1α, SIRT1, AMPK-α1, PPARα and PPARγ mRNA in iWAT of mice. CONCLUSION: CAVAF treatment significantly promoted browning of WAT in HFD-fed mice. These results suggested that flavonoid extracts from blossom of CAVA were probably promising candidates for the treatment of obesity.

Exploration of costunolide derivatives as potential anti-inflammatory agents for topical treatment of atopic dermatitis by inhibiting MAPK/NF-κB pathways.

Atopic dermatitis (AD) is a common inflammatory disease and it is very difficult to treat. In the present work, a series of costunolide derivatives have been prepared, and in vitro and in vivo anti-inflammatory activities have evaluated. The results showed that most derivatives displayed good inhibition of NO generation with low cytotoxicity, and 7d could inhibit the phosphorylation of P38, P65 NF-κB and IκB-α in LPS-induced RAW264.7 model. The in vivo researches showed that 7d could improve skin injury symptoms, decrease Th2-type cytokine levels, inhibit HIS levels, alleviate scratching and repaire the damaged skin barrier through the inhibition of phosphorylation of MAPK and NF-κB signaling pathways on MC903-induced AD model. Therefore, costunolide derivatives may be new potent anti-AD agents for further study.

Pregnancy characteristics and adverse outcomes in offspring of women with epilepsy: a prospective registry study from Mainland China.

Objective: This study aimed to explore the influencing factors of adverse outcomes in the offspring of women with epilepsy (WWE) and to analyze the changes brought about by the epilepsy knowledge popularization campaign in China (EKPCIC). Methods: This nested case-control study focused on WWE and their offspring from a female epilepsy cohort in mainland China. From January 2009 to August 2022, WWE was prospectively enrolled in 32 study centers. This study aimed to observe the health outcomes of their offspring within 1 year of age. The main outcome measure assessed the health status of the offspring within their first year of age. We aimed to analyze the effects of seizures, anti-seizure medicines (ASMs), and a lack of folic acid supplementation on adverse outcomes in the offspring of WWE and to explore the changes in perinatal management and adverse outcomes of the offspring after dissemination of the EKPCIC in 2015. Additionally, subgroup analyses were conducted to compare seizure control during pregnancy between the valproate and non-valproate groups. Results: In total, 781 pregnancies in 695 WWE were included, of which 186 (23.69%) had adverse outcomes. The National Hospital Epilepsy Severity Scale score, number of seizures, status epilepticus, ASM type, and valproate and folic acid doses were associated with a high risk of adverse outcomes. After the EKPCIC, the use of ASMs (P = 0.013) and folic acid (P < 0.001), the seizure-free rate during pregnancy (P = 0.013), and the breastfeeding rate (P < 0.001) increased, whereas the incidence of complications during pregnancy decreased (P = 0.013). However, there was no significant difference in the incidence of adverse outcomes between the analyzed offspring pre-/post-EKPCIC. Additionally, there was no association between the frequency of seizures at different time points during pregnancy and the use of valproate (F = 1.514, P = 0.221). Conclusion: Possible factors influencing adverse outcomes in the offspring of WWE include seizures, type and number of ASM usage, and a lack of folic acid supplementation. Although the management of WWE during pregnancy is now more standardized, further efforts are needed to reduce adverse outcomes in offspring.

Acupuncture for tumor-related depression: a systematic review and meta-analysis.

Introduction: Tumor-related depression is a series of symptoms or states triggered by a tumor as the basic disease. It does not belong to psychiatric depression but dramatically affects individuals' quality of life. Acupuncture is extensively used to treat tumor-related depression, but the effect of body acupuncture on tumor-related depression is still unsubstantiated. This work, therefore, set out to assess the effect of acupuncture on tumor-related depression. Methods: Eight databases were searched from inception to October 2022 for randomized controlled trials (RCTs). Two researchers separately implemented the database search, study selection, data extraction, and quality assessment. All analyses were performed by using Review Manager 5.3. Results: A total of 10 studies, including 725 participants, were included. A majority of studies recruited patients diagnosed with various tumor types and statuses. Meta-analysis revealed that acupuncture had a beneficial effect compared with usual care on the Hamilton depression scale (HAMD) (mean difference (MD) = -2.23, 95% CI [-4.43, -0.03], p = 0.05), self-rating depression scale (SDS) (MD= -6.22, 95% CI [-10.67, -1.78], p = 0.006), effective rate (RR = 1.23, 95% CI [1.06, 1.43], p = 0.006), and quality-of-life questionnaire (QLQ-C30) (MD = 6.08, 95% CI [3.72, 8.43], p<0.0001). In the dimension of the HAMD (MD = -4.41, 95% CI [-6.77, -2.05], p = 0.0002) and SDS (MD = -9.19, 95% CI [-13.14, -5.24], p <0.00001), subgroup analysis also highlighted that acupuncture combined with usual care had an advantage over usual care. However, there was no superiority in acupuncture itself compared to usual care on the HAMD (MD = -1.25, 95% CI [-4.34, -1.84], p = 0.43) and SDS (MD = -3.08, 95% CI [-11.14, 4.98], p = 0.45). Acupuncture also reduced the incidence of adverse effects (RR=0.43, 95% CI [0.23, 0.80], p = 0.008). Conclusion: Acupuncture is a safe and effective complementary therapy for tumor-related depression. This technique can provide clinical references for the medical field. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022372513.

p-Synephrine ameliorates alloxan-induced diabetes mellitus through inhibiting oxidative stress and inflammation via suppressing the NF-kappa B and MAPK pathways.

Oxidative stress and inflammation play important roles in the development of diabetes mellitus. p-Synephrine, the primary pharmacologically active protoalkaloid in Citrus species, has been popularly consumed as a dietary supplement for weight loss management. However, the effects of p-synephrine on diabetes mellitus and the action mechanisms have not been clearly elucidated. In this study, the in vitro antioxidant effects of p-synephrine were evaluated. The data showed that p-synephrine treatment exhibited significant scavenging effects against DPPH, ABTS and OH radicals and showed high reducing power. Diabetic mice were developed by alloxan injection, followed by p-synephrine administration to investigate its hypoglycemic effects in vivo. The results showed that p-synephrine intervention significantly prevented alloxan-induced alteration in body weight, organ indexes, serum uric acid content and serum creatinine content. Meanwhile, p-synephrine application significantly improved the lipid profiles, superoxide dismutase (SOD) and catalase (CAT) activities and glutathione (GSH) contents in the serum and kidneys of diabetic mice and reduced the malondialdehyde (MDA) content in the serum of diabetic mice. Further assays suggested that p-synephrine treatment improved alloxan-induced decreases of glucose tolerance and insulin sensitivity. Also, p-synephrine supplementation altered histopathological changes in the kidneys and interscapular brown adipose tissues in diabetic mice. In addition, p-synephrine administration inhibited renal inflammation through suppressing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) gene expression levels, as well as CD45 expression levels. The anti-inflammatory effects were probably involved in the regulation of nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation. In conclusion, p-synephrine application significantly ameliorated alloxan-induced diabetes mellitus by inhibiting oxidative stress via suppressing the NF-κB and MAPK pathways.

An R2R3-MYB FtMYB11 from Tartary buckwheat has contrasting effects on abiotic tolerance in Arabidopsis.

R2R3-MYB transcription factors play important roles in response to abiotic stresses in planta, such as salt, drought, and osmotic stress. However, the role of FtMYB11 in Tartary buckwheat (Fagopyrum tataricum) in drought and osmotic tolerance has not yet been elucidated. In this study, we found that FtMYB11 was markedly induced by exogenous abscisic acid (ABA), salinity, and mannitol. Further, FtMYB11-overexpressing Arabidopsis showed hypersensitivity to ABA-mediated seed germination and seedling establishment through regulating transcripts of AtCBF1, AtDREB2A, and AtRD20, compared with wild type, indicating that FtMYB11 plays a positive role in ABA signaling. In contrast, transgenic lines overexpressing FtMYB11 were sensitive to mannitol and NaCl treatments, suggesting that FtMYB11 plays a negative role in osmotic tolerance. Intriguingly, the transcripts of ABA biosynthetic enzyme genes were significantly elevated in plants overexpressing FtMYB11 after exposure to osmotic stresses, such as AtABA3 and AtNCED3. In addition, flavonoid biosynthesis genes were also upregulated in transgenic Arabidopsis under ABA, salt, and drought treatments, including AtC4H, AtF3H, AtANS, AtFLS, and At4CL. The drought tolerance assay showed that plants overexpressing FtMYB11 displayed greater tolerance to water deficit through regulating MDA and proline content. Taken together, FtMYB11 has opposite roles in response to abiotic stresses, but it may mediate flavonoid biosynthesis through regulation of related enzyme genes.

Lead exposure represses mitochondrial metabolism by activation of heme-binding protein BACH1 in differentiated SH-SY5Y cell.

Exposure to lead (Pb), a known toxin causing developmental neurotoxicity, can impair neurogenesis and oxidative phosphorylation (OXPHOS), but the mechanism is not clarified. In the current study, we aim to explore the effects of Pb on the differentiation of SH-SY5Y cells and investigate the role of heme and heme-binding protein BACH1 during differentiation. We found that Pb exposure caused a shift from OXPHOS to glycolysis, resulting in neurogenesis impairment by decreasing neurite growth and downregulation of PSD95 and Synapsin-1 in differentiated SH-SY5Y cells. Heme reduction mediated this mitochondria metabolism repression caused by Pb depending on BACH1 activation. Hemin supplement alleviated Pb-induced OXPHOS damage and adenosine triphosphate (ATP) reduction in differentiated SH-SY5Y cells, and further protected for Pb-induced damage of synapse. Heme binding factor BACH1 was negatively regulated by heme content and BACH1 knockout rescued the Pb-induced transcription and expression decline of genes related to OXPHOS and abrogated Pb-induced growth inhibition of axon promotion and synapse formation. Collectively, the present study demonstrates that heme deficiency mediates OXPHOS damage caused by Pb through BACH1 activation, resulting in neurogenesis impairment.

Role of polyphenols from Polygonum multiflorum Caulis in obesity-related disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Caulis (PMC) has been widely consumed as folk medicine in China for anti-obesity, sleep-enhancing and many other pharmacological effects. However, the material basis and underlying mechanism of PMC on obesity-related disorders were still not clear. AIM OF THE STUDY: To screen active constituents from PMC and explore their multitarget mechanisms in the treatment of obesity and its associated disorders. MATERIALS AND METHODS: Several major constituents were extracted from PMC and LC-MS assay were used to identify the compounds. The lipase inhibitory activity and lipid accumulation in 3T3-L1 preadipocytes were determined. Furthermore, Caenorhabditis elegans (C. elegans) and high-fat diet (HFD)-induced mice were established to explore the potential pharmacological functions and related mechanisms using kits, RT-qPCR and biochemical analysis. RESULTS: Regarding the lipase inhibitory activity, the inhibition rate of EA and n-Bu extracts at 4 mg/mL reached over 80%. Effects on 3T3-L1 preadipocytes proliferation and differentiation were also obvious, indicating that EA and n-Bu extracts might exert potential anti-obesity functions. LC-MS assay further showed that polyphenols including emodin and physcion comprised majority of EA and n-Bu extracts. EA and n-Bu extracts treatment could significantly modulate the antioxidant response and lipid accumulation in C. elegans, as evidenced by increased SOD and CAT contents, reduced MDA levels, higher TG contents and changes of related mRNA expression levels. In HFD-induced mice, the inhibition ratio of body weight as well as the histological and biochemical indexes of liver, plasma and epididymal adipose tissues were also reversed by EA and n-Bu extracts treatment. Moreover, EA and n-Bu extracts administration increased the microbial diversity, reshaped the microbiota structure and enhanced the relative abundance of Bifidobacterium. CONCLUSIONS: This study demonstrated the multicomponent and multitarget characteristics of PMC in preventing obesity related disorders. The results provided novel insights for the development and utilization of PMC.

Natural bioactive constituents from herbs and nutraceuticals promote browning of white adipose tissue.

Obesity is a significant public health problem worldwide that is characterized by abnormal or excessive fat accumulation. Unfortunately, the application of available weight-loss drugs has been restricted because of their serious adverse effects. Browning of white adipose tissue (WAT), which refers to the transformation of white adipocytes to beige adipocytes under certain stimulations, is regarded as a new strategy to solve the obesity problem. Numerous studies have recently evidenced that traditional Chinese medicine (TCM) could promote browning of WAT with multi-component and multi-target characteristics. This article summarizes natural constituents from TCM with stimulatory effects on browning of WAT in the past two decades. The active ingredients can be generally divided into polyphenols, saponins, alkaloids, terpenoids, phenylpropanoids and others, such as resveratrol, quercetin, curcumin, genistein, capsaicin, epigallocatechin gallate (EGCG), berberine, menthol, emodin and ginsenosides. Simultaneously, the chemical structures, source, model, efficacy and mechanism of these monomeric compounds are also described. And the mechanisms of these active ingredients are mainly involved in the regulation of PRDM16, PGC-1α, PPARγ, SIRT1, AMPK, ß3-adrenergic receptors, TRPV1 and TRPM8 channels, FGF21 and miRNAs. The present article opens opportunities for developing novel drugs or supplements from TCM with wide acceptability to prevent obesity progression and its associated metabolic disorders.

Inhibitory effect of chloroform extracts from Citrus aurantium L. var. amara Engl. on fat accumulation.

BACKGROUND: Excess lipid accumulation can accelerate the development of various metabolic diseases. Blossoms of Citrus aurantium L. var. amara Engl. (CAVA) have been reported to possess inhibitory capacities on lipid deposition. However, the constituents responsible for the observed bioactivity and the underlying mechanisms are still not clearly understood. PURPOSE: To screen constituents from blossoms of CAVA with inhibitory effects on lipid accumulation and to explore the action mechanism. METHODS: The chloroform (CHL) extracts are prepared from blossoms of CAVA by fractional extraction and are characterized using LC-MS assay. 3T3-L1 preadipocytes are induced with differentiation medium (DMI) and treated with CHL extracts. High fat diet (HFD)-induced obese mice are further established and administrated with CHL extracts for 12 weeks. Hematoxylin and eosin (HE) staining, Oil Red O staining, ELISA, RT-qPCR, western blot and 16S rRNA gene sequence methods are employed. RESULTS: 14 compounds are identified in CHL extracts and trigonelline hydrochloride, nobiletin and 7-demethylsuberosin are most abundant. CHL extracts treatment significantly inhibit differentiation of 3T3-L1 cells by regulating expression of preadipocyte factor-1 (Pref-1), fatty acid synthase (FAS) and CCAAT/enhancer binding protein α (C/EBPα). CHL extracts intervention also significantly attenuate features of obesity and improved plasma biochemical profiles in HFD-fed mice. HFD-triggered hepatic steatosis and epididymal adipose tissues (EATs) hypertrophy are also reversed by CHL extracts administration through enhancing antioxidant responses and modulating lipogenesis and energy expenditure-related genes and proteins. 16S rRNA gene sequence data further show that CHL extracts enhance the diversity of gut microbiota. CHL extracts at lower concentrations reduce the ratio of Firmicutes to Bacteroidetes and the abundance of Erysipelotrichaceae. CHL extracts at higher doses markedly increase the abundance of Lachnospiraceae. CONCLUSION: These findings suggest that CHL extracts probably suppress lipid accumulation through inhibiting differentiation of 3T3-L1 cells and attenuating metabolic syndromes in HFD-fed mice.

The response of tartary buckwheat and 19 bZIP genes to abscisic acid (ABA).

Tartary buckwheat is a kind of plant which can be used as medicine as well as edible. Abscisic acid (ABA) signaling plays an important role in the response of plants such as tartary buckwheat to drought and other stress. However, there are not many studies on tartary buckwheat by ABA treatment. In this study, the germination, root length, stoma, and anthocyanin accumulation of tartary buckwheat were all significantly affected by ABA. ABA signaling is important for plants to respond to drought and other stresses, the bZIP gene family is an important member of the ABA signaling pathway. Through the analysis of the origin relationship between tartary buckwheat bZIP family and its related species, 19 bZIP genes in tartary buckwheat were found to be relatively conserved, which laid a foundation for further study of bZIP family. The qRT-PCR results showed that most of the group members were induced by ABA treatment, including 0, 15, 30, 50, 70 µM ABA and 0, 0.5, 2, 4, 8, 16, 24 h ABA treatment. These results suggested that ABA could affect the growth and development of tartary buckwheat, and FtbZIPs might have different functions in the response of tartary buckwheat to drought. This study will be helpful to further analyze the genetic breeding and economic value of tartary buckwheat resistance.

Characterization of abscisic acid (ABA) receptors and analysis of genes that regulate rutin biosynthesis in response to ABA in Fagopyrum tataricum.

Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn.) is a nutritional crop, which has high rutin, and is good for health. Until now, plant genetic engineering is insufficient for Tartary buckwheat. Abscisic acid (ABA), as one of phytohormones, is involved in the regulation of plant growth and development, and responses to diverse environmental challenges. Although ABA receptors have been well characterized in Arabidopsis, it is little understood in Tartary buckwheat. In this study, we identified 12 ABA receptors, designated as FtRCAR1 through FtRCAR12 in Tartary buckwheat. FtRCARs are divided into three subfamily. Based on the similarity, we could predict that FtRCARs comprise of the monomeric (FtRCAR1, 3, 4, 5, 9, 10, 11 and 12) and the dimeric (FtRCAR2, 7 and 8) state in solution. The analysis of the transcript pattern indicated that most of FtRCARs were significantly variable among the root, stem, leaf, flower and seed, while FtRCAR4 transcript was undetectable under in all tissues. The transcript levels of FtRCARs under ABA treatment indicated that most FtRCARs transcripts were depressed, indicating a possible feedback regulation of ABA signaling. The analysis of rutin biosynthesis related-genes indicated that ABA up-graduated CHS, CHI, F3'H, F3H and FLS transcript levels, while transcripts of 4CL and PAL were down-regulated. In addition, the transcription factors that mediated the rutin biosynthesis related-genes were also regulated by exogenous ABA. Thus, the identification and the characterization of FtRCARs would enable us to further understand the role of ABA signal in Tartary buckwheat.

Close arrangement of CARK3 and PMEIL affects ABA-mediated pollen sterility in Arabidopsis thaliana.

Abscisic acid (ABA) signaling is a vital plant signaling pathway for plant responses to stress conditions. ABA treatment can alter global gene expression patterns and cause significant phenotypic changes. We investigated the responses to ABA treatment during flowering in Arabidopsis thaliana. Dipping the flowers of CARK3 T-DNA mutants in ABA solution, led to less reduction of pollen fertility than in the wild type plants (Col-0). We demonstrated that PMEIL, a gene located downstream of CARK3, directly affects pollen fertility. Due to the close arrangement of CARK3 and PMEIL, CARK3 expression represses transcription of PMEIL in an ABA-dependent manner through transcriptional interference. Our study uncovers a molecular mechanism underlying ABA-mediated pollen sterility and provides an example of how transcriptional interference caused by close arrangement of genes may mediate stress responses during plant reproduction.

Effects of Postoperative Parenteral Nutrition Enhanced by Multivitamin on Metabolic Phenotype in Postoperative Gastric Cancer Patients.

SCOPE: To investigate the effects of postoperative parenteral nutrition (PN) with multivitamins supplementation on oxidative stress and metabolism. METHODS AND RESULTS: The participants are randomly assigned in a 1:1 ratio to groups: total nutrient admixture (TNA) + multivitamin (n = 14, Group A) and TNA + normal saline (n = 16, Group B). The levels of blood vitamins, ILs, and MDA are assessed and the dysregulation of metabolism is analyzed using nontargeted metabolite profiling. The degree of postoperative stress in Group A is significantly lower than that in Group B by analyzing changes in the levels of IL-8 and MDA. A set of 43 features are qualified to have a variable importance parameter score of >1.5 of a partial least-squares discriminate analysis model and fold change of >1.5 at p-value <0.05 between Groups A and B. The principal metabolic alternations in Group A include increased tricarboxylic acid cycle and ketogenesis with reduced plasma-free amino acids. Backing the results of clinical biomarkers, increased levels of antioxidative molecules, together with decreased levels of inflammatory related polyunsaturated fatty acids, are observed. CONCLUSION: Postoperative PN enhanced by multivitamins can alleviate traumatic stress and improve metabolic transition from catabolism to anabolism in gastric cancer patients.

Correlation of auditory event-related potentials and magnetic resonance spectroscopy measures in mild cognitive impairment.

This study was aimed to examine the changes in auditory event-related potentials (AERPs) and their relationship with brain metabolic changes in mild cognitive impairment (MCI). 34 MCI patients and 34 healthy elderly controls were subjected to auditory stimulus oddball task, and then post-stimulus potentials (P50, N100, P200, N200, and P300) were obtained, levels of N-acetylaspartate (NAA), creatine (Cr) and the ratio of NAA/Cr were measured by proton magnetic resonance spectroscopy (1H-MRS) in left frontal, left temporal and right parietal cortex. Compared with the control group, the MCI group had significantly increased P50 amplitudes and P300 latency, and the NAA/Cr was abnormal. Linear progression analysis revealed a strong negative correlation between P50 amplitudes and NAA/Cr in left frontal cortex, and negative correlation between P300 latency and NAA/Cr in left frontal and left temporal, as well as correlation of AERP components and MRS metabolites with clinical scores of cognitive tests. These findings suggest that metabolic abnormalities of different brain regions may reflect the changes of underlying brain activities that are instrumental in the MCI. Therefore AERPs and MRS measurements may offer a mean to track changes of brain activities associated with functional changes, and to assess early cognitive impairment in MCI.