Gemcitabine enhances pharmacokinetic exposure of the major components of Danggui Buxue Decoction in rat via the promotion of intestinal permeability and down-regulation of CYP3A for combination treatment of non-small cell lung cancer.

CONTEXT: Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine's active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD's major components remains unclear. OBJECTIVE: This study evaluates the herb-drug interaction between DBD's major components and gemcitabine and validates the underlying pharmacokinetic mechanism. MATERIALS AND METHODS: The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis. RESULTS: The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD's major components in rats. The Cmax and AUC of calycosin-7-O-ß-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression. DISCUSSION AND CONCLUSIONS: Gemcitabine could modulate the pharmacokinetics of DBD's major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.

Lightweight Object Detection Algorithm for UAV Aerial Imagery.

Addressing the challenges of low detection precision and excessive parameter volume presented by the high resolution, significant scale variations, and complex backgrounds in UAV aerial imagery, this paper introduces MFP-YOLO, a lightweight detection algorithm based on YOLOv5s. Initially, a multipath inverse residual module is designed, and an attention mechanism is incorporated to manage the issues associated with significant scale variations and abundant interference from complex backgrounds. Then, parallel deconvolutional spatial pyramid pooling is employed to extract scale-specific information, enhancing multi-scale target detection. Furthermore, the Focal-EIoU loss function is utilized to augment the model's focus on high-quality samples, consequently improving training stability and detection accuracy. Finally, a lightweight decoupled head replaces the original model's detection head, accelerating network convergence speed and enhancing detection precision. Experimental results demonstrate that MFP-YOLO improved the mAP50 on the VisDrone 2019 validation and test sets by 12.9% and 8.0%, respectively, compared to the original YOLOv5s. At the same time, the model's parameter volume and weight size were reduced by 79.2% and 73.7%, respectively, indicating that MFP-YOLO outperforms other mainstream algorithms in UAV aerial imagery detection tasks.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Exogenous hydrogen sulfide and methylglyoxal alleviate cadmium-induced oxidative stress in Salix matsudana Koidz by regulating glutathione metabolism.

BACKGROUND: Cadmium (Cd) is a highly toxic element for plant growth. In plants, hydrogen sulfide (H2S) and methylglyoxal (MG) have emerged as vital signaling molecules that regulate plant growth processes under Cd stress. However, the effects of sodium hydrosulfide (NaHS, a donor of H2S) and MG on Cd uptake, physiological responses, and gene expression patterns of Salix to Cd toxicity have been poorly understood. Here, Salix matsudana Koidz. seedlings were planted in plastic pot with applications of MG (108 mg kg- 1) and NaHS (50 mg kg- 1) under Cd (150 mg kg- 1) stress. RESULTS: Cd treatment significantly increased the reactive oxygen species (ROS) levels and malondialdehyde (MDA) content, but decreased the growth parameters in S. matsudana. However, NaHS and MG supplementation significantly decreased Cd concentration, ROS levels, and MDA content, and finally enhanced the growth parameters. Cd stress accelerated the activities of antioxidative enzymes and the relative expression levels of stress-related genes, which were further improved by NaHS and MG supplementation. However, the activities of monodehydroascorbate reductase (MDHAR), and dehydroascorbate reductase (DHAR) were sharply decreased under Cd stress. Conversely, NaHS and MG applications restored the MDHAR and DHAR activities compared with Cd-treated seedlings. Furthermore, Cd stress decreased the ratios of GSH/GSSG and AsA/DHA but considerably increased the H2S and MG levels and glyoxalase I-II system in S. matsudana, while the applications of MG and NaHS restored the redox status of AsA and GSH and further improved glyoxalase II activity. In addition, compared with AsA, GSH showed a more sensitive response to exogenous applications of MG and NaHS and plays more important role in the detoxification of Cd. CONCLUSIONS: The present study illustrated the crucial roles of H2S and MG in reducing ROS-mediated oxidative damage to S. matsudana and revealed the vital role of GSH metabolism in regulating Cd-induced stress.

Sodium houttuyfonate derived from Houttuynia cordata Thunb improves intestinal malfunction via maintaining gut microflora stability in Candida albicans overgrowth aggravated ulcerative colitis.

Candida albicans is a common opportunistic pathogen and normally resides in the human gut. Increasing number of reports link the overgrowth of C. albicans to the severity of ulcerative colitis (UC). Sodium houttuyfonate (SH), a derivative of the medicinal herb Houttuynia cordata Thunb, has been demonstrated to exhibit decent antifungal and anti-inflammatory activities. We showed previously that SH could ameliorate colitis mice infected with C. albicans. However, it is unclear whether the therapeutic effect of SH is connected to its modulation of intestinal microflora in UC. In this study, the impact of SH on the gut microbiota was explored in both cohabitation and non-cohabitation patterns. The results showed that in UC mice inflicted by C. albicans, the administration of SH could greatly improve the pathological signs, weaken the oxidative stress and inflammatory response, and enhance the intestinal mucosal integrity. By 16S rRNA gene sequencing, we found that C. albicans interference caused intestinal microbiota dysbiosis accompanied by an increase of some harmful pathogens including Klebsiella and Bacteroides. In contrast, SH could modulate the abundance and diversity of microbiota with an increase of several beneficial bacteria comprising short-chain fatty acid-producing bacteria (Lachnospiraceae_NK4A136_group, Intestinimonas) and probiotics (Lactobacillus and Alloprevotella). Furthermore, the cohabitation strategy could also prove the efficacy of SH, indicating a role of transmissible gut flora in the colitis model. These findings suggest that SH might be an effective compound for the treatment of UC complicated by C. albicans overgrowth through maintaining gut microbiota homeostasis, thereby improving intestinal function.

A survey of male and female dairy calf care practices and opportunities for change.

The primary objective of this study was to compare male and female dairy calf management practices and evaluate risk factors associated with differences in care. Secondary objectives were to understand surplus calf transportation and marketing practices and investigate incentives to motivate calf care improvements. An online survey was distributed to all dairy producers in Ontario (n = 3,367) from November 2020 to March 2021 and Atlantic Canada (n = 557) from April to June 2021. Dairy producers were identified through provincial dairy associations and contacted via e-mail and social media. Descriptive statistics were computed, and a logistic regression model was created to evaluate factors associated with using discrepant feeding practices (i.e., fed less colostrum, fed colostrum later, or fed raw, unsalable milk) for male calves compared with females. The survey had a 7.4% response rate (n = 289/3,924) and was primarily filled out by farm owners (76%). Although colostrum and milk feeding practices were similar between male and female calves, male calves received less milk while still on the dairy farm of origin compared with females. Male calves were also more likely to be fed a higher proportion of raw, unsalable milk. Female producers and those that kept their male calves beyond 10 d of age had lower odds of using poorer feeding practices for male calves. Male calves were mostly sold between 1 and 10 d (64%), primarily through direct sales to a calf-rearing facility (45%), with auctions being the next most common method (35%). A small but notable proportion of producers (18%) agreed that euthanizing male calves is a reasonable alternative when their sale price is very low; however, few producers (13%) reported that financial costs limited their male calf care. The largest proportion (43%) of producers reported that a price premium for more vigorous calves would motivate them to take better care of their male calves. Conversely, only 28% of producers reported that a price discount for calves in poor condition would be motivating. Producers placed importance on the opinion of their calf buyer, their herd veterinarian, and the Canadian Code of Practice for the Care and Handling of Dairy Cattle when considering their calf care practices, and they highly valued practices that promote calf health. Respondents to this survey reported a lower proportion of tiestall barn use and higher milk productivity compared with typical dairy herds in the region, suggesting selection bias for more progressive dairy producers. Nevertheless, our results suggest that dairy producers provide similar care between male and female calves, but some male calves experience challenges due to milk feeding and marketing practices. Feedback from calf buyers along with continued support and guidance from herd veterinarians and the Code of Practice may motivate dairy producers to improve male calf care.

Structural compositions and biological activities of cell wall polysaccharides in the rhizome, stem, and leaf of Polygonatum odoratum (Mill.) Druce.

Polygonatum odoratum is a perennial rhizomatous medicinal plant and different plant parts have been used in the treatment of various ailments. Herein, we have investigated the structural compositions of rhizome, leaf, and stem cell walls. We found 30-44% of polysaccharides in these wall preparations were cyclohexanediaminetetraacetic acid (CDTA) extractable, the proportion of heteromannans (HMs) in the rhizome is nearly three-fold compared to that of the leave and stem. The pectic polysaccharides of the rhizome are also structurally more diverse, with arabinans and type I and type II arabinogalactans being richest as shown by linkage study of the sodium carbonate (Na2CO3) extract. In addition, the 2-linked Araf was rhizome-specific, suggesting the cell walls in the rhizome had adapted to a more complex structure compared to that of the leaf and stem. Water-soluble polysaccharide fractions were also investigated, high proportion of Man as in 4-linked Manp indicated high proportion of HMs. The 21.4 kDa pectic polysaccharides and HMs derived from rhizome cell walls induced specific immune response in mice macrophage cells producing IL-1α and hematopoietic growth factors GM-CSF and G-CSF in vitro.

Sodium houttuyfonate enhances the mono-therapy of fluconazole on oropharyngeal candidiasis (OPC) through HIF-1α/IL-17 axis by inhibiting cAMP mediated filamentation in Candida albicans-Candida glabrata dual biofilms.

Candida albicans and Candida glabrata are two common opportunistic fungi that can be co-isolated in oropharyngeal candidiasis (OPC). Hypha is a hallmark of the biofilm formation of C. albicans, indispensable for the attachment of C. glabrata, which is seldom in mycelial morphology. Increasing evidence reveals a hypoxic microenvironment in interior fungal biofilms, reminding of a fact that inflammation is usually accompanied by oxygen deprivation. As a result, it is assumed that the disaggregation of hypha-mediated hypoxia of biofilms might be a solution to alleviate OPC. Based on this hypothesis, sodium houttuyfonate (SH), a well-identified traditional herbal compound with antifungal activity, is used in combination with fluconazole (FLU), a well-informed synthesized antimycotics, to investigate their impact on filamentation in C. albicans and C. glabrata dual biofilms and the underlying mechanism of their combined treatment on OPC. The results show that compared with the single therapy, SH plus FLU can inhibit the hyphal growth in the mixed biofilms in vitro, decrease the fungal burden of oral tissues and internal organs, restore mucosal epithelial integrity and function, and reduce hypoxic microenvironment and inflammation in a mice OPC model. The possible mechanism of the combined therapy of SH plus FLU can be attributed to the regulation of HIF-1α/IL-17A axis through direct abrogation of the dual Candida biofilm formation. This study highlights the role of HIF-1α/IL-17A axis and the promising application of SH as a sensitizer of conventional antifungals in the treatment of OPC.

[Effect of Tiaoshen Qianyang acupuncture on blood pressure and sleep quality in patients with stroke-related sleep disorders complicated with hypertension].

OBJECTIVE: To observe the effect of Tiaoshen Qianyang acupuncture on morning blood pressure, sleep quality and post-stroke nerve function recovery in patients with stroke-related sleep disorders (SSD) complicated with hypertension. METHODS: A total of 120 patients were randomized into an observation group (60 cases) and a control group (60 cases, 1 case dropped off). Both groups were treated with Xingnao Kaiqiao acupuncture (Neiguan [PC 6], Shuigou [GV 26], Sanyinjiao [SP 6], Jiquan [HT 1], Chize [LU 5] and Weizhong [BL 40]). In addition, Tiaoshen Qianyang acupuncture was applied in the observation group, deep needling at Baihui (GV 20) and Sishencong (EX-HN 1) for 5 h. Once a day, 5 times a week, 30 times in total. The morning blood pressure was measured during treatment in the two groups, the Pittsburgh sleep quality index (PSQI) and National Institute of Health stroke scale (NIHSS) scores before and after treatment were observed in the two groups. RESULTS: Compared before treatment, the morning systolic blood pressure (SBP) after treatment were decreased in the two groups (P<0.05), and the morning diastolic blood pressure (DBP) after treatment was decreased in the observation group (P<0.05). The levels of SBP and DBP after treatment in the observation group were lower than the control group (P<0.05). Compared before treatment, the total score of PSQI and NIHSS score after treatment in the observation group were decreased (P<0.01, P<0.05), which were lower than the control group (P<0.01, P<0.05), the decreasing rate of NIHSS score in the observation group was higher than the control group (P<0.05). CONCLUSION: On the basis of Xingnao Kaiqiao acupuncture, Tiaoshen Qianyang acupuncture could improve morning blood pressure and sleep quality for patients with SSD complicated with hypertension, promote the recovery of nerve function.

Regorafenib for Taiwanese patients with unresectable hepatocellular carcinoma after sorafenib failure: Impact of alpha-fetoprotein levels.

BACKGROUND AND AIMS: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. METHODS: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. RESULTS: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml. CONCLUSIONS: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response.

Effect of Tiaoshen Qianyang acupuncture on blood pressure and sleep quality in patients with stroke-related sleep disorders complicated with hypertension / 中国针灸

OBJECTIVE@#To observe the effect of Tiaoshen Qianyang acupuncture on morning blood pressure, sleep quality and post-stroke nerve function recovery in patients with stroke-related sleep disorders (SSD) complicated with hypertension.@*METHODS@#A total of 120 patients were randomized into an observation group (60 cases) and a control group (60 cases, 1 case dropped off). Both groups were treated with Xingnao Kaiqiao acupuncture (Neiguan [PC 6], Shuigou [GV 26], Sanyinjiao [SP 6], Jiquan [HT 1], Chize [LU 5] and Weizhong [BL 40]). In addition, Tiaoshen Qianyang acupuncture was applied in the observation group, deep needling at Baihui (GV 20) and Sishencong (EX-HN 1) for 5 h. Once a day, 5 times a week, 30 times in total. The morning blood pressure was measured during treatment in the two groups, the Pittsburgh sleep quality index (PSQI) and National Institute of Health stroke scale (NIHSS) scores before and after treatment were observed in the two groups.@*RESULTS@#Compared before treatment, the morning systolic blood pressure (SBP) after treatment were decreased in the two groups (P<0.05), and the morning diastolic blood pressure (DBP) after treatment was decreased in the observation group (P<0.05). The levels of SBP and DBP after treatment in the observation group were lower than the control group (P<0.05). Compared before treatment, the total score of PSQI and NIHSS score after treatment in the observation group were decreased (P<0.01, P<0.05), which were lower than the control group (P<0.01, P<0.05), the decreasing rate of NIHSS score in the observation group was higher than the control group (P<0.05).@*CONCLUSION@#On the basis of Xingnao Kaiqiao acupuncture, Tiaoshen Qianyang acupuncture could improve morning blood pressure and sleep quality for patients with SSD complicated with hypertension, promote the recovery of nerve function.

Effects of High-Frequency Repetitive Transcranial Magnetic Stimulation on Upper Limb Dystonia in Patients With Wilson's Disease: A Randomized Controlled Trial.

Background: Upper limb dystonia is a frequent complication of Wilson's disease (WD). It can lead to poor quality of life and disability. Currently, no effective treatment for it exists. Therefore, we carried out a clinical trial to determine whether high frequency repetitive transcranial magnetic stimulation (rTMS) on the primary motor cortex alleviates upper limb dystonia in WD patients. Methods: This study was a single-center, double-blind, randomized clinical study, included 60 WD patients with upper limb dystonia from a research base of WD in Hefei, China. Participants were randomly divided into a treatment group (TG) and a control group (CG). The TG received rTMS at 10 Hz, while the CG received sham stimulation for 7 consecutive days. Participants were assessed at baseline, after the seventh treatment session, and at 2 and 4 weeks after the seventh treatment session. The primary outcomes included patients' objective muscle tension and stiffness as measured with the MyotonPRO device. The secondary results were scores on clinical scales assessing muscle spasm and motor symptoms, which included the Modified Ashworth Scale (MAS), Unified Wilson's Disease Rating Scale (UWDRS), Burke Fahn Marsden Scale (BFM), and the Activities of Daily Living (ADL) scale. Results: The analysis revealed that after 10 Hz rTMS, muscle tension (P < 0.01) and stiffness (P < 0.01) as measured by the MyotonPRO device decreased significantly in the TG compared to the CG. Moreover, clinically relevant scale scores, including the MAS (P < 0.01), UWDRS (P < 0.01), BFM (P < 0.01), and ADL (P < 0.01) were also significantly reduced. Conclusion: High-frequency rTMS over the primary motor cortex may be an effective complementary and alternative therapy to alleviating upper limb dystonia in WD patients. Clinical Trial Registration: http://www.chictr.org.cn/, identifier: ChiCTR2100046258.

Exploratory Evaluation of Rhythm Control by Dronedarone in Combination With Low-Dose Rivaroxaban, Warfarin, Antiplatelet, or None of the Antithrombotic Therapy in High-Risk Patients With Non-Permanent Atrial Fibrillation: A Retrospective Cohort Study.

The emerging data supports rhythm control to prevent major adverse cardiac events (MACE) in high-risk patients with atrial fibrillation (AF). Limited data demonstrated rivaroxaban 10 mg combining dronedarone seemed feasible. This study aimed at investigating clinical events in a dronedarone-treated cohort. This exploratory, retrospective chart review was conducted in nonpermanent AF patients receiving dronedarone for ≥ 3 months between 2009/1 and 2016/2. In Taiwan, dronedarone's labeled indication was strict to age ≥ 70 or 65 to 70 years with either hypertension, diabetes, prior stroke, or left atrium >50 mm. We divided all into 4 groups using antithrombotic strategies to evaluate the safety, effectiveness, and MACE endpoints. A total of 689 patients (mean CHA2DS2-VASc score 3.8 ± 1.4) were analyzed: rivaroxaban 10 mg (n = 93, 13.5%), warfarin (n = 89, 12.9%), antiplatelet (n = 331, 48.0%), and none (n = 176, 25.5%). During the follow-up period (mean 946 ± 493.8 days), the rivaroxaban group did not report any stroke or thromboembolism (ishcmeic stroke rate: antiplatelet [0.6%], none [1.1%]; hemorrahgic stroke rate: warfarin [2.2%]; thromboembolism rate: warfarin [2.2%]). There was no significant difference in safety, effectiveness, and MACE endpoints between groups. Also, >104 weeks of dronedarone use was the independent predictor for MACE after adjusting the strategy and other covariates (hazard ratio 0.14 [95% confidence interval 0.04-0.44], P = .001). Our findings warrant concomitant rivaroxaban 10 mg and dronedarone for further investigation. Regardless of antithrombotic strategies, a more extended persistence of dronedarone was associated with fewer MACE.

Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease.

The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine, Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found that the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.

Parkinson's disease is a brain disorder that leads to tremors and difficulties with balance and coordination. These symptoms are caused by the loss of neurons which release a chemical messenger that is needed to regulate movement called dopamine. Most treatments for this disease work by boosting levels of dopamine in the brain, but this can lead to severe side effects and these drugs often become less effective over time. A traditional Chinese medicine called Gastrodia elata Blume (or GE for short) has previously been reported to relieve symptoms of Parkinson's disease in both human and animal studies when administered as a decoction or formula. However, it is unclear how GE protects dopamine-producing neurons and if this mechanism involves another type of brain cell known as glia that has also been linked to Parkinson's disease. To investigate, Lin et al. studied fruit flies and mice that carry a genetic mutation that produces the symptoms and molecular characteristics of Parkinson's disease. The experiments showed that when the flies and mice were fed food containing water extracts of GE, they experienced less difficulties moving and had a higher number of intact dopamine-producing neurons. Lin et al. found that GE switched on a protein in glial cells located near dopamine-producing neurons. Activation of this protein, called Nrf2, inhibited a signaling pathway in degenerating neurons that leads to the disease state. As a result, less dopamine-producing neurons were damaged and the animals' coordination and balance were maintained. These findings suggest that GE could potentially provide an alternative or complementary therapy for Parkinson's disease, although it still needs to be studied further in humans. If the same effect is observed, the specific compounds in GE that have this protective effect could be isolated and analyzed to see if they could be used for treatment.

Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection.

The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 µM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.

Safety and Effectiveness of Rivaroxaban in Combination with Various Antiarrhythmic Drugs in Patients with Non-Permanent Atrial Fibrillation.

INTRODUCTION: Rivaroxaban reduces the risk of thromboembolism in atrial fibrillation (AF) patients, who often also receive antiarrhythmic drugs (AADs) to maintain sinus rhythm. Current guidelines contraindicate concomitant use of rivaroxaban with the popular AAD dronedarone, despite little data demonstrating interactions with AADs. This study investigates the outcomes of concomitant rivaroxaban and AAD drug use in a real-world cohort. METHODS: This retrospective study included 1777 non-permanent AF patients taking rivaroxaban for ≥ 1 month between 2011 and 2016 from a multicenter cohort in Taiwan, and compared concomitant AAD use against clinical outcome endpoints for safety, effectiveness, and major adverse cardiac events (MACE). Multivariate Cox proportional hazard analyses were used to evaluate the association between concomitant AAD use and outcomes. RESULTS: Patients were divided into rivaroxaban alone (n = 1205) and with concomitant amiodarone (n = 177), dronedarone (n = 231), or propafenone (n = 164) groups. The proportion of patients using rivaroxaban 10 mg was highest in the concomitant dronedarone group: rivaroxaban alone, 53.6%; with amiodarone, 57.6%; with dronedarone, 77.1%; and with propafenone, 46.3% (p < 0.001). The cumulative incidences of safety (p = 0.892), effectiveness (p = 0.336), and MACE (p = 0.674) were similar between the four groups; however, there were significantly fewer new systemic thromboembolisms in the dronedarone group: rivaroxaban alone, 2.5%; with amiodarone, 0.6%; with dronedarone, 0%; and with propafenone, 1.2% (p = 0.029). The all-cause death rate was also lowest in the dronedarone group: rivaroxaban alone, 9.0%; with amiodarone, 9.6%; with dronedarone, 3.0%; and with propafenone: 6.1% (p = 0.013). After covariate adjustment, there were no differences in the safety, effectiveness, and MACE endpoints between patients receiving or not receiving AADs. CONCLUSION: Concomitant use of rivaroxaban with AADs appears to be well tolerated, warranting further investigation into the apparent benefits of a reduced dose of rivaroxaban combined with dronedarone.

Effect of Tongqiao Huoxue Decoction Combined with Western Medicine on Ischemic Stroke: A Systematic Review.

OBJECTIVE: We conducted a systematic review and meta-analysis to systematically evaluate the curative effect of Tongqiao Huoxue Decoction (TQHXD) combined with Western medicine treatment (WMT) on Ischemic Stroke (IS). METHODS: Randomized controlled trials (RCTs) of TQHXD in the treatment of IS by computer retrieval of PubMed, Embase, Web of Science, Chinese Biomedical Literature Service System, CNKI, Wanfang Database, and Weipu Database. The retrieval time was taken from the establishment of the database to July 30, 2020. Two researchers, respectively, conducted a strict evaluation of the quality of the literature and extracted the data which were then entered in the RevMan5.3 software for meta-analysis. RESULTS: 40 articles were listed, which involved 3260 patients. Meta-analysis results show that TQHXD combined with WMT can significantly reduce patients' NIHSS score, serum hypersensitivity C-reactive protein (hs-CRP), plasma viscosity, serum fibrinogen, serum total cholesterol, and serum triglycerides and improve patients' ADL-Barthel scoring and treatment efficiency. However, there is no evidence that TQHXD combined with the WMT group can significantly decrease the incidence of adverse events. CONCLUSION: The therapeutic effect of TQHXD combined with the WMT group was significantly better than that of the WMT alone group. For the treatment of patients with IS, TQHXD combined with WMT is worthy of application and promotion.

Effects of three medicinal herbs Bidens pilosa, Lonicera japonica, and Cyathula officinalis on growth and non-specific immune responses of cobia (Rachycentron canadum).

This study investigates the effects of three medicinal herbal extracts, namely Bidens pilosa (BPE), Lonicera japonica (LJE), and Cyathula officinalis (COE), on nonspecific immune parameters of cobia (Rachycentron canadum) in vitro and in vivo. During in vitro tests, BPE treatment increased reactive oxygen species (ROS) production in a dose-dependent manner in primary head kidney leukocytes. Similarly, ROS production rates were enhanced by LJE (50 and 100 mg/ml) and COE (100 mg/ml). This suggests that these three herbal extracts possess immunostimulating properties. We then conducted two feeding trials to examine the effects of these three herbal extracts on growth and innate immune parameters of cobia, and sought an optimal dietary supplementation proportion required for activating the non-specific immune responses. In the first trial, we supplemented the diet with 1, 5, or 10% of the individual extracts. After a ten-week feeding trial, no negative impacts on weight gain, feed conversion rate, and survival rate were observed in fish offered experimental diets. Further, ROS production, phagocytic capacity of the head kidney leukocytes, and serum lysozyme activity were enhanced by differing degrees in fish fed the herbal extracts compared to fish in the control group. A similar albumin/globulin ratio was seen between each experimental group and the control group regardless of the type and dose of herbal extract used, indicating these medicinal herbal extracts are safe for cobia. We then performed a 30-day feeding trial with lower extract concentrations (1, 3, and 5% of the diet) to identify dose responses in cobia at various time points so that we could establish a cost-effective manner of administering the three extracts for cobia. All BPE fed fish had higher ROS production compared to the control group, while phagocytosis rate and index were simultaneously raised in only the BPE30 group (3% BPE). Immune parameters such as ROS production, phagocytic rate, and serum lysozyme activity were triggered when fish received 30 g LJE per kg of feed. However, ROS production only increased in the LJE10 group (1% LJE) on day 30 and was not enhanced in the LJE50 group (5% LJE). Additionally, although the phagocytic rate and phagocytic index were induced in the LJE50 group, serum lysozyme activity was not elevated in this group (LJE50) at any time point examined. ROS production was greatly improved in all COE fed groups, but only the COE30 group (3% COE) showed prolonged enhanced phagocytic rate over the 30-day feeding trial.

Cationic Pillar[6]arene Induces Cell Apoptosis by Inhibiting Protein Tyrosine Phosphorylation Via Host-Guest Recognition.

We reported for the first time that cationic pillar[6]arene (cPA6) could tightly bind to peptide polymer (MW~20-50 kDa), an artificial substrate for tyrosine (Tyr) phosphorylation, and efficiently inhibit Tyr protein phosphorylation through host-guest recognition. We synthesized a nanocomposite of black phosphorus nanosheets loaded with cPA6 (BPNS@cPA6) to explore the effect of cPA6 on cells. BPNS@cPA6 was able to enter HepG2 cells, induced apoptosis, and inhibited cell proliferation by reducing the level of Tyr phosphorylation. Furthermore, BPNS@cPA6 showed a stronger ability of inhibiting cell proliferation in tumor cells than in normal cells. Our results revealed the supramolecular modulation of enzymatic Tyr phosphorylation by the host-guest recognition of cPA6.