Efficacy of acupuncture (Jin's three-needle) on motor symptoms and anxiety in patients with Parkinson's disease: protocol for a multicentre, randomised, assessor-blinded clinical trial.

INTRODUCTION: Parkinson's disease (PD) has a significant impact on a substantial number of individuals in China. Notably, 31% of patients with PD also grapple with the additional burden of anxiety. This dual challenge of managing both PD and anxiety underscores the complexity of the condition and the diverse range of symptoms patients may experience. Considering the circumstances, the cost and potential drawbacks associated with traditional antiparkinsonian drugs become increasingly relevant. Acupuncture emerges as a significant non-pharmacological adjunct therapy. Offering a potentially safer and more cost-effective option, acupuncture addresses the pressing need for holistic and complementary treatments that may alleviate both the motor symptoms of PD and the accompanying anxiety. METHODS AND ANALYSIS: This is a multicentre, randomised controlled and assessor-blind trial. A total of 210 eligible patients with PD will be randomly assigned (1:1) to Jin's three-needle (JTN) acupuncture group or waitlist (WL) group. Patients in the JTN group will receive acupuncture therapy three times per week for 4 weeks. Patients in the WL group will maintain their original dosage of antiparkinsonian drugs and receive acupuncture therapy after the observation period. The primary outcome measure will be the Unified Parkinson's Disease Rating Scale score. The secondary outcome measures will be the scores of the Hoehn-Yahr Rating Scale, Unified Dyskinesia Rating Scale, Non-Motor Symptoms Scale, 39-item Parkinson's Disease Questionnaire, Parkinson Anxiety Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Zarit burden interview and the level of cortisol and adrenocorticotropic hormone. The evaluation will be executed at baseline, the end of the treatment and a follow-up period. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (K[2023]014). All patients have to provide written, informed consent. The study will be disseminated through presentations in peer-reviewed international journals and at national and international conferences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry; ChiCTR2300074675.

A vertical-flow constructed wetland-microalgal membrane photobioreactor integrated system for treating high-pollution-load marine aquaculture wastewater: A lab-scale study.

Individual biological water treatment techniques often prove ineffective in removing accumulated high concentrations of nitrogen and phosphorus in the late stages of biofloc aquaculture. To address this issue, we integrated a previously developed autotrophic denitrification and nitrification integrated constructed wetland (ADNI-CW) with a microalgal membrane photobioreactor (MPBR). Under high nitrogen and phosphorus pollution loads in the influent, the standalone ADNI-CW system achieved removal rates of only 24.17 % ± 2.82 % for total nitrogen (TN) and 25.30 % ± 2.59 % for total phosphorus (TP). The optimal conditions for TN and TP degradation and microalgal biomass production in the Chlorella MPBR, determined using response surface methodology, were an inoculum OD680 of 0.394, light intensity of 161.583 µmol/m2/s, and photoperiod of 16.302 h light:7.698 h dark. Under the optimal operating conditions, the integrated ADNI-CW-MPBR system achieved remarkable TN and TP removal rates of 92.63 % ± 2.8 % and 77.46 % ± 8.41 %, respectively, and a substantial microalgal biomass yield of 54.58 ± 6.8 mg/L/day. This accomplishment signifies the successful achievement of efficient nitrogen and phosphorus removal from high-pollution-load marine aquaculture wastewater along with the acquisition of valuable microalgal biomass. A preliminary investigation of the microbial community composition and algal-bacterial interactions in different operational stages of the MPBR system revealed that unclassified_d__Bacteria, Chlorophyta, and Planctomycetes were predominant phyla. The collaborative relationships between bacteria and Chlorella surpassed competition, ensuring highly efficient nitrogen and phosphorus removal in the MPBR system. This study laid the foundation for the green and sustainable development of the aquaculture industry.

Fluorescence and pectinase double-triggered chitosan/pectin/calcium propionate/curcumin-ß-cyclodextrin complex film for pork freshness monitoring and maintenance.

An intelligent and active food packaging film based on chitosan (CS), pectin (P), calcium propionate (CP), and curcumin-ß-cyclodextrin complex (Cur-ß-CD) was prepared. The CS/P/CP/Cur-ß-CD film exhibited improved hydrophobicity (74.78 ± 0.53°), water vapor (4.55 ± 0.16 × 10-11 g·(m·s·Pa)-1), and oxygen (1.50 ± 0.06 × 10-12 g·(m·s·Pa)-1) barrier properties, as well as antioxidant (72.34 ± 3.79 % for DPPH and 86.05 ± 0.14 % for ABTS) and antibacterial (79.41 ± 2.89 % for E. coli and 83.82 ± 3.96 % for S. aureus) activities. The release of CP and Cur could be triggered by pectinase, with their cumulative release reaching 92.62 ± 1.20 % and 42.24 ± 1.15 %, respectively. The CS/P/CP/Cur-ß-CD film showed delayed alterations in surface color, pH value, total volatile bases nitrogen, total viable counts, thiobarbituric acid reactive substance, hardness, and springiness of pork. Additionally, the fluorescence intensity of the film gradually decreased. In conclusion, we have developed a pH-responsive film with pectinase-triggered release function, providing a new concept for the design of multi-signal responsive intelligent food packaging.

Mulches assist degraded soil recovery via stimulating biogeochemical cycling: metagenomic analysis.

Soil degradation of urban greening has caused soil fertility loss and soil organic carbon depletion. Organic mulches are made from natural origin materials, and represent a cost-effective and environment-friendly remediation method for urban greening. To reveal the effects of organic mulch on soil physicochemical characteristics and fertility, we selected a site that was covered with organic mulch for 6 years and a nearby lawn-covered site. The results showed that soil organic matter, total nitrogen, and available phosphorus levels were improved, especially at a depth of 0-20 cm. The activities of cellulase, invertase, and dehydrogenase in soil covered with organic mulch were 17.46%, 78.98%, and 283.19% higher than those under lawn, respectively. The marker genes of fermentation, aerobic respiration, methanogenesis, and methane oxidation were also enriched in the soil under organic mulch. Nitrogen cycling was generally repressed by the organic mulch, but the assimilatory nitrate and nitrite reduction processes were enhanced. The activity of alkaline phosphatase was 12.63% higher in the mulch-covered soil, and functional genes involved in phosphorus cycling were also enriched. This study presents a comprehensive investigation of the influence of organic mulch on soil microbes and provides a deeper insight into the recovery strategy for soil degradation following urban greening. KEY POINTS: • Long-term cover with organic mulches assists soil recovery from degradation • Soil physical and chemical properties were changed by organic mulches • Organic mulches enhanced genes involved in microbially mediated C and P cycling • Soil organic matter was derived from decomposition of organic mulch and carbon fixation • N cycling was repressed by mulches, except for assimilatory NO2- and NO3- reductions.

Effects of Fermented Extracts of Wuniuzao Dark Loose Tea on Hepatic Sterol Regulatory Element-Binding Protein Pathway and Gut Microbiota Disorder in Obese Mice.

BACKGROUND: Artificially fermented dark loose tea is a type of novel dark tea prepared via fermentation by Eurotium cristatum. The effects of artificially fermented dark loose tea on lipid metabolism are still unclear. OBJECTIVES: This study aimed to explore if artificially fermented dark loose tea has the same effects as naturally fermented dark loose tea in regulating hepatic lipid metabolism. METHODS: Thirty-six 8-wk-old male C57BL/6 mice were randomly divided into 6 treatment groups, including normal control (NC), high-fat diet (HFD), positive control (PC), Wuniuzao dark raw tea (WDT), Wuniuzao naturally fermented dark loose tea (NFLT), and Wuniuzao artificially fermented dark loose tea (AFLT) groups. The HFD, PC, WDT, NFLT, and AFLT groups were fed a HFD. The PC group was supplemented with atorvastatin (10 mg/kg). The WDT group was supplemented with WDT (300 mg/kg), the NFLT group with NFLT (300 mg/kg), and the AFLT group with AFLT (300 mg/kg). RESULTS: The study compared the effect of WDT, NFLT, and AFLT on liver steatosis and gut microbiota disorder in obese mice. All 3 tea extracts reduced body weight, glucose tolerance, and serum lipid concentrations. Via sterol-regulatory element binding protein (SREBP)-mediated lipid metabolism, all 3 tea extracts alleviated hepatic steatosis in mice with obesity. Furthermore, NFLT and AFLT intervened in the abundance of Firmicutes, Bacteroidetes, Clostridia, Muribaculaceae, and Lachnospiraceae. CONCLUSION: In mice with obesity induced by a HFD, WDT, NFLT, and AFLT may improve hepatic steatosis through an SREBP-mediated lipid metabolism. Moreover, NFLT and AFLT improved the composition of gut microbiota.

Theabrownin from Wuniuzao Dark Tea Regulates Hepatic Lipid Metabolism and Gut Microbiota in Mice Fed High-Fat Diet.

The search for functional foods with no side effects that can alleviate obesity has been a common trend. Wuniuzao dark tea could be a safe choice. This study aimed to explore whether theabrownin from Wuniuzao dark tea could regulate hepatic lipid metabolism and gut microbiota in mice fed a high-fat diet. In total, fifty 8-week-old male C57BL/6 mice were randomly divided into five treatment groups, including a normal control group, high-fat diet group, positive control group, low-dose theabrownin group, and high-dose theabrownin group. After a 9-week intervention, these mice were selected from each treatment group for sampling. The results showed that the body weight and epididymis fat weight of obese mice fed with theabrownin were decreased. Serum total triglycerides, total cholesterol, and low-density lipoprotein cholesterol, and activities of aspartate aminotransferase and alanine aminotransferase were also decreased. Protein and mRNA expression of fatty acid synthesis and lipid production-related genes of mice fed with theabrownin were downregulated. The gut microbiota composition in the theabrownin group was improved. The study indicated that theabrownin from Wuniuzao dark tea could achieve the liver protection and anti-obesity effects by regulating the Srebp lipid metabolism pathway and bile acid metabolism process, and improving the gut microbiota composition of mice.

Tanshinone IIA alleviates atherosclerosis in LDLR-/- mice by regulating efferocytosis of macrophages.

Background: Tanshinone IIA (TIIA) is the major lipid-soluble active ingredient of the traditional Chinese medicine Salvia miltiorrhiza, which slows down atherosclerosis (AS). However, it remains unclear whether TIIA has the potential to enhance macrophage efferocytosis and thereby improve atherosclerosis. Objective: The focus of this examination was to determine if TIIA could reduce lipid accumulation and treat AS by enhancing efferocytosis. Methods: Firstly, we conducted in vivo experiments using LDLR knockout (LDLR-/-) mice for a period of 24 weeks, using histopathological staining, immunofluorescence and Western blot experiments to validate from the efficacy and mechanism parts, respectively; in addition, we utilized cells to validate our study again in vitro. The specific experimental design scheme is as follows: In vivo, Western diet-fed LDLR-/- mice for 12 weeks were constructed as an AS model, and normal diet-fed LDLR-/- mice were taken as a blank control group. The TIIA group and positive control group (atorvastatin, ATO) were intervened for 12 weeks by intraperitoneal injection (15 mg/kg/d) and gavage (1.3 mg/kg/d), respectively. In vitro, RAW264.7 cells were cultured with ox-LDL (50 ug/mL) or ox-LDL (50 ug/mL) + TIIA (20 uM/L or 40 uM/L). Pathological changes in aortic plaques and foam cell formation in RAW264.7 cells were evaluated using Masson and Oil Red O staining, respectively. Biochemical methods were used to detect lipid levels in mice. The immunofluorescence assay was performed to detect apoptotic cells and efferocytosis-related signal expression at the plaques. RT-qPCR and Western blot were carried out to observe the trend change of efferocytosis-related molecules in both mouse aorta and RAW264.7 cells. We also used the neutral red assay to assess RAW264.7 cells' phagocytic capacity. Results: Compared with the model group, TIIA decreased serum TC, TG, and LDL-C levels (p < 0.01), reduced the relative lumen area of murine aortic lipid-rich plaques (p < 0.01), enhanced the stability of murine aortic plaques (p < 0.01), reduced ox-LDL-induced lipid build-up in RAW264.7 cells (p < 0.01), and upregulated efferocytosis-related molecules expression and enhance the efferocytosis rate of ox-LDL-induced RAW264.7 cells. Conclusion: TIIA might reduce lipid accumulation by enhancing the efferocytosis of macrophages and thus treat AS.

Thermal treatment enhances the resisting exercise fatigue effect of Phyllanthus emblica L.: novel evidence from tannin conversion in vitro, metabolomics, and gut microbiota community analysis.

Polyphenols are the main component of Phyllanthus emblica (PE). However, polyphenols are so easy to transform that it is unknown that how drying methods driven by heating affect the anti-fatigue effect of PE. This manuscript investigated the effects of five drying methods on the chemical composition transformation and anti-fatigue of PE, and discussed the action mechanism. The results suggested that the anti-fatigue effect of PE with hot-air-dried at 100 °C was the best, which was as 1.63 times as that with freeze-drying. Ellagic acid (EA) may be a key component of PE in anti-fatigue, and its mechanism of action may be related to regulating intestinal microbiota, protecting mitochondria, and regulating energy metabolism. This study first revealed the thermal transformation of polyphenols in PE, found the most effective strategy for enhancing the anti-fatigue function, and explores its action mechanism.

Subtractive Nanopore Engineered MXene Photonic Nanomedicine with Enhanced Capability of Photothermia and Drug Delivery for Synergistic Treatment of Osteosarcoma.

Two-dimensional (2D) nanomaterials as drug carriers and photosensitizers have emerged as a promising antitumor strategy. However, our understanding of 2D antitumor nanomaterials is limited to intrinsic properties or additive modification of different materials. Subtractive structural engineering of 2D nanomaterials for better antitumor efficacy is largely overlooked. Here, subtractively engineered 2D MXenes with uniformly distributed nanopores are synthesized. The nanoporous defects endowed MXene with enhanced surface plasmon resonance effect for better optical absorbance performance and strong exciton-phonon coupling for higher photothermal conversion efficiency. In addition, porous structure improves the binding ability between drug and unsaturated bonds, thus promoting drug-loading capacity and reducing uncontrolled drug release. Furthermore, the porous structure provides adhesion sites for filopodia, thereby promoting the cellular internalization of the drug. Clinically, osteosarcoma is the most common bone malignancy routinely treated with doxorubicin-based chemotherapy. There have been no significant treatment advances in the past decade. As a proof-of-concept, nanoporous MXene loaded with doxorubicin is developed for treating human osteosarcoma cells. The porous MXene platform results in a higher amount of doxorubicin-loading, faster near-infrared (NIR)-controlled doxorubicin release, higher photothermal efficacy under NIR irradiation, and increased cell adhesion and internalization. This facile method pioneers a new paradigm for enhancing 2D material functions and is attractive for tumor treatment.

Attenuation of binuclear hepatocytes in the paracancerous liver tissue is associated with short-term recurrence of hepatocellular carcinoma post-radical surgery.

Short-term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high-recurrence risk patients to provide adjuvant treatment is necessary. Herein, based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short-term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha-fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short-term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short-term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA-II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short-term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short-term HCC recurrence.

Levistilide A ameliorates neuroinflammation via inhibiting JAK2/STAT3 signaling for neuroprotection and cognitive improvement in scopolamine-induced Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with cognitive impairment and dementia, which has become a major public health problem. There are no effective therapeutic agents used to treat AD in clinic for the extremely complex pathogenesis. Here we identify Levistilide A (LA), one of the major active natural terpene lactone constituents from Chinese herbal medicine Angelicae sinensis and Chuanxiong Rhizoma, as a potent neuroinflammation inhibitor for neuroprotection and cognitive improvement of AD. We show that LA suppresses neuronal apoptosis, restores cholinergic system function, and lowers neuroinflammation in vivo to improve scopolamine (SCOP)-induced learning and memory deficits. In addition, LA inhibits the release of IL-1ß, IL-6 and TNF-α, while increasing the production of IL-4 and IL-10 for anti-inflammatory effects in LPS or Aß-induced BV2 and HMC3 cells. Furthermore, the conditioned medium (CM) from LA-treated BV2 or HMC3 cells enhances the viability of SH-SY5Y and HT-22 cells, and LA reverses M1 to M2 phenotype transformation of BV2 and HMC3 cells accompanied by the inhibited Iba-1 expression and mRNA level of IL-1ß, IL-6, TNF-α and NOS2, and the increased expression of ARG1, CD206 and CD163. Mechanistically, we analyze JAK2/STAT3 signaling as possible targets of LA using network pharmacology approaches, and further experimentally validate that LA inhibits the phosphorylation of JAK2 and STAT3, and STAT3 expression within nucleus both in vitro and in vivo. Collectively, we identify LA as a potential neuroinflammation inhibitor for neuroprotection and cognitive improvement, which is expected to be a candidate for AD therapy.

Emerging 2D pnictogens: a novel multifunctional photonic nanoplatform for cutting-edge precision treatment.

The elements of the pnictogen group, known as the 15th (VA) family in the periodic table, including phosphorus (P), arsenic (As), antimony (Sb) and bismuth (Bi), have been widely used by alchemists to treat various diseases since ancient times and hold a pivotal position in the history of medicine, owing to their diverse pharmacological activities. Recently, with the development of modern nanotechnology, pnictogen group elements appear in a more innovative form, namely two-dimensional (2D) pnictogens (i.e. phosphorene, arsenene, and bismuthene) with a unique layered crystal structure and extraordinary optoelectronic characteristics, which endow them with significant superiority as a novel multifunctional photonic nanoplatform for cutting-edge precision treatment of various diseases. The puckered layer structure with ultralarge surface area make them ideal drug and gene delivery vectors that can avoid degradation and reduce target effects. The anisotropic morphology allows their easier internalization by cells and may improve gene transfection efficiency. Tunable optoelectronic characteristics endow them with excellent phototherapy performance as well as the ability to act as an optical switch to initiate subsequent therapeutic events. This review provides a brief overview of the properties, preparation and surface modifications of 2D pnictogens, and then focuses on its applications in cutting-edge precision treatment as a novel multifunctional photonic nanoplatform, such as phototherapy, photonic medicine, photo-adjuvant immunotherapy and photo-assisted gene therapy. Finally, the challenges and future development trends for 2D pnictogens are provided. With a focus on 2D pnictogen-based multifunctional photonic nanoplatforms, this review may also provide profound insights for the next generation innovative precision therapy.

Reactive Oxygen Species-Triggered Curcumin Release from Hollow Mesoporous Silica Nanoparticles for PM2.5-Induced Acute Lung Injury Treatment.

Exposure to fine particulate matter with a diameter ≤2.5 µm (PM2.5) can result in serious inflammation and oxidative stress in lung tissue. However, there is presently very few effective treatments for PM2.5-induced many pulmonary diseases, such as acute lung injury (ALI). Herein, curcumin-loaded reactive oxygen species (ROS)-responsive hollow mesoporous silica nanoparticles (Cur@HMSN-BSA) are proposed for scavenging the intracellular ROS and suppressing inflammatory responses against PM2.5-induced ALI. The prepared nanoparticles were coated with bovine serum albumin (BSA) via an ROS-sensitive thioketal (TK)-containing linker, in which the TK-containing linker would be cleaved by the excessive amounts of ROS in inflammatory sites to induce the detachment of BSA from the nanoparticles surface and thus triggering release of loaded curcumin. The Cur@HMSN-BSA nanoparticles could be used as ROS scavengers because of their excellent ROS-responsiveness, which were able to efficiently consume high concentrations of intracellular ROS. Furthermore, it was also found that Cur@HMSN-BSA downregulated the secretion of several important pro-inflammatory cytokines and promoted the polarization from M1 phenotypic macrophages to M2 phenotypic macrophages for eliminating PM2.5-induced inflammatory activation. Therefore, this work provided a promising strategy to synergistically scavenge intracellular ROS and suppress the inflammation responses, which may serve as an ideal therapeutic platform for pneumonia treatment.

Research progress in physiological effects of resistant substances of Urtica dioica L. on animal performance and feed conversion.

Several members of family Urticaceae are mainly found in the temperate and subtropical zones of the Northern Hemisphere and are important medicinal plants. Among them, Urtica dioica L. (Urticaceae) is an annual or perennial herb that has been used for feeding and medicinal purposes since long time and is the most exploited species of Urticaceae. Recently, it has received attention to be used as animal feed, as its fresh leaves fed to animals in moderate, dried, and other forms. This review details the advantages of U. dioica as an alternative feed in terms of germplasm specificity, nutritional composition, and feed application status. Its roots, stems, leaves, and seeds are rich in active ingredients. It has also been found to have anticancer effects through antioxidant action and promotion of apoptosis of cancer cells. In shady conditions, U. dioica is highly adaptable while under stressful conditions of drought; it also reduces light absorption and ensures carbon assimilation through light energy conversion efficiency. Therefore, it can be added to animal diets as a suitable feed to reduce costs and improve economic efficiency. This paper investigates the feasibility of using U. dioica as a feed and systematically presents the progress of research and exploitation of U. dioica.

Fabrication of an Injectable Star-polylactide/Thiolated Hyaluronate Hydrogel as a Double Drug-Delivery System for Cancer Treatment.

Unsatisfactory solid-tumor penetration or rapid metabolism of nanomaterials limits their therapeutic efficacy. Here, we designed an injectable thiolated hyaluronate (HA-SH) hydrogel as a stable drug-releasing platform for in situ tumor treatment. Biodegradable star-shaped polylactide (S-PLLA) was first synthesized and fabricated to porous microspheres to encapsulate hydrophobic curcumin (Cur@S-PLLA), which was then blended with hydrophilic doxorubicin (Dox) and the HA-SH precursor to form composite in situ formable hydrogels [Cur@S-PLLA/(Dox)HA-SH]. The results showed that adding the microspheres improved the performance of the hydrogel, such as decreasing the gelation time from 1080 s to 960 s and also the swelling ratio. The mechanical strength increased from 27 to 45 kPa. In addition, the double drug system guaranteed a sustained release of drugs, releasing Dox at the early stage, with the continuous later release of Cur after gel swelling or S-PLLA degradation to achieve long-lasting tumor suppression, which inhibits the survival of cancer cells. The inhibitory effects of the hydrogels on MCF-7 were studied. The cell activity in the double-loaded hydrogel was significantly lower than that of the control groups, and apparent dead cells appeared in 2 days and fewer living cells with time. Flow cytometry revealed that the Cur@S-PLLA/(Dox)HA-SH group had the highest apoptosis ratio of 86.60% at 12 h, and the drugs caused the cell cycle to be blocked in phase M to reduce cell division. In summary, the innovative release platform is expected to be used in long-lasting tumor suppression and provides more ideas for the design of drug carriers.

An engineered cascade-sensitized red-emitting upconversion nanoplatform with a tandem hydrophobic hydration-shell and metal-phenolic network decoration for single 808 nm triggered simultaneous tumor PDT and PTT enhanced CDT.

Near-infrared light (NIR) driven lanthanide-doped upconversion nanoparticle (UCNP) based photo-dynamic therapy (PDT) holds a great promise for the non-invasive treatment of deep-seated tumors. However, it has also been highly hindered by the low upconversion luminescence (UCL) efficiency, hypoxia nature of solid tumors, and low therapeutic efficiency using single modality. Herein, we present a novel Nd3+ → Yb3+ → Tm3+ → Er3+ cascade-sensitized red-emitting UCNP with tandem hydrophobic hydration-shell (HHS) and metal-phenolic network (Fe-tannic acid, Fe-TA) decoration (UCNP@HHS@Fe-TA, denoted as UCFS@Fe-TA) for single 808 nm triggered simultaneous tumor PDT and photothermal therapy (PTT) enhanced chemo-dynamic therapy (CDT). The UCNP can supply intense red emission under high tissue penetrating/minimized tissue overheating 808 nm excitation, and their HHS coating with perfluorocarbon/photosensitizer Ce6 co-doping can not only realize UCL-based PDT, but also strengthen PDT of as-formed UCFS via O2-carrying/UCL protection capacity of the HHS. Fe-TA coating can supply 808 nm triggered PTT, and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster ˙OH production rate of CDT to match with the real-timely released 1O2 in PDT. The as-designed UCFS@Fe-TA thus can achieve a single 808 nm triggered simultaneous PDT and PTT enhanced CDT, leading to a PTT-assisted reactive oxygen species storm for efficient tumor suppression. Such a design also renders the nanoplatform lower cell dark toxicity. In addition, the single excitation-triggered multimodal therapy mode might address the excitation wavelength mismatch issue in dual laser-triggered PTT/PDT mode. This study has therefore presented an efficient nanotherapeutic platform enabling synergistic multimodal tumor therapies with high biocompatibility.

Toxic effects of Tripterygium glycoside tablets on the reproductive system of male rats by metabolomics, cytotoxicity, and molecular docking.

BACKGROUND: Tripterygium glycoside tablets (TGT) is the most common preparation from Tripterygium wilfordii Hook F, which is widely used in clinical for treating rheumatoid arthritis (RA) and other autoimmune diseases. However, its serious reproductive toxicity limits its application. PURPOSE: This study aimed to elucidate the toxic effects of TGT on the reproductive system of male RA rats and its potential toxic components and mechanism. METHODS: Collagen-induced arthritis (CIA) rat model was established, and TGT suspension was given at low, medium, and high doses. Gonadal index, pathological changes, and the number of spermatogenic cells were used to evaluate the toxic effects of TGT on the reproductive system. Non-targeted metabolomics of testicular tissue was conducted by UHPLC-QTOF/MS. Combined with network toxicology, the key targets of TGT-induced reproductive toxicity were screened and RT-qPCR was used to validation. In vitro toxicity of 19 components of TGT was evaluated using TM3 and TM4 cell lines. Molecular docking was used to predict the interaction between toxic components and key targets. RESULTS: TGT reduced testicular and epididymis weight. Pathology analysis showed a lot of deformed and atrophic spermatogenic tubules. The number of spermatogenic cells decreased significantly (P<0.0001). A total of 58 different metabolites including platelet-activating factor (PAF), lysophosphatidylcholine (Lyso PC), phosphatidylinositol (PI), glutathione (GSH), and adenosine monophosphate (AMP) were identified by testicular metabolomics. Glycerophospholipid metabolism, ether lipid metabolism, and glutathione metabolism were key pathways responsible for the reproductive toxicity of TGT. Ten key reproductive toxicity targets were screened by network toxicology. The cytotoxicity test showed that triptolide, triptonide, celastrol, and demethylzeylasteral could significantly reduce the viability of TM3 and TM4 cells. Alkaloids had no apparent toxic effects. Molecular docking showed that the four toxic components had a good affinity with 10 key targets. All binding energies were less than -7 kcal/mol. The RT-qPCR results showed the Cyp19a1 level was significantly up-regulated. Pik3ca and Pik3cg levels were significantly down-regulated. CONCLUSION: Through testicular metabolomics, we found that TGT may cause reproductive toxicity through CYP19A1, PIK3CA, and PIK3CG three target, which was preliminarily revealed. This study laid the foundation for elucidating the toxicity mechanism of TGT and evaluating its safety and quality.

Total saponins from Panax japonicus reduce inflammation in adipocytes through the miR155/SOCS1/NFκB signaling pathway.

BACKGROUND: The rising incidence of metabolic diseases due to chronic inflammation in the adipose tissue has been attributed to factors such as high fat diet (HFD). Previous studies have demonstrated that the total saponins from Panax japonicus (TSPJ) can reduce HFD-induced adipocyte inflammation, but the underlying mechanism remains unclear. In this work, we explored the molecular mechanism by which TSPJ reduces inflammation response in adipocytes. METHODS: We first established C57BL/6 mouse and 3T3-L1 adipocyte models. Lentiviruses packaged with the plasmids were injected into mice through the tail vein or into adipocytes to generate the in vivo and in vitro models with miR155 knockdown and overexpression. The mice were fed with HFD to trigger inflammation and administered TSPJ (25 mg/kg∙d and 75 mg/kg∙d) by gavage. The adipocytes were treated with palmitic acid (PA) to trigger inflammation response, then treated with TSPJ (25 µg/ml and 50 µg/ml). Finally, the expression of miR155, inflammatory factors, SOCS1, and NFκB pathway-related proteins was explored. RESULTS: TSPJ significantly inhibited the expression of inflammation-related genes and the miR155 expression in adipocytes both in vitro and in vivo. The dual luciferase reporter gene assay revealed that miR155 mediated the downregulation of SOCS1. TSPJ significantly inhibited and upregulated the phosphorylation of the NFκB protein and the SOCS1 proteins, respectively. CONCLUSION: TSPJ inhibits miR155 to upregulate the SOCS1 expression, which subsequently inhibits the NFκB signaling pathway, thereby mitigating the inflammatory response in the adipocytes of HFD mice.

Bushen-Yizhi formula exerts neuroprotective effect via inhibiting excessive mitophagy in rats with chronic cerebral hypoperfusion.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription widely used in treating mental retardation and neurodegenerative diseases with kidney deficiency, has been reported to attenuate oxidative stress-related neuronal apoptosis. Chronic cerebral hypoperfusion (CCH) is considered to be related to cognitive and emotional disorders. However, it remains to be clarified that the effect of BSYZ on CCH and its underlying mechanism. AIM OF THE STUDY: In the present study, we aimed to investigate the therapeutic effects and underlying mechanisms of BSYZ on CCH- injured rats based on the domination of oxidative stress balance and mitochondrial homeostasis through inhibiting abnormal excessive mitophagy. MATERIALS AND METHODS: The in vivo rat model of CCH was established by bilateral common carotid artery occlusion (BCCAo), while the in vitro PC12 cell model was exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) condition, and a mitophagy inhibitor (chloroquine) by decreasing autophagosome-lysosome fusion was used as reverse validation in vitro. The protective role of BSYZ on CCH-injured rats was measured by open field test, morris water maze test, analysis of amyloid fibrils and apoptosis, and oxidative stress kit. The expression of mitochondria-related and mitophagy-related proteins was evaluated by Western blot, immunofluorescence, JC-1 staining assay and Mito-Tracker Red CMXRos assay. The components of BSYZ extracts were identified by HPLC-MS. The molecular docking studies were used to investigate the potential interactions of characteristic compounds in BSYZ with lysosomal membrane protein 1 (LAMP1). RESULTS: Our result indicated that BSYZ improved the cognition and memory abilities of the BCCAo rats by diminishing the occurrence of apoptosis and abnormal amyloid deposition accumulation, suppressing oxidative stress damage for abnormal excessive mitophagy activation in the hippocampus. Moreover, in OGD/R-damaged PC12 cells, BSYZ drug serum treatment substantially enhanced the PC12 cell viability and suppressed intracellular reactive oxygen species (ROS) accumulation for protecting against oxidative stress, along with the improvement of mitochondrial membrane activity and lysosomal proteins. Our studies also showed that inhibiting of autophagosome-lysosome fusion to generate autolysosomes by using chloroquine abrogated the neuroprotective effects of BSYZ on PC12 cells regarding the modulation of antioxidant defence and mitochondrial membrane activity. Furthermore, the molecular docking studies supported the direct bindings between lysosomal associated membrane protein 1 (LAMP1) and compounds in BSYZ extract to inhibit excessive mitophagy. CONCLUSION: Our study demonstrated that BSYZ played a neuroprotective role in rats with CCH and reduced neuronal oxidative stress via promoting the formation of autolysosomes to inhibit abnormal excessive mitophagy.

Extracellular vesicles from medicated plasma of Buyang Huanwu decoction-preconditioned neural stem cells accelerate neurological recovery following ischemic stroke.

Introduction: The neurological impairment of survivors after ischemic stroke poses a serious risk to their quality of life and health. Effective therapeutic options are still lacking. Neural stem cells (NSCs) promote neurogenesis via secreted extracellular vesicles (NSC-EVs), which would be a potential therapeutic option, but the insufficient quantity of NSC-EVs in vivo restrains clinical application. Buyang Huanwu Decoction (BHD), a classic traditional Chinese medicine (TCM) decoction, is promising to alleviate neurological impairment after ischemic stroke. It was speculated that BHD might promote neurological recovery through the NSC-EVs. Methods: The medicated plasma of BHD (MP-BHD) was prepared to precondition NSCs and isolate EVs (BHD-NSC-EVs). Middle cerebral artery occlusion (MCAO) models and primary NSCs were administered to evaluate the therapeutic effect. Next-generation sequencing was performed to explore the mechanism. Results: The BHD-NSC-EVs more significantly accelerated neurological recovery after MCAO and promoted NSCs proliferation and differentiation than BHD and NSC-EVs alone. MP-BHD enhanced the largescale generation of BHD-NSC-EVs, which encapsulated functional miRNA and may play critical roles in neurogenesis. Discussion: In replacing BHD or NSCs, the preconditioned NSC-EVs present a more efficient therapeutic strategy for ischemic stroke. Based on the clinical efficacy of TCM, the preconditioning of NSC-derived EVs via the MP of TCM herbs would presents a newly promising therapeutic strategy for neurological diseases.