High-dose vitamin C improves norepinephrine level in patients with septic shock: A single-center, prospective, randomized controlled trial.

BACKGROUND: The effects of vitamin C supplementation on patients with septic shock remain controversial. We aimed to evaluate the effects of different vitamin C dosages on norepinephrine (NE) synthesis in adult patients with septic shock. METHODS: A total of 58 patients with septic shock admitted to our intensive care unit (ICU) between July 2021 and December 2022 were included. Patients were randomly divided into 3 groups: high-dose vitamin C (150 mg/kg/d, group A), low-dose vitamin C (50 mg/kg/d, group B), and placebo (group C). NE synthesis-related indicators (dopamine-ß-hydroxylase [DßH], tyrosine hydroxylase [TH], tetrahydrobiopterin [BH4], and dopamine [DA]), plasma NE, and vitamin C levels were measured every 24 hours and analyzed. All-cause mortality within 28 days and other clinical outcomes (including Acute Physiology and Chronic Health Evaluation [APACHE], Sequential Organ Failure Assessment [SOFA], and Multiple-Organ Dysfunction Syndrome [MODS] scores) were compared. RESULTS: Changes in TH, BH4, and DßH levels at 96 hours in groups A and B were greater than those in group C. These differences became more pronounced over the course of the intravenous vitamin C administration. Significant differences between groups A and C were detected at 96-hours TH, 72-hours BH4, 96-hours BH4, 96-hours DA, and DßH levels every 24 hours. The 96-hours TH, 96-hours BH4, and 48-hours DßH in group B were significantly higher than those in group C. The NE levels every 24 hours in groups A and B were higher than those in group C, group A and group C had a statistically significant difference. The 96-hours exogenous NE dosage in groups A and B was significantly lower than that in group C. No significant reductions in APACHE, SOFA, or MODS scores were observed in the vitamin C group, including the duration of ICU stay and mechanical ventilation. The 28-days mortality was lower in groups A and B than in group C (0%, 10%, and 16.67%, P = .187), but the difference was not significant. CONCLUSION: For patients with septic shock, treatment with vitamin C significantly increased TH, BH4, and DßH levels and reduced the exogenous NE dosage, but did not significantly improve clinical outcomes.

Drug repurposing-based nanoplatform via modulating autophagy to enhance chemo-phototherapy against colorectal cancer.

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

PI3K/AKT mediated De novo fatty acid synthesis regulates RIG-1/MDA-5-dependent type I IFN responses in BVDV-infected CD8+T cells.

Bovine viral diarrhea virus (BVDV) has caused massive economic losses in the cattle business worldwide. Fatty acid synthase (FASN), a key enzyme of the fatty acid synthesis (FAS) pathway, has been shown to support virus replication. To investigate the role of fatty acids (FAs) in BVDV infection, we infected CD8+T lymphocytes obtained from healthy cattle with BVDV in vitro. During early cytopathic (CP) and noncytopathic (NCP) BVDV infection in CD8+ T cells, there is an increase in de novo lipid biosynthesis, resulting in elevated levels of free fatty acids (FFAs) and triglycerides (TG). BVDV infection promotes de novo lipid biosynthesis in a dose-dependent manner. Treatment with the FASN inhibitor C75 significantly reduces the phosphorylation of PI3K and AKT in BVDV-infected CD8+ T cells, while inhibition of PI3K with LY294002 decreases FASN expression. Both CP and NCP BVDV strains promote de novo fatty acid synthesis by activating the PI3K/AKT pathway. Further investigation shows that pharmacological inhibitors targeting FASN and PI3K concurrently reduce FFAs, TG levels, and ATP production, effectively inhibiting BVDV replication. Conversely, the in vitro supplementation of oleic acid (OA) to replace fatty acids successfully restored BVDV replication, underscoring the impact of abnormal de novo fatty acid metabolism on BVDV replication. Intriguingly, during BVDV infection of CD8+T cells, the use of FASN inhibitors prompted the production of IFN-α and IFN-ß, as well as the expression of interferon-stimulated genes (ISGs). Moreover, FASN inhibitors induce TBK-1 phosphorylation through the activation of RIG-1 and MDA-5, subsequently activating IRF-3 and ultimately enhancing the IFN-1 response. In conclusion, our study demonstrates that BVDV infection activates the PI3K/AKT pathway to boost de novo fatty acid synthesis, and inhibition of FASN suppresses BVDV replication by activating the RIG-1/MDA-5-dependent IFN response.

Fingerprint analysis of dang-gui-Si-Ni decoction and its anticoagulant activity in vivo-in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Dang-Gui-Si-Ni (DGSN) decoction is a classic prescription in the clinical practice of traditional Chinese Medicine (TCM). DGSN decoction is often used to relieve symptoms of cold coagulation and blood stasis recorded by Treatise on Febrile Diseases (Shang Han Lun) and treat Raynaud's disease, dysmenorrhea, arthritis, migraine in TCM clinic. Accumulated evidences have suggested that this diseases are related to microcirculation disturbance. However, the anticoagulant activity and underlying mechanisms of DGSN decoction responsible for the therapeutic not well understood. AIM OF THE STUDY: The fingerprint and anticoagulant activity in vivo-in vitro of DGSN decoction were evaluated to strengthen the quality control and activity study of formulas. MATERIALS AND METHODS: The chemical components of DGSN decoction were analyzed by HPLC and its fingerprint similarity were evaluated by "Chinese Medicine Chromatographic Fingerprint Similarity Evaluation Software (2012 Edition)". The anticoagulant activity of DGSN decoction was assessed by measuring four coagulation factors (PT, TT, APTT, FIB) in vitro. Zebrafish thrombosis model induced by punatinib was established to evaluate the activity of improving microvascular hemodynamics in vivo. Quantitative real-time polymerase chain reaction (q-PCR) were adopted to compare the changes in the RNA expression levels of coagulation factor II (FII), VII (FVII), IX (FIX) and X (FX) in zebrafish thrombosis model. RESULTS: The fingerprint similarity evaluation method of DGSN decoction was established. The results showed that 18 samples had higher similarity (S1-S18 > 0.878). Pharmacodynamic results showed that DGSN decoction could extend PT, TT and APTT, and reduce FIB content in vitro. Meanwhile, it markedly enhanced the cardiac output and blood flow velocity at low dosage (500 µg mL-1) in vivo. q-PCR data demonstrated that DGSN decoction (500 µg mL-1) could downregulate the RNA expression of FII, FVII, FIX and FX. Interestingly, there were a bidirectional regulation of FII, FIX and FX in a certain concentration range. In general, DGSN decoction can significantly improve hemodynamics and downregulate coagulation factors, and the results were consistent both in vitro - in vivo. CONCLUSION: The fingerprint study provide a new perspective for improving the quality control of DGSN decoction. DGSN decoction possess anticoagulant activity by regulating multiple coagulation factors simultaneously. Thus, it has the potential to develop into the novel raw material of anticoagulant drugs.

Selenium in the treatment of mild-to-moderate Graves' orbitopathy: a 5-year prospective controlled cohort study.

PURPOSE: Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease. However, limited studies have investigated the actual efficacy of selenium in GO therapy. This longitudinal study explored the effect of selenium on QOL and prognosis of patients with mild-to-moderate GO. METHODS: We conducted a 5-year prospective controlled cohort clinical trial to determine the effect of selenium on 74 patients with mild-to-moderate GO. Patients received selenium yeast or placebo orally for 6 months and were followed up at 6 months and at 5 years by biochemical examination, ophthalmologist evaluation and QOL questionnaire to assess oculopathy and QOL. RESULTS: (1) During a follow-up period of 3-6 months, in the selenium group, the symptoms of tearing, grittiness and conjunctival congestion improved (P < 0.01); clinical activity scores and total GO-QOL scores increased relative to baseline (P < 0.01); TRAb was decreased at the 6-month evaluation (P = 0.003); and patients treated with selenium had a higher rate of improvement and a lower rate of worsening than patients treated with placebo (P < 0.05). (2) Exploratory evaluations at 6 months after drug withdrawal confirmed the earlier results; further changes included alleviation of blurred vision and double vision symptoms in the selenium group (P < 0.01). (3) At the 5-year follow-up, compared with baseline, proptosis, clinical activity scores, TRAb level and total GO-QOL scores in both the selenium and placebo groups were significantly improved (P < 0.01). CONCLUSION: Six months of selenium supplementation may effectively change the early course of mild-to-moderate GO, but this regimen makes no difference in long-term outcomes.

Causal relationship between diet and knee osteoarthritis: A Mendelian randomization analysis.

BACKGROUND: Knee osteoarthritis (KOA) is a common disabling joint disease that affects millions of people worldwide. Diet may play a role in the etiology and progression of KOA, but evidence for a causal relationship is limited. We aimed to investigate the causal impact of dietary intake on KOA risk using Mendelian randomization (MR). METHODS: We used summary-level data from genome-wide association studies (GWAS) including dietary intake (n = 335, 394-462, 342), and KOA (n = 403, 124). We selected 6-77 genetic variants as instrumental variables for 18 dietary factors, including processed meat, poultry, beef, oily fish, non-oily fish, pork, lamb, frequency of alcohol intake, alcoholic beverages, tea, coffee, dried fruit, cereals, cheese, bread, cooked vegetables, salad/raw vegetables, and fresh fruit. We performed univariate and multivariate MR analyses to estimate the causal effect of each dietary factor on KOA risk. We also performed some sensitivity analyses to assess the validity of the MR hypothesis. RESULTS: We found that higher coffee intake was associated with increased KOA risk, whereas higher intake of dried fruits, grains, cheese, and oily fish was associated with reduced KOA risk. After multivariate adjustment, we found that coffee and oily fish intake may affect KOA through obesity, body mass index (BMI), diabetes, hypertension, and prolonged standing. Sensitivity analyses did not reveal any evidence of pleiotropy. CONCLUSIONS: Our study provides new causal evidence that dietary intake may influence KOA risk. Specifically, we suggest that increased intake of dried fruits, grains, cheese, and oily fish and decreased coffee intake may be beneficial in preventing and mitigating KOA. further studies are needed to elucidate the underlying mechanisms and to confirm our findings in different populations.

Causal Association between Tea Intake and Acute Cerebrovascular Events: A Multivariate Mendelian Randomized Study in European Populations.

BACKGROUND: Numerous research works have investigated the association between tea consumption and the risk of acute cerebrovascular events; however, the results are inconsistent. OBJECTIVES: We used Mendelian randomization (MR) to evaluate the causal association between tea intake and several acute cerebrovascular events, including any ischemic stroke, large atherosclerotic stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), intracranial hemorrhage (ICH), and subarachnoid hemorrhage (SAH). METHODS: We obtained summary genome-wide association study (GWAS) data on tea intake and acute cerebrovascular events in populations of European ancestry. The GWAS on tea intake is derived from the UK Biobank, where we have chosen single-nucleotide polymorphisms (SNPs) closely associated with it as instrumental variables. We also obtained summary data on ischemic stroke from a GWAS meta-analysis, as well as summary data on ICH and SAH from the FinnGen study. We first explored the causal association between tea intake and several acute cerebrovascular events using univariate Mendelian randomization (UVMR), and then further assessed the causal association between tea intake and SVS using multivariate Mendelian randomization (MVMR) corrected for multiple confounders. RESULTS: In UVMR, genetically predicted increases in tea intake were linked to a lower risk of SVS (OR: 0.58; 95% CI: 0.39, 0.86). There was no causal association between tea intake and the risk of other acute cerebrovascular events. In the MVMR, our results show that there was still a significant causal association between drinking tea and SVS, after adjusting body mass index, total cholesterol, low-density lipoprotein cholesterol, diabetes, hypertension, smoking, and alcohol consumption. CONCLUSION: This MR study provides new genetic evidence that increased tea intake reduces the risk of SVS in the European population. However, possibly because of limited statistical power, the study did not find that tea consumption reduced the risk of several other acute cerebrovascular events.

Diet and risk of low back pain: a Mendelian randomization analysis.

PURPOSE: Previous epidemiological and other studies have shown an association between diet and low back pain (LBP). This study aimed to investigate the causal relationship between diet and LBP using a Mendelian randomization (MR) approach. METHODS: The three main methods in this study were weighted median, MR-Egger, and inverse variance weighting (IVW). We utilized MR-PRESSO to eliminate abnormal SNPs. Additionally, tests for pleiotropy and heterogeneity were conducted. Utilizing IVW and MR-Egger's Cochran's Q test, heterogeneity was evaluated. MR-Egger intercepts were used in pleiotropy tests. A leave-one-out analysis was also used to evaluate the stability of the study's findings. RESULTS: The frequency of alcohol intake was associated with an increased risk of LBP. Increased processed meat intake, dried fruit intake, cereal intake, and tea intake were causally associated with a decreased risk of LBP (alcohol intake frequency: odds ratio (OR) = 1.28; 95% confidence interval (CI), 1.11-1.47; P = 0.0006; processed meat intake: OR = 0.60, 95%CI 0.39-0.92, P = 0.019; dried fruit intake: OR = 0.43, 95%CI 0.29-0.66, P = 0.00008; cereal intake: OR = 0.62, 95%CI 0.42-0.92, P = 0.018; tea intake: OR = 0.75, 95%CI 0.58-0.97, P = 0.029). Heterogeneity and pleiotropy were also not found in the sensitivity analysis. The leave-one-out analysis also showed more robust results. Other dietary intakes were not causally associated with LBP. CONCLUSIONS: This two-sample MR study found that frequency of alcohol intake was associated with an increased risk of LBP, and intake of processed meat, dried fruit, cereals, and tea was associated with a decreased risk of LBP. Moreover, no causal relationship was found with LBP in the other 13 diets.

Responses of root-associated fungal community structure of mycorrhizal plants to nitrogen and/or phosphorus addition in a subtropical forest.

Root-associated fungi play a vital role in maintaining nutrient absorption and health of host plants. To compare the responses of root-associated fungal community structures to nitrogen (N) and/or phosphorus (P) additions across differential mycorrhizal types, we collected roots of nine plant species belonging to three mycorrhizal types (arbuscular mycorrhiza, ectomycorrhiza, and ericoid mycorrhiza) under control and N and/or P addition treatments from a subtropical forest, and detected the diversity and community composition of fungi inhabiting roots through the high-throughput sequencing technique. The results showed that root-associated fungal communities of all nine plant species were mainly composed of Basidiomycota and Ascomycota. The relative abundance of Ascomycota and Basidiomycota was significantly lower and higher under the P addition than that under control, respectively. The relative abundance of Ascomycota of ericoid mycorrhizal trees was significantly higher than those of arbuscular mycorrhizal and ectomycorrhizal trees, while the relative abundance of Basidiomycota was significantly lower than the other two mycorrhizal types. Compared with the control, P addition significantly reduced the α-diversity and changed community composition of root-associated fungi across different mycorrhizal plant types, while no effect of N addition or mycorrhizal type was observed. Compared with the control and N addition treatments, NP addition caused root-associated fungal communities of all plants becoming integrally divergent. In addition, the fungal communities of ectomycorrhizal mycorrhizal trees became apparently convergent in comparison with those of arbuscular and ericoid mycorrhizal trees under the NP addition. Collectively, our results highlighted that P was a critical factor influencing community structures of tree root-associated fungi in subtropical forest soils. This study would enhance our understanding of the responses and maintenance mechanisms of plant root-associated fungal diversity under global environmental changes in the subtropical region.

Association between the Triglyceride Glucose Index and Hyperuricemia in Patients with Primary Hypertension: A Cross-Sectional Study.

Objective: The aim of this study was to investigate the association between the triglyceride glucose (TyG) index and hyperuricemia (HUA) in patients with grades 1-3 hypertension. Study Design. This is a cross-sectional study. A total of 1,707 patients from the cardiovascular department of Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine were studied. In this study, 899 patients with grades 1-2 hypertension were included, of which 151 had HUA; additionally, 808 patients with grade 3 hypertension were included, of which 162 patients had HUA. This study obtained all patient data from the electronic medical record system of the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine. The TyG index was calculated as Ln (triglycerides × fasting glucose/2). Hyperuricemia was defined as uric acid ≥420 µmol/L (7 mg/dL). Multivariate logistic regression, penalized spline regression, and generalized additive models were used to evaluate the association between the TyG index and HUA. Stratified analyses were performed to assess the association in populations with different grades of hypertension. Results: The average TyG index was 8.71 ± 0.58. After adjusting for correlated variables, the logistic regression analysis revealed a positive correlation between the TyG index and HUA (OR = 1.83; 95% CI: 1.40-2.39). Smooth curve fitting showed that this correlation was linear in the whole range of the TyG index. In the subgroup analysis, the TyG index more strongly associated with HUA in the grades 1-2 hypertension group (OR = 2.22; 95% CI: 1.44-3.42) compared to that in the grade 3 hypertension group (OR = 1.58; 95% CI: 1.11-2.24; P for interaction = 0.03). In addition, this association was consistent in all models. Conclusion: The TyG index was positively associated with HUA in patients with hypertension, and the association was more strongly confirmed in those with grades 1-2 hypertension rather than in those with grade 3 hypertension.

Identification of the Constituents of Ethyl Acetate Fraction from Smilax china L. and Determination of Xanthine Oxidase Inhibitory Properties.

The aim of this work was to investigate the xanthine oxidase (XO)-inhibitory activity of ethanol extracts from Smilax china L. and to identify the active compounds in the ethyl acetate (EtOAc) fraction. Extraction of ethanol extracts from Smilax china L. and then ethanol extracts were concentrated, and the polyphenolic compounds were extracted with petroleum ether (PE), chloroform, EtOAc, n-butanol (n-BuOH), and residual ethanol fractions. Their effects on XO activity were then compared separately. The polyphenolic components of the EtOAc fraction were identified by HPLC and HPLC-mass spectrometry (HPLC-MS) analysis. Kinetic analysis demonstrated that all these extracts showed XO-inhibitory properties, and among them the EtOAc fraction had the strongest inhibitory effect (IC50 = 101.04 µg/mL). The inhibitory constant (Ki) of the EtOAc fraction on XO activity was 65.20 µg/mL, showing excellent inhibition on XO in the competitive mode. Sixteen compounds were identified from the EtOAc fraction. The study demonstrates that the EtOAc fraction of Smilax china L. may be a potential functional food to inhibit XO activity.

Aptamer and Peptide-Engineered Polydopamine Nanospheres for Target Delivery and Tumor Perfusion in Synergistic Chemo-Phototherapy of Pancreatic Cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer death, and the 5 year survival rate is only 4%. Chemotherapy is the treatment option for the majority of PC patients diagnosed at an advanced stage, whereas the desmoplastic stroma of PC could block the perfusion of chemotherapeutic agents to tumor tissues and contribute generally to chemoresistance. Therefore, the clinical status of PC calls for an urgent exploration in the effective treatment strategy. Chemo-phototherapy is an emerging modality against malignant tumors, but owing to the low targeting ability of theranostic agents or unspecific accumulation in the tumor region, majority of chemo-phototherapy techniques have disappointing therapeutic efficiencies. Herein, we have explored CD71-specific targeting aptamers and paclitaxel (PTX)-modified polydopamine (PDA) nanospheres with the conjugation of peptidomimetic AV3 (termed Apt-PDA@PTX/AV3 bioconjugates) to specifically target and combat PC in vivo by synergistic chemo-phototherapy. After the delivery of nanotheranostic agents to the tumor microenvironment (TME) or subsequent endocytic uptake by PC cells, a simultaneous release of AV3 and PTX from Apt-PDA@PTX/AV3 bioconjugates via near-infrared (NIR) irradiation can decrease desmoplastic stroma to enhance tumor perfusion and tumor-killing effects. Meanwhile, PDA cores utilize NIR laser to create unendurable hyperthermia within TME to "cook" tumors. Taken together, the current study finally suggests that our Apt-PDA@PTX/AV3 bioconjugates could act as a novel therapeutic approach by synergistic chemo-phototherapy for the programmable inhibition of PC.

Protective effect of ZYMT, a traditional Chinese patent medicine in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is the most common genetic disorder that causes blindness. At present, there exists no remedy for the disease. The aim of the current research was to investigate the protective effect of Zhangyanming Tablets (ZYMT) in a mouse model of RP, and explore the underlying mechanism. Eighty RP mice were randomly divided into two groups. The mice in ZYMT group were administered with ZYMT suspension(0.0378 g/mL), while the mice in model group were given the same volume of distilled water. At day 7 and day 14 after intervention, electroretinogram (ERG), fundus photography, and histological examination were used to assess the retinal function and structure. TUNEL, immunofluorescence and qPCR were used to evaluate cell apoptosis and expressions of Sirt1, Iba1, Bcl-2, Bax and Caspase-3. A significantly shortened latency of ERG waves was observed in ZYMT-treated mice, in comparison to those in the model group (P < 0.05). Histologically, ultrastructure of the retina was better preserved, and the outer nuclear layer (ONL) exhibited marked increase in thickness and cell count in ZYMP group (P < 0.05). The apoptosis rate was decreased markedly in ZYMT group. Immunofluorescence analysis showed that the expressions of Iba1 and Bcl-2 in the retina were increased, Bax and Caspase-3 were decreased after ZYMT intervention, while the qPCR revealed that the expressions of Iba1 and Sirt1 were significantly increased (P < 0.05). This study indicated that ZYMT has protective effect on retinal function and morphology of inherited RP mice in the early stage, possibly mediated via the regulation of antioxidant and anti-/pro-apoptotic factors expressions.

Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Effects of dry needling intervention on lower limb dysfunction after stroke: study protocol for a randomised controlled trial.

INTRODUCTION: Lower limb dysfunction is among the common sequelae of patients who had a poststroke and often results in the reduction of the quality of life. This study aims to assess the short and interim-term efficacy of dry needling (DN) intervention on lower extremity function, balance and gait in lower limb dysfunction after stroke. METHODS AND ANALYSIS: This protocol entails an assessor and statistician-blinded, single-centre study with a randomised controlled trial. Forty-four patients who had a poststroke will be randomly allocated (1:1) to either the conventional treatment group (n=22) or the DN group (n=22). The conventional treatment group will receive conventional rehabilitation treatment once a day for 40 min each time. The treatment will be performed five times a week for 2 weeks. In the DN group, participants will be treated with DN on the basis of the conventional treatment. The intervention will be performed thrice a week for 2 weeks. The primary outcome that determines the efficacy of lower limb dysfunction will be the change in the Fugl-Meyer Assessment of Lower Extremity scale. The secondary indicators include the range of motion of knee and ankle joints, limits of stability, modified Clinical Test of Sensory Interaction on Balance, Timed Up and Go test, Modified Ashworth Scale and Barthel Index. Results will be evaluated at baseline, at 24 hours after intervention, at 2 weeks after intervention and at 3-month follow-up. Data will be released after the completion of the study. Adverse events will be reported. ETHICS AND DISSEMINATION: The experiment was approved by the Ethical Committee of Shanghai Tong Ren Hospital in October 2021 (approval number: 202105702). The results of this study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2000040754.

Essential oil of Ligusticum chuanxiong Hort. Regulated P-gp protein and tight junction protein to change pharmacokinetic parameters of temozolomide in blood, brain and tumor.

ETHNOPHARMACOLOGICAL RELEVANCE: The existence of the blood-brain barrier/blood tumor barrier (BBB/BTB) severely restricts the effectiveness of anti-tumor drugs, thus glioma is still an incurable disease with a high fatality rate. Chuanxiong (Ligusticum chuanxiong Hort., Umbelliferae) was used as a messenger drug to increase the distribution of drugs in brain tissue, and its application in Chinese herbal formula for treating glioma was also the highest. AIM OF THE STUDY: Our previous researches showed that essential oil (EO) of chuanxiong could promote temozolomide (TMZ) entry into glioma cells in vitro and enhance TMZ-induced anticancer efficiency in vivo, and therefore, the aim of this study was to investigate whether EO could increase the concentration accumulation of TMZ in brain or tumor of C6 glioma rats and the related mechanisms. MATERIALS AND METHODS: The pharmacokinetics were conducted in C6 glioma rats by administering either TMZ alone or combined with EO through oral routes. TMZ concentration in blood, brain and tumor was detected using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and then pharmacokinetic parameters were calculated. The changed expressions of P-gp protein, tight junction occludin, claudin-5 and zonula occludens-1 (ZO-1) in brain of glioma rats were studied by Western blot to clarify the mechanism. Finally, the chemical composition of EO was analyzed by gas chromatography-massspectrometry (GC-MS). RESULTS: The results showed that EO significantly affected the pharmacokinetic parameters such as Tmax, Cmax and CL (p < 0.01), but did not significantly change the AUC(0→∞) of TMZ in blood (p > 0.05). However, EO markedly improved the AUC(0→∞)of TMZ in brain and tumor (p < 0.01). The calculate drug targeting index was greater than 1, indicating that EO could promote the distribution of TMZ to the brain and tumor. Western blot analysis showed that EO significantly inhibited the expression of P-gp, tight junction protein claudin-5, occludin and ZO-1. And meanwhile, the expressions of P-gp, claudin-5 and occludin also markedly down-regulated in EO-TMZ co-administration treatment. GC-MS analysis of the TIC component of EO was (E)-Ligustilide (36.93%), Terpinolene (7.245%), gamma-terpinene (7.225%) etc. CONCLUSION: EO could promote the distribution of TMZ in the brain and tumor of C6 glioma rats, which may attribute to down-regulate the expression of P-gp, claudin-5 and occludin.

The cumulative therapeutic effect of acupuncture in patients with migraine without aura: Evidence from dynamic alterations of intrinsic brain activity and effective connectivity.

We explored the dynamic alterations of intrinsic brain activity and effective connectivity after acupuncture treatment to investigate the underlying neurological mechanism of acupuncture treatment in patients with migraine without aura (MwoA). The Functional Magnetic Resonance Imaging (fMRI) scans were separately obtained at baseline, after the first and 12th acupuncture sessions in 40 patients with MwoA. Compared with the healthy controls (HCs), patients with MwoA mostly showed a decreased dynamic amplitude of low-frequency fluctuation (dALFF) variability in the rostral ventromedial medulla (RVM), superior lobe of left cerebellum (Cerebellum_Crus1_L), right precuneus (PCUN.R), and so on. The decreased dALFF variability of RVM, Cerebellum_Crus1_L, and PCUN.R progressively recovered after the first and 12th acupuncture treatment sessions as compared to the baseline. There was gradually increased dynamic effective connectivity (DEC) variability in RVM outflow to the right middle frontal gyrus, left insula, right precentral gyrus, and right supramarginal gyrus, and gradually enhanced DEC variability from the right fusiform gyrus inflow to RVM. Furthermore, the gradually increased DEC variability was found from Cerebellum_Crus1_L outflow to the left middle occipital gyrus and the left precentral gyrus, from PCUN.R outflow to the right thalamus. These dALFF variabilities were positively correlated with the frequency of migraine attacks and negatively correlated with disease duration at baseline. The dynamic Granger causality analysis (GCA) coefficients of this DEC variability were positively correlated with Migraine-Specific Quality of Life Questionnaire scores and negatively correlated with the frequency of migraine attacks and visual analog scale (VAS) scores after 12th acupuncture sessions. Our results were analyzed by a longitudinal fMRI in the absence of a sham acupuncture control group and provided insight into the dynamic alterations of brain activity and effective connectivity in patients with MwoA after acupuncture intervention. Acupuncture might relieve MwoA by increasing the effective connectivity of RVM, Cerebellum_Crus1_L, and PCUN.R to make up for the decreased dALFF variability in these brain areas.

Structural Equation Modeling Analysis of Factors Influencing Family Doctor Contracted Services Based on Survey Data from Changning District, Shanghai.

Objective: Family doctors fulfill the role of gatekeepers in protecting residents' health with contracted services. Providing these valuable services involves multiple causes, relationships, and indirectly observable variables. This study used structural equation modeling to construct a dynamic model of the work of family doctors to provide a basis for incentives. Methods: This study used 2-year follow-up data from a survey of 294 family doctors in Changning District, Shanghai. Data were analyzed using confirmatory factor analysis and structural equation modeling. The measurement model and structural model were defined, identified, verified, integrated, and revised to identify the factors motivating family doctors to provide contracted services. A dynamic path for the family doctor contracted services model was established and eventually modified with six endogenous latent variables: cognition, environmental satisfaction, income satisfaction, support satisfaction, stability, and contracting performance, underpinned by 27 measurement variables. Result: The standardized regression coefficient of the effect of cognition on environmental satisfaction was 0.37 (P < 0.05) and the degree of variation interpretation was 0.14. The effect of cognition on income satisfaction was 0.54 (P < 0.05) and the degree of variation interpretation was 0.29. The effect of cognition on stability was 0.40 (P < 0.01), the effect of environmental satisfaction on stability was 0.12 (P < 0.05), and the effect of income satisfaction on stability was 0.22 (P < 0.05), all with a degree of variation interpretation of 0.369. Finally, the effect of stability on contracting performance was 0.51 (P < 0.05) with a degree of variation interpretation of 0.343. Conclusions: The degree of family doctors' understanding (cognition) of their own work largely determines their behavioral orientation and service effectiveness. These results raise the possibility of enhancing family doctors' work stability and improving the performance of contracted services by increasing the income of family doctors.

Computational Analysis of the Related Factors of Deep Vein Thrombosis (DVT) Formation in Patients Undergoing Hip Fracture Surgery.

A retrospective study was conducted on 51 patients undergoing hip fracture surgery to investigate the factors associated with the formation of deep venous thrombosis (DVT). The independent sample t-test and correlation analysis were used to sort out and analyze the data. The findings are as follows. (1) Different gender samples showed significant differences in the Caprini score and thrombus location. Most DVTs in females are located in the posterior tibial vein and intermuscular veins. The Caprini score of females was significantly higher than that of males. (2) Age displays a positive correlation with DVT, coronary heart disease, hypertension, and different surgical types, respectively. (3) There is a correlation between age and operation duration. (4) Hyperlipidemia and cerebrovascular disease show a positive correlation with DVT. (5) There was a significant negative correlation between the Caprini score and the quantification of D-dimer. This indicates that in this sample, the higher the patients' Caprini score is, the lower the quantitation of D-dimer will be. (6) Hyperlipidemia and cardiac insufficiency show a positive correlation with cerebrovascular disease. Patients with hyperlipidemia and cardiac insufficiency may also suffer from cerebrovascular diseases.

Smilax china Polyphenols Stimulate Browning via [Formula: see text]3-Adrenergic Receptor/AMP-Activated Protein Kinase [Formula: see text] Signaling Pathway in 3T3-L1 Adipocytes.

The aim of this study is to investigate the molecular mechanism of Smilax china L. polyphenols (SCLPs) in enhancing lipid metabolism and stimulating browning to reduce lipid accumulation in 3T3-L1 adipocytes. SCLP treatment obviously decreased lipid content in a dose-dependent manner (10-40 µg/mL) in adipocytes. SCLP treatment cooperated with noradrenalin to increase lipolysis. SCLPs reduced the gene expressions of C/EBP[Formula: see text] and Ap2 and enhanced the expressions of ACO, CPT, pHSL/HSL, ATGL, and PKA in adipocytes. Furthermore, SCLPs increased mRNA and protein expressions of brown adipocyte-specific factors (UCP-1, PRDM16, PGC-1α, and PPARγ) and mRNA expressions of beige adipocyte-specific markers (CD137, Tbx1, and Tmem26) in 3T3-L1 adipocytes, as well as mitochondrial biogenesis genes (Nrf1 and Tfam). In addition, according to the immunofluorescence staining, the mitochondria number was increased by SCLP. Moreover, ß3-AR or AMPK agonist synergistic SCLPs enhanced the expressions of UCP-1, PRDM16, and PGC-1α. While ß3-AR or AMPK antagonist significantly decreased the expressions of these brown adipocyte-specific factors, SCLP treatment inhibited the effect of antagonist to improve the expression of UCP-1, PRDM16, and PGC-1α. These results indicated that SCLPs may regulate lipid metabolism and stimulate browning via the ß3-AR/AMPKα signaling pathway. Thus, SCLPs likely have potential therapeutic effects on obesity.