Neuroprotective effect of green tea extract (-)-epigallocatechin-3-gallate in a preformed fibril-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The main bioactive component of green tea polyphenols (-)-epigallocatechin-3-gallate (EGCG) exerts protective effects against diseases such as neurodegenerative diseases and cancer. Therefore, this study investigated the effect of EGCG on the amelioration of neural damage in a chronic PD mouse model induced by α-synuclein preformed fibrils (α-syn-PFFs). A total of 20 C57BL/6J female mice were randomly divided into 3 groups: control group (saline, n = 6), model group (PFFs, n = 7), and prevention group (EGCG+PFFs, n = 7). A chronic PD mouse model was obtained by the administration of α-syn-PFFs by stereotaxic localization in the striatum. Behavioral tests were performed to evaluate PD-related anxiety-like behavior and motor impairments in the long-term PD progression. Tyrosine hydroxylase (TH) immuno-positive neurons and Ser129-phosphorylated α-syn (p-α-syn) were identified by immunohistochemistry. Pro-inflammatory and anti-inflammatory cytokines were measured by real-time quantitative PCR. EGCG pretreatment reduced anxiety-like behavior and motor impairments as revealed by the long-term behavioral test (2 weeks, 1 month, 3 months, and 6 months) on PD mice. EGCG also ameliorated PFF-induced degeneration of TH immuno-positive neurons and accumulation of p-α-syn in the SN and striatum at 6 months. Additionally, EGCG reduced the expression of pro-inflammatory cytokines while promoting the release of anti-inflammatory cytokines. EGCG exerts a neuroprotective effect on long-term progression of the PD model.

Multifunctional Two-Dimensional Bi2Se3 nanodisks as a Non-Inflammatory photothermal agent for glioma treatment.

Photothermal therapy (PTT) has gained widespread attention due to its significant advantages, such as noninvasiveness and ability to perform laser localization. However, PTT usually reaches temperatures exceeding 50 °C, which causes tumor coagulation necrosis and unfavorable inflammatory reactions, ultimately decreasing its efficacy. In this study, multifunctional two-dimensional Bi2Se3 nanodisks were synthesized as noninflammatory photothermal agents for glioma therapy. The Bi2Se3 nanodisks showed high photothermal stability and biocompatibility and no apparent toxicology. In addition, in vitro and in vivo studies revealed that the Bi2Se3 nanodisks effectively ablated gliomas at relatively low concentrations and inhibited tumor proliferation and migration. Moreover, the multienzymatic activity of the Bi2Se3 nanodisks inhibited the PTT-induced inflammatory response through their high ability to scavenge reactive oxygen species. Finally, the Bi2Se3 nanodisks demonstrated computed tomography capabilities for integrating diagnosis and treatment. These findings suggest that multifunctional Bi2Se3 nanodisk nanozymes can enable more effective cancer therapy and noninflammatory PTT.

Genetically determined circulating micronutrients and the risk of nonalcoholic fatty liver disease.

Evidence from epidemiological literature on the association of circulating micronutrients with risk of nonalcoholic fatty liver disease (NAFLD) is inconsistent. We aimed to elucidate the causal relationships using Mendelian randomization (MR). Single-nucleotide polymorphisms associated with 14 circulating micronutrients (ß-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, B12, C, D, K1 and zinc) were employed as instrumental variables. Summary level data for NAFLD were obtained from a genome-wide association study (GWAS) meta-analysis of 8434 cases and 770,180 controls (discovery stage) and another two datasets including 1483 NAFLD cases and 17,781 controls (replication stage 1) and 2134 NAFLD cases and 33,433 controls (replication stage 2). Inverse variance-weighted method (IVW) was used as primary analysis, supplemented with a series of sensitivity analysis. Genetically predicted higher ß­carotene levels were suggestively associated with reduced NAFLD risk [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66-0.99; P = 0.047], whereas the association did not survive the false discovery rates (FDR) correction (PFDR = 0.164). Genetically predicted circulating iron (OR 1.16, 95% CI 1.05-1.29; P = 0.006, PFDR = 0.028), selenium (OR 1.11, 95% CI 1.03-1.20; P = 0.005, PFDR = 0.028) and vitamin B12 (OR 1.08, 95% CI 1.03-1.13; P = 0.002, PFDR = 0.028) were significantly associated with increased risk of NAFLD. Moreover, the findings were consistent in individual datasets (Pheterogeneity > 0.05) and confirmed in sensitivity analysis. Our study provided evidence that circulating iron, selenium and vitamin B12 might be causally linked to the risk of NAFLD, which deserves further exploration of the potential biological mechanism.

Migration and transformation of phosphorus and toxic metals during sludge incineration with Ca additives.

The recycling and utilization of phosphorus resources in sludge is becoming increasingly important. In this study, we compared the conversion of phosphorus and toxic metal passivation effects of different Ca additives under oxygen-rich combustion conditions and elucidated their specific mechanisms of action. The experimental results indicated that four Ca-based additives improved the recovery rate of total phosphorus, and promoted the generation of stable apatite phosphorus (AP). The effect of CaCl2 and CaO was greater than that of Ca(OH)2 and CaSO4. CaCl2 promoted the formation of Ca3(PO4)2 and Ca2P2O7, and CaSO4 improved the conversion of AlPO4 to Ca(H2PO4)2 with increasing temperature. The conversion capacity of CaO on non-apatite inorganic phosphorus to AP was greater than that of Ca(OH)2, and more CaH2P2O7, Ca(PO3)2, and Ca-Al-P minerals were found. Toxic metal percentages decreased after sludge incineration with CaCl2. Compared with CaO and Ca(OH)2, the toxic metal adsorption effect of CaSO4 was more significant. The influence of Ca additives on the conversion of Zn into stable components was as follows: CaCl2 > Ca(OH)2 > CaO > CaSO4. Ca additives reduced the toxic metal contamination level and ecological risk index values, and the order of toxic metal contamination levels was Ni > Zn > Cr > Cu > Mn. The experiment confirmed the conversion of phosphorus and the toxic metal passivation effect of Ca additives during oxy-fuel combustion of sludge, which is beneficial for its resource utilization.

Renzhu Ointment Regulates L-Type Voltage-Dependent Calcium Channel in Mice Model of Senna-Induced Diarrhea by Transdermal Administration.

Purpose: In China, herbal preparation is commonly administered transdermally for treating pediatric diarrhea. However, few studies have probed into their antidiarrheal mechanisms. This study was designed to investigate the antidiarrheal effect of Renzhu ointment (Renzhuqigao, RZQG) and its underlying mechanisms via transdermal administration. Methods: The main components of RZQG were confirmed by gas chromatography-mass spectrometry (GC-MS). The effect of RZQG on L-type voltage-dependent calcium channel (L-VDCC) was evaluated by CaCl2- and ACh-induced contraction in isolated colon. The antidiarrheal efficacy of RZQG was further investigated by the senna-induced diarrhea mice based on the frequency of loose stools, diarrhea rate and index, fecal moisture content, and the basal tension of the colon. Additionally, the protein expression of CACNA1C, CACNA1D, cAMP, and PKA were detected with Western blot and immunohistochemistry (IHC). Results: GC-MS analysis determined 14 components in RZQG. In vitro, RZQG relaxed the CaCl2- and ACh-induced tension, while nifedipine (a L-VDCC inhibitor) and H-89 (a PKA inhibitor) decreased the relaxation. In vivo, animal model showed that transdermal administration of RZQG exhibited a significant reduction in the frequency of loose stools, diarrhea rate and index, fecal moisture content and the basal tension. Compared to the model group, the colon of mice treated with RZQG showed lower expression of CACNA1C, CACNA1D, cAMP, and PKA. IHC results showed that cAMP was downregulated in colonic smooth muscle after RZQG treatment. Conclusion: RZQG improved diarrhea symptoms and down-regulated the expression of CACNA1C and CACNA1D via transdermal administration, which is closely associated with the cAMP/PKA signaling pathway in colonic smooth muscle.

A Responsive Nanorobot Modulates Intracellular Zinc Homeostasis to Amplify Mitochondria-Targeted Phototherapy.

Zinc has been proven to interweave with many critical cell death pathways, and not only exhibits potent anticancer activity solely, but sensitizes cancer cells to anticancer treatment, making zinc supplementation ideal for boosting odds against malignancy. Herein, a smart nanorobot (termed as Zinger) is developed, composed of iRGD-functionalized liposome encapsulating black phosphorus nanosheet (BPNs) doped zeolite imidazole framework-8 (BPN@ZIF-8), for advancing zinc-promoted photodynamic therapy (PDT). Zinger exhibits photo-triggered sequential mitochondria-targeting ability, and can induce zinc overload-mediated mitochondrial stress, which consequently sensitized tumor to PDT through synergistically modulating reactive oxygen species (ROS) production and p53 pathway. It is identified that Zinger selectively triggered intracellular zinc overload and photodynamic effect in cancer cells, which together enhanced PDT treatment outcomes. Importantly, Zinger shows high efficacy in overcoming various treatment barriers, allowing for effectively killing cancer cells in the complex circumstances. Particularly, Zinger exhibits good tumor accumulation, penetration, and even cell uptake, and can respond to light stimulation to eliminate tumors while avoiding normal tissues, thereby prolonging survival of tumor-bearing mice. Therefore, the study provides a novel insight in the development of novel zinc-associated therapy for advancing cancer treatment approaches.

Celastrol relieves myocardial infarction-induced cardiac fibrosis by inhibiting NLRP3 inflammasomes in rats.

BACKGROUND: Myocardial infarction (MI) triggers a strong inflammatory response mediating by NLRP3 inflammasome which is associated with cardiac fibrosis. The key players in this response are Interleukin (IL)-1 and IL-18, which are regulated by NLRP3 inflammasomes. Celastrol, a traditional Chinese medicine with strong anti-inflammatory activity, has recently reported as a cardioprotective agent. However, the mechanisms by which celastrol is cardioprotective in MI remain elusive. We hypothesized that Celastrol could reduce IL-1ß and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in rats, improve poor heart remodeling, and preserve heart function. METHODS: Myocardial infarction (MI) was caused by ligating the left anterior descending of male SD rats. Celastrol (1 mg/kg) or saline was administered every other day for 4 weeks. Heart function and fibrosis were assessed. Inflammatory and fibrotic markers in the myocardia were evaluated with immunohistochemistry, western blot, and ELISA. Molecular docking was employed to predict Celastrol's binding to NLRP3 protein. The effects of Celastrol on the expression of NLRP3 inflammasome and myocardial fibrosis genes were then examined in vitro. RESULTS: Celastrol maintained the left ventricular fractional shortening (FS) and ejection fraction (EF). Fibrosis was significantly reduced in animals treated with 1 mg/kg Celastrol (15.17 ± 1.82%) relative to controls (29.88 ± 4.28%). Celastrol also significantly reduced the NLRP3, IL-18, and IL-1ß levels, together with macrophage and neutrophil infiltration in the myocardium. Molecular docking predicted that NLRP3 would bind tightly to Celastrol [Docking energy: -8.9 (kcal/mol)]. In vitro experiments showed reduced NLRP3 inflammasome and myocardial fibrosis-associated proteins expression in neonatal rat cardiac fibroblasts treated with Celastrol. CONCLUSIONS: In post-MI rats, Celastrol, a naturally occurring active ingredient, was able to reduce myocardial fibrosis and improve cardiac function, according to our study. These effects may result from inhibiting the NLRP3 inflammasome and attenuating the early inflammatory storm after MI, suggesting that Celastrol may be useful in treating acute MI.

Multiple stimulus-response berberine plus baicalin micelles with particle size-charge-release triple variable properties for breast cancer therapy.

OBJECTIVE: The aim was to develop a nanoscale drug delivery system with enzyme responsive and acid sensitive particle size and intelligent degradation aiming to research the inhibitory effect on breast cancer. SIGNIFICANCE: The delivery system addressed the problems of tissue targeting, cellular internalization, and slow drug release at the target site, which could improve the efficiency of drug delivery and provide a feasible therapeutic approach for breast cancer. METHODS: The acid sensitive functional material DSPE-PEG2000-dyn-PEG-R9 was synthesized by Michael addition reaction. Then, the berberine plus baicalin intelligent micelles were prepared by thin-film hydration. Subsequently, we characterized the physical and chemical properties of berberine plus baicalin intelligent micelles, evaluated its anti-tumor effects in vivo and in vitro. RESULTS: The target molecule was successfully synthesized, and the intelligent micelles showed excellent chemical and physical properties, delayed drug release and high encapsulation efficiency. In vitro and in vivo experiments also confirmed that the intelligent micelles could effectively target tumor sites, penetrate tumor tissues, enrich in tumor cells, inhibit tumor cell proliferation, inhibit tumor cell invasion and migration, and induce tumor cell apoptosis. CONCLUSION: Berberine plus baicalin intelligent micelles have excellent anti-tumor effects and no toxicity to normal tissues, which provides a new potential drug delivery strategy for the treatment of breast cancer.

Crosslinked albumin-manganese nanoaggregates with sensitized T1 relaxivity and indocyanine green loading for multimodal imaging and cancer phototherapy.

Albumin-manganese-based nanocomposites (AMNs) characterized by simple preparation and good biocompatibility have been widely used for in vivo T1-weighted magnetic resonance imaging (MRI) and cancer theranostics. Herein, an aggregation and crosslinking assembly strategy was proposed to achieve the sensitization to T1 relaxivity of the albumin-manganese nanocomposite. At a relatively low Mn content (0.35%), the aggregation and crosslinking of bovine serum albumin-MnO2 (BM) resulted in a dramatic increase of T1 relaxivity from 5.49 to 67.2 mM-1 s-1. Upon the loading of indocyanine green (ICG) into the crosslinked BM nanoaggregates (C-BM), the T1 relaxivity of the C-BM/ICG nanocomposite (C-BM/I) was further increased to 97.3 mM-1 s-1, which was much higher than those reported previously even at high Mn contents. Moreover, the presence of C-BM greatly enhanced the photoacoustic (PA) and photothermal effects of ICG at 830 and 808 nm, respectively, and the second near infrared fluorescence (NIR-II FL) of ICG also showed better stability. Therefore, the synthesized C-BM/ICG nanocomposite exhibited remarkable performance in in vivo multimodal imaging of tumors, such as T1-weighted MRI, NIR-II FL imaging and PA imaging, and cancer phototherapy with little side effects. This work provided a highly efficient and promising multifunctional nanoprobe for breaking through the limits of cancer theranostics, and opened a new avenue for the development of high-relaxivity AMNs and multimodal imaging methodology.

Yin-Yang tongue sign: An imaging clue of lesions involving the skull base segment in the hypoglossal pathway.

OBJECTIVE: To investigate the diagnostic value of the Yin-Yang tongue sign in patients with tongue deviation. METHODS: According to the presence of the Yin-Yang tongue sign on CT/MR, 107 patients with tongue deviation were divided into a positive group and a negative group. The involvement categories of the hypoglossal canal (HC) in the positive group were evaluated and classified as HC dilation and HC erosion. The correlations between HC involvement categories and the presence of the sign were analysed. RESULTS: There were 55 cases (55/107, 51.4%) in the positive group and 52 cases (52/107, 48.6%) in the negative group. Hypoglossal nerve (HN) involvement mainly occurred in the skull base (61.8%), skull base and carotid space (10.9%), and carotid space segment (12.7%). Neurogenic (50.9%), squamous cell carcinoma (14.5%), and metastases (12.7%) were the predominant aetiologies. The sensitivity, specificity, and accuracy of this sign for suggesting skull base lesions around HC were 72.4%, 80.8%, and 76.6%, respectively. In the positive group, HC dilation was seen in 21 patients (21/55, 38.2%) and 21 cases were all benign. HC erosion were noted in 19 patients (19/55, 34.5%), of whom 12 cases were malignant. CONCLUSION: The Yin-Yang tongue sign is formed by unilateral tongue atrophy and fat infiltration caused by lesions in the HN pathway, especially compressive or invasive lesions involving the skull base segment.

Danhong injection alleviates cerebral ischemia-reperfusion injury by inhibiting autophagy through miRNA-132-3p/ATG12 signal axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI) is a renowned traditional Chinese medicine often used clinically to treat cardiovascular and cerebrovascular diseases. Studies have shown that DHI can significantly alter microRNA (miRNA) expression in the brain tissue. Therefore, exploring specific miRNAs' regulatory mechanisms during treatment with DHI is essential. AIM OF THE STUDY: To investigate DHI's regulatory mechanism on cerebral autophagy in rats with cerebral ischemia-reperfusion injury (CIRI). MATERIAL AND METHODS: Rats were randomly divided into the sham, middle cerebral artery occlusion (MCAO) model, and DHI-treatment groups. The extent of brain damage was evaluated using triphenyl tetrazolium chloride and hematoxylin-eosin staining. Hippocampal cell autophagy was observed using transmission electron microscopy. Autophagy-related proteins were analyzed using western blotting. Differentially expressed miRNAs were screened using high-throughput and real-time quantitative reverse transcription PCR. The relationship between miR-132-3p and ATG12 was confirmed using a dual-luciferase assay. The miR-132-3p mimics and inhibitors were transfected into PC12 cells subjected to oxygen-glucose deprivation (OGD) in vitro and MCAO model rats in vivo. RESULTS: DHI significantly altered the miRNA expression profile in rat brain tissues. The pathological changes in the brain tissues were improved, and the autophagic hippocampal cell vehicles were significantly reduced after DHI treatment. miRNA-132-3p, one of the miRNAs with a significantly different expression, was screened. Kyoto Encyclopedia of Genes and Genomes signal pathway analysis showed that its target genes were closely related to autophagy. Western blotting revealed that the p-PI3K, p-AKT, and mTOR expression increased significantly; AMPK, ULK1, ATG12, ATG16L1, and LC3II/I were downregulated in the DHI group. Dual-luciferase reporter gene experiments showed that miRNA-132-3p could target the ATG12 3'-UTR region directly. In vitro, miRNA-132-3p had a protective effect on OGD/R-induced oxidative stress injury in PC12 cells, improving cell viability, and affecting the expression of autophagy pathway-related proteins. In vivo transfection experiments showed that miR-132-3p could regulate ATG12 expression in CIRI rats' lateral brain tissue, affecting the autophagy signaling pathway. miR-132-3p overexpression reduces CIRI-induced autophagy and protects neurons. CONCLUSION: This study showed that DHI inhibits neuronal autophagy after cerebral ischemia-reperfusion. This may have resulted from miR-132-3p targeting ATG12 and regulating the autophagy signaling pathway protein expression.

Genetically predicted iron status was associated with the risk of prostate cancer.

Introduction: Observational studies have reported a relationship between iron status and the risk of prostate cancer. However, it remains uncertain whether the association is causal or due to confounding or reverse causality. To further clarify the underlying causal relationship, we conducted a Mendelian randomization (MR) analysis. Methods: We selected three genetic variants (rs1800562, rs1799945, and rs855791) closely correlated with four iron status biomarkers (serum iron, log-transformed ferritin, transferrin saturation, and transferrin) as instrumental variables. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was conducted primarily to estimate the association of genetically predicted iron status and the risk of prostate cancer, supplemented with simple-median, weighted-median and maximum-likelihood methods as sensitivity analysis. MR-Egger regression was used to detect directional pleiotropy. We also conducted a meta-analysis of observational studies to assess the associations between iron status and the risk of prostate cancer. Results: Genetically predicted increased iron status was associated with the decreased risk of prostate cancer, with odds ratio of 0.91 [95% confidence interval (CI): 0.84, 0.99; P = 0.035] for serum iron, 0.81 (95% CI: 0.65, 1.00; P = 0.046) for log- transformed ferritin, 0.94 (95% CI: 0.88, 0.99; P = 0.029) for transferrin saturation, and 1.15 (95% CI: 0.98, 1.35; P = 0.084) for transferrin (with higher transferrin levels representing lower systemic iron status), using the inverse-variance weighted method. Sensitivity analyses produced consistent associations, and MR-Egger regression indicated no potential pleiotropy. Our replication analysis based on FinnGen research project showed compatible results with our main analysis. Results from our meta-analysis similarly showed that serum ferritin [standardized mean difference (SMD): -1.25; 95% CI: -2.34, -0.16; P = 0.024] and transferrin saturation (SMD: -1.19; 95% CI: -2.34, -0.05; P = 0.042) were lower in patients with prostate cancer compared with that in controls. Discussion: Our study suggests a protective role of iron in the risk of prostate cancer, further investigations are required to clarify the underlying mechanisms.

Ursolic acid regulates gut microbiota and corrects the imbalance of Th17/Treg cells in T1DM rats.

Ursolic acid (UA), a natural pentacyclic triterpenoid obtained from fruit and several traditional Chinese medicinal plants, exhibits anti-inflammatory and hypoglycemic properties. However, its protective effects against type 1 diabetes mellitus (T1DM) have not been explored. In this study, streptozotocin-induced T1DM rat models were established and treated with UA for six weeks. T1DM rats treated with UA were used to observe the effects of UA on body weight and fasting blood glucose (FBG) levels. Pathological changes in the pancreas were observed using immunohistochemical staining. The gut microbiota distribution was measured using 16S rDNA high-throughput sequencing. The proportions of Th17 and Treg cells were examined using flow cytometry. Protein and mRNA expression of molecules involved in Th17/Treg cell differentiation were assessed by quantitative real-time PCR and western blotting. The correlation between gut microbiota and Th17/Treg cell differentiation in T1DM was analyzed using redundancy analysis (RDA) analysis. Compared with the model group, FBG levels declined, and the progressive destruction of pancreatic ß cells was alleviated. The diversity and uniformity of gut microbiota in T1DM rats treated with UA increased significantly. Interestingly, the Th17/Treg cell differentiation imbalance was corrected and positively correlated with the expression of Foxp3 and IL-10, and negatively correlated with the expression of RORγt, IL-17A, and TNF-α. These findings suggest that UA can lower FBG levels in T1DM rats, delay the progressive destruction of pancreatic ß-cells, and modulate gut microbiota homeostasis and immune function in streptozotocin-induced T1DM rats.

Nutrient budgets drive the changes in shoot N and P concentrations of plants in Inner Mongolia's grasslands over the past 40 years.

The nutrient budgets of grassland ecosystems have been extensively disturbed by human activity. The aims of this study were to quantify nitrogen (N) and phosphorus (P) budgets, and evaluate their contributions to changes in shoot nutrient concentrations of dominant plants in Inner Mongolia's grasslands over the past 40 years. N and P budgets were assessed using a nutrient budget model based on flowing intensity of nutrients in and out of the grassland. Meta-analysis was then conducted to quantify changes in shoot nutrient concentrations. The N budget remained positive and continued to increase throughout the study period, while enhanced N deposition and increased supplementary feeding dominated N input (76% of the total in 2017). In contrast, the P budget was negative until 2003, and became positive thereafter. The P input was mainly attributed to supplementary feeding (88% of the total in 2017). The mean shoot N concentration in 1979-1986 was 2.25%, while an increase to 2.53% was observed in 2006-2016. In contrast, the mean shoot P concentration was 0.17% in 1979-1991, subsequently leveling off at 0.17% in 2006-2016. The mean shoot N: P ratio basically remain unchanged over time from 16.72 to 15.85. The N surplus caused major increases in the shoot N concentration of the grassland plants; also, the increased P budget to compensate for past P deficiency resulted in no significant change of shoot P concentrations. Consequently, the grassland system had been in the joint N and P co-limitation over the past 40 years.

Hygromycin A derivatives isolated from Streptomyces sp. PC-22 in the rhizosphere soil of Pulsatilla chinensis.

On the basis of the one strain-many compounds (OSMAC) strategy, two new hygromycin A derivatives (3, 4), together with six known compounds were isolated from a medicinal plant inter rhizospheric Streptomyces in Pulsatilla chinensis. The structures of 3 and 4 were elucidated using NMR and HRESIMS analyses. A plausible biosynthetic pathway for these compounds was discussed. All the compounds were evaluated for their antimicrobial and cytotoxic activities. Compound 5 exhibited potent inhibitory activity against S. aureus and B. subtilis with the MICs of 16 and 8 µg ml-1, while 4 showed weak inhibitory activity against S. aureus.

A network pharmacology-based approach to explore the active ingredients and molecular mechanism of Lei-gong-gen formula granule on a spontaneously hypertensive rat model.

BACKGROUND: Lei-gong-gen formula granule (LFG) is a folk prescription derived from Zhuang nationality, the largest ethnic minority among 56 nationalities in China. It consists of three herbs, namely Eclipta prostrata (L.) L., Smilax glabra Roxb, and Centella asiatica (L.) Urb. It has been widely used as health protection tea for hundreds of years to prevent hypertension in Guangxi Zhuang Autonomous Region. The purpose of this study is to validate the antihypertensive effect of LFG on the spontaneously hypertensive rat (SHR) model, and to further identify the effective components and anti-hypertension mechanism of LFG. METHODS: The effects of LFG on blood pressure, body weight, and heart rate were investigated in vivo using the SHR model. The levels of NO, ANG II, and ET-1 in the serum were measured, and pathological changes in the heart were examined by H&E staining. The main active components of LFG, their corresponding targets, and hypertension associated pathways were discerned through network pharmacology analysis based on the Traditional Chinese Medicine Systems Pharmacology (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Then the predicted results were further verified by molecular biology experiments such as RT-qPCR and western blot. Additionally, the potential active compounds were predicted by molecular docking technology, and the chemical constituents of LFG were analyzed and identified by UPLC-QTOF/MS technology. Finally, an in vitro assay was performed to investigate the protective effects of potential active compounds against hydrogen peroxide (H2O2) induced oxidative damage in human umbilical vein endothelial cells (HUVEC). RESULTS: LFG could effectively reduce blood pressure and increase serum NO content in SHR model. Histological results showed that LFG could ameliorate pathological changes such as cardiac hypertrophy and interstitial inflammation. From network pharmacology analysis, 53 candidate active compounds of LFG were collected, which linked to 765 potential targets, and 828 hypertension associated targets were retrieved, from which 12 overlapped targets both related to candidate active compounds from LFG and hypertension were screened and used as the potential targets of LFG on antihypertensive effect. The molecular biology experiments of the 12 overlapped targets showed that LFG could upregulate the mRNA and protein expressions of NOS3 and proto-oncogene tyrosine-protein kinase SRC (SRC) in the thoracic aorta. Pathway enrichment analysis showed that the PI3K-AKT signaling pathway was closely related to the expression of NOS3 and SRC. Moreover, western blot results showed that LFG significantly increased the protein expression levels of PI3K and phosphorylated AKT in SHR model, suggesting that LFG may active the PI3K-AKT signaling pathway to decrease hypertension. Molecular docking study further supported that p-hydroxybenzoic acid, cedar acid, shikimic acid, salicylic acid, nicotinic acid, linalool, and histidine can be well binding with NOS3, SRC, PI3K, and AKT. UPLC-QTOF/MS analysis confirmed that p-hydroxybenzoic acid, shikimic acid, salicylic acid, and nicotinic acid existed in LFG. Pre-treatment of HUVEC with nicotinic acid could alleviate the effect on cell viability induced by H2O2 and increase the NO level in cell supernatants. CONCLUSIONS: LFG can reduce the blood pressure in SHR model, which might be attributed to increasing the NO level in serum for promoting vasodilation via upregulating SRC expression level and activating the PI3K-AKT-NOS3 signaling pathway. Nicotinic acid might be the potential compound for LFG antihypertensive effect.

Effect of the duration of the capecitabine regimen following colon cancer surgery in an elderly population: a retrospective cohort study.

BACKGROUND: Only 50-70% of elderly colon cancer patients could complete the recommended 6 months of postoperative chemotherapy. It is unknown whether a shorter duration of postoperative capecitabine-alone chemotherapy would compromise survival. We thus conducted this study to analyze the association between postoperative chemotherapy duration of a capecitabine-alone regimen and cancer-specific survival (CSS) and disease-free survival (DFS) of surgery-treated elderly colon cancer patients. METHODS: We performed a retrospective cohort study of surgically treated stage III and high-risk stage II colon cancer patients aged ≥ 70 treated at two medical centers. Cox proportional hazard regression models were utilized to calculate crude and adjusted hazard ratios (HRs). The nonlinear relationship between postoperative chemotherapy duration and survival was analyzed through restricted cubic spline regression analysis, and the threshold effect was calculated by the two-piecewise Cox proportional hazard model. RESULTS: A total of 1217 surgery-treated colon cancer patients between August 1, 2013, and September 1, 2019, were reviewed, and 257 stage III and high-risk stage II patients aged ≥ 70 were enrolled. Postoperative chemotherapy with capecitabine was administered to 114 patients, and 143 patients only received surgery. As the duration of chemotherapy increased by 1 week, the risk of cancer-specific death was reduced by 11% (HR = 0.89, 95% confidence interval (CI) 0.82-0.96), and the risk of recurrence was reduced by 10% (HR = 0.90, 0.82-0.96). Nonlinearity exploration suggested a threshold effect of capecitabine duration on CSS in stage III disease. The HR for death was 0.79 (95% CI, 0.68-0.92) with duration ≤ 16 weeks and 1.34 (95% CI, 0.91-1.97) with duration > 16 weeks. CONCLUSIONS: The postoperative capecitabine duration was significantly associated with a decrease in death risk and recurrence risk in elderly colon cancer patients. However, the threshold effect of capecitabine duration on survival suggests that short-term chemotherapy may improve survival in elderly stage III colon cancer patients.

The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.

New limonoids and quinolone alkaloids with cytotoxic and anti-platelet aggregation activities from Evodia rutaecarpa (Juss.) Benth.

One new limonoid, named 19-hydroxy methyl isoobacunoate diosphenol (1); one new degraded limonoid, named 9α-methoxyl dictamdiol (9); two new quinolone alkaloids, 1-methyl-3-[(7E,9E,12Z)-7,9,12-pentadecadienyl]-4(1H)-quinolone (11) and 1-methyl-3-[(7E,9E,11E)-7,9,11-pentadecadienyl]-4(1H)-quinolone (12), along with eight known compounds, evodol (2), 7ß-acetoxy-5-epilimonin (3), rutaevine (4), 6ß-acetoxy-5-epilimonin (5), limonin (6), obacunone (7), clauemargine L (8), hiiranlactone E (10) were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth.. Structures of the four new compounds were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR techniques. Compounds 3, 5, 9, 11 and 12 showed obviously cytotoxic activity against six human tumor lines, while compounds 11, 12 displayed anti-platelet aggregation induced by ADP at 50 µM and 100 µM.

Effects of phosphorus deficiency on the absorption of mineral nutrients, photosynthetic system performance and antioxidant metabolism in Citrus grandis.

Phosphorus (P) is an essential macronutrient for plant growth, development and production. However, little is known about the effects of P deficiency on nutrient absorption, photosynthetic apparatus performance and antioxidant metabolism in citrus. Seedlings of 'sour pummelo' (Citrus grandis) were irrigated with a nutrient solution containing 0.2 mM (Control) or 0 mM (P deficiency) KH2PO4 until saturated every other day for 16 weeks. P deficiency significantly decreased the dry weight (DW) of leaves and stems, and increased the root/shoot ratio in C. grandis but did not affect the DW of roots. The decreased DW of leaves and stems might be induced by the decreased chlorophyll (Chl) contents and CO2 assimilation in P deficient seedlings. P deficiency heterogeneously affected the nutrient contents of leaves, stems and roots. The analysis of Chl a fluorescence transients showed that P deficiency impaired electron transport from the donor side of photosystem II (PSII) to the end acceptor side of PSI, which showed a greater impact on the performance of the donor side of PSII than that of the acceptor side of PSII and photosystem I (PSI). P deficiency increased the contents of ascorbate (ASC), H2O2 and malondialdehyde (MDA) as well as the activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR) and glutathione reductase (GR) in leaves. In contrast, P deficiency increased the ASC content, reduced the glutathione (GSH) content and the activities of SOD, CAT, APX and monodehydroascorbate reductase (MDHAR), but did not increase H2O2 production, anthocyanins and MDA content in roots. Taking these results together, we conclude that P deficiency affects nutrient absorption and lowers photosynthetic performance, leading to ROS production, which might be a crucial cause of the inhibited growth of C. grandis.