Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway.

OBJECTIVE: This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats. METHODS: The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA. RESULTS: APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05). CONCLUSION: EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP. Please cite this article as: Ding YY, Xu F, Wang YF, Han LL, Huang SQ, Zhao S, Ma LL, Zhang TH, Zhao WJ, Chen XD. Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway. J Integr Med. 2023; 21(5): 496-508.

[Cluster needling of scalp points improves cognitive dysfunction by regulating NF-κB activity in rats with Alzheimer's disease].

OBJECTIVE: To observe the effect of cluster needling of scalp points on nuclear transcription factor kappa B p65 (NF-κB p65)，NF-κB inhibitory protein α (IKBα)ï¼Œß secretase 1 (BACE1)，beta-amyloid protein (Aß) and hippocampal morphology in Alzheimer's disease (AD) rats，so as to reveal its mechanism underlying improvement of AD. METHODS: Male Wistar rats were randomly divided into sham operation，model，clustering acupuncture and medication groups，with 12 trats in each group. AD model was induced by Aß1-42 injection into bilateral hippocampus. In the clustering acupuncture group，"Baihui" (DU20) and 1 mm on left and right sides of DU20 were needled for 30 min，once daily for 14 d. Rats of the medication group were given donepezil hydrochloride (0.5 mg·kg-1·d-1) intragastric perfusion once a day for 14 d. Morris water maze test was used to evaluate the cognitive function of rats. HE staining was used to observe the structure changes of hippocampal tissue. The expressions of NF-κB p65，IKBα and BACE1 in hippocampus were detected by Western blot. ELISA was used to detect the levels of Aß in hippocampus and serum of rats. RESULTS: Compared with sham operation group，the escape latency of Morris water maze test in the model group was prolonged，the number of crossing the original platform was decreased(P<0.01)，the protein expressions of NF-κB p65 and BACE1 in hippocampus，and the levels of Aß in hippocampus and serum of AD rats were increased (P<0.01，P<0.05)，while the expression of IKBα protein was decreased (P<0.01). Compared with the model group，the escape latency of Morris water maze test was shortened and the number of crossing the original platform was increased in the clustering acupuncture and medication groups (P<0.01，P<0.05)，and the protein expressions of NF-κB p65 and BACE1 in hippocampus，the levels of Aß in hippocampus and serum were decreased (P<0.01，P<0.05)，while the expression of IKBα protein was increased (P<0.01). In comparison of the medication group，the protein expressions of NF-κB p65 and IKBα was lower in the clustering acupuncture group (P<0.05). HE staining showed that cells in the hippocampus were arranged loosely and disordered，some cytoplasm was hyperchromatic，nucleus was pyknotic，inflammatory cells were infiltrated in the model group，which were relatively milder in the clustering acupuncture and medication groups. CONCLUSION: Cluster needling at scalp points may improve the cognitive impairment in AD rats by reducing inflammatory infiltration in hippocampus，regulating the expressions of NF-κB p65，IKBα and BACE1，and inhibiting the aggregation of Aß.

A cyclic brush zwitterionic polymer based pH-responsive nanocarrier-mediated dual drug delivery system with lubrication maintenance for osteoarthritis treatment.

Enhanced joint synergistic lubrication combined with anti-inflammatory therapy is an effective strategy to delay the progression of early osteoarthritis (OA) but has been rarely reported. The hydration lubrication of zwitterions and inherent super-lubrication properties of the cyclic brush, as well as the enhancement of the steric stability of the cyclic topology, can effectively improve the drug loading and utilization; herein we report a pH-responsive cyclic brush zwitterionic polymer (CB) with SBMA and DMAEMA as brushes and a cyclic polymer (c-P(HEMA)) as the core template, possessing a low coefficient of friction (0.017). After loading with hydrophobic curcumin and hydrophilic loxoprofen sodium it demonstrates high drug-loading efficiency. In vitro and in vivo experiments confirmed the triple function of the CB on superlubrication, sequence controlled release and anti-inflammatory effects demonstrated by Micro CT, histological analysis and qRT-PCR. Overall, the CB is a promising long-acting lubricating therapeutic agent, with potential for OA treatment or other diseases.

A biomimetic nanoplatform for precise reprogramming of tumor-associated macrophages and NIR-II mediated antitumor immune activation.

The therapeutic effects of photothermal therapy (PTT) are dependent on the photothermal conversion efficiency of photothermal agents (PTAs) in tumors and the subsequent activation of the antitumor immune system. However, the insufficient tumor accumulation of current PTAs and the inevitable recruitment of tumor-associated macrophages (TAMs) could further compromise the antitumor activities of PTT. To address these issues, a biomimetic photothermal nanoplatform Au@Fe-PM is developed for the targeted remodeling of TAMs, which promotes the antitumor immunity of PTT. Au nanorods with second near-infrared (NIR-II) absorptions are fabricated to serve as PTAs to induce immunogenic cell death in tumor cells. The ferric hydroxide shell coated on Au nanorods can release iron ions to repolarize M2-like TAMs into the tumoricidal M1 phenotype via P38 and STAT1-mediated signaling pathways. Moreover, the surface decoration of platelet membranes endows biomimetic nanoplatform with enhanced tumor targeting ability for precise tumor ablation and TAM regulation. Consequently, Au@Fe-PM under NIR-II laser irradiation exhibits significantly higher inhibitory effects in a poor immunogenic 4T1 tumor-bearing mouse model with a 50% complete remission rate compared to conventional PTT (0%). By simultaneously reversing the immunosuppressive tumor microenvironment, this biomimetic nanoplatform offers a promising strategy for enhancing the antitumor efficacy of PTT. STATEMENT OF SIGNIFICANCE: The therapeutic effects of current photothermal therapy (PTT) are hindered by the insufficient tumor accumulation of conventional photothermal agents and the recruitment of immunosuppressive tumor-associated macrophages (TAMs) after PTT. Herein, we report a biomimetic iron-based second near-infrared (NIR-II) photothermal nanoplatform (Au@Fe-PM) for targeted TAMs reprogramming and NIR-II mediated anti-tumor immunity. Au@Fe-PM can actively target the tumor site with the help of surface-decorated platelet membranes. Meanwhile, iron ions would be released from Au@Fe-PM in acidic lysosomes to reprogram TAMs into tumoricidal M1-like macrophages, which promotes the antitumor responses elicited by NIR-II PTT, thereby contributing to remarkable tumor inhibitory effects, with 50% higher complete remission rate than that of conventional PTT.

Iron (oxyhydr)oxides are responsible for the stabilization of Cu and Zn in AMD after treatment with limestone.

The formation and transformation of secondary iron (oxyhydr)oxides and their role in the stabilization of copper (Cu) and zinc (Zn) in acid mine drainage (AMD) after limestone treatment are worth studying to better understand the impacts of limestone AMD treatment. In this study, the wastewater from a copper mine ditch was sampled. Two different doses of limestone (S: 5.33 g L-1 and SS: 8.00 g L-1) were applied to adjust the pH range of the sampled AMD. The concentrations of Fe, Cu and Zn in the supernatant and the levels of iron (oxyhydr)oxides and heavy metals in AMD sediments were dynamically monitored for 300 days to analyze the transformation of the secondary iron mineral phase and the role iron (oxyhydr)oxides play in the removal and stabilization of Cu and Zn. The results showed that the pH rose rapidly to 6.82, decreased to 5.82 on the 150th day, and finally decreased to approximately 4.63 by the 300th day, when the dosage of limestone (S) was 5.33 g L-1. Goethite was the main form of iron oxides in the sediments. As the incubation time increased, so did the content of crystalline Fe (oxyhydr)oxides. In addition, the Cu and Zn content in the fraction of crystalline Fe (oxyhydr)oxides increased as the corresponding iron (oxyhydr)oxide increased. When the high dosage of limestone (8.00 g L-1 or SS) was applied, the pH remained at approximately at 7.46 during the whole period and goethite and lepidocrocite were present in the sediment. Amorphous/ poorly crystalline Fe-oxyhydroxide was the main product after SS limestone dosage, indicating that the risk of Cu and Zn reactivation in the sediment was higher with a higher limestone treatment dosage.

Establishment and Evaluation of Artificial Intelligence-Based Prediction Models for Chronic Kidney Disease under the Background of Big Data.

Objective: To establish a prediction model for the risk evaluation of chronic kidney disease (CKD) to guide the management and prevention of CKD. Methods: A total of 1263 patients with CKD and 1948 patients without CKD admitted to the Tongde Hospital of the Zhejiang Province from January 1, 2008, to December 31, 2018, were retrospectively analyzed. Spearman's correlation was used to analyze the relationship between CKD and laboratory parameters. XGBoost, random forest, Naive Bayes, support vector machine, and multivariate logistic regression algorithms were employed to establish prediction models for the risk evaluation of CKD. The accuracy, precision, recall, F1 score, and area under the receiver operating curve (AUC) of each model were compared. The new bidirectional encoder representations from transformers with light gradient boosting machine (MD-BERT-LGBM) model was used to process the unstructured data and transform it into researchable unstructured vectors, and the AUC was compared before and after processing. Results: Differences in laboratory parameters between CKD and non-CKD patients were observed. The neutrophil ratio and white blood cell count were significantly associated with the occurrence of CKD. The XGBoost model demonstrated the best prediction effect (accuracy = 0.9088, precision = 0.9175, recall = 0.8244, F1 score = 0.8868, AUC = 0.8244), followed by the random forest model (accuracy = 0.9020, precision = 0.9318, recall = 0.7905, F1 score = 0.581, AUC = 0.9519). Comparatively, the predictions of the Naive Bayes and support vector machine models were inferior to those of the logistic regression model. The AUC of all models was improved to some extent after processing using the new MD-BERT-LGBM model. Conclusion: The new MD-BERT-LGBM model with the inclusion of unstructured data has contributed to the higher accuracy, sensitivity, and specificity of the prediction models. Clinical features such as age, gender, urinary white blood cells, urinary red blood cells, thrombin time, serum creatinine, and total cholesterol were associated with CKD incidence.

pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy.

Background: Despite their outstanding properties in high surface-to-volume ratio and deep penetration, the application of ultrasmall nanoparticles for tumor theranostics remains limited because of their dissatisfied targeting performance and short blood circulation lifetime. Various synthetic materials with complex structures have been prepared as a multifunctional platform for loading ultrasmall nanoparticles. However, their use in nanomedicine is restricted because of unknown metabolic processes and potential physiological toxicity. Therefore, versatile and biocompatible nanoplatforms need to be designed through a simple yet effective method for realizing specific delivery and responsible release of ultrasmall nanoparticles. Methods: Iron-gallic acid coordination polymer nanodots (FeCNDs) exhibits outstanding photothermal ability and Fenton catalytic performance, which can be applied for tumor inhibition via hyperthermia and reactive oxygen species. A pH-responsive platelet-based hybrid membrane (pH-HCM) was prepared via co-extrusion and acted as a safe nanoplatform to load FeCNDs (pH-HCM@FeCNDs). Subsequently, their responsive performance and penetration ability were valued considering the multicellular sphere (MCS) model in an acidic or neutral environment. Thereafter, in vivo fluorescence image was performed to assess targeting capability of pH-HCM@FeCNDs. Finally, the corresponding antitumor and antimetastatic effects on orthotropic breast cancer were investigated. Results: In 4T1 MCS model, pH-HCM@FeCNDs group exhibited higher penetration efficiency (72.84%) than its non-responsive counterparts (17.77%) under an acidic environment. Moreover, the fluorescence intensity in pH-HCM@FeCNDs group was 3.18 times higher than that in group without targeting performance in the in vivo fluorescence image experiment. Finally, through in vivo experiments, pH-HCM@FeCNDs was confirmed to exhibit the best antitumor effect (90.33% tumor reduction) and antimetastatic effects (only 0.29% tumor coverage) on orthotropic breast cancer. Conclusions: Hybrid cell membrane was an ideal nanoplatform to deliver nanodots because of its good responsibility, satisfactory targeting ability, and excellent biocompatibility. Consequently, this study provides novel insights into the delivery and release of nanodots in a simple but effect method.

Spermine-Responsive Intracellular Self-Aggregation of Gold Nanocages for Enhanced Chemotherapy and Photothermal Therapy of Breast Cancer.

Improving the precise accumulation and retention of nanomedicines in tumor cells is one of the keys to effective therapy of tumors. Herein, supramolecular peptides capped Au nanocages (AuNCs) that may self-aggregate into micron-sized clusters intracellularly in response to spermine (SPM), leading to specific accumulation and retention of AuNCs in SPM-overexpressed tumor cells, are developed. In this design, polydopamine (PDA) is in situ coated on the surface of AuNCs with doxorubicin (DOX) encapsulated. A small peptide, Phe-Phe-Val-Leu-Lys (FFVLK), is conjugated with PDA via esterification, and cucurbit[7]uril (CB[7]) is threaded onto the N-terminal Phe via host-guest interactions. Once the supramolecular peptide (CB[7]-FFVLK) capped AuNCs are internalized in SPM-overexpressed breast cancer cells, CB[7] can be competitively removed from FFVLK by SPM, due to the much higher binding affinity between CB[7] and SPM than that between CB[7] and Phe, leading to exposure of free FFVLK, which can subsequently self-assemble and induce the aggregation of AuNCs to micron-sized clusters, resulting in the significantly enhanced accumulation and retention of DOX-loaded AuNCs in tumor cells. Under NIR laser irradiation, the enhanced photothermal conversion of AuNCs aggregates, together with photothermia-induced release of DOX leads to synergistic photothermal therapy and chemotherapy against breast cancer.

[Effect of Tiaoshen acupuncture on anxiety after methamphetamine withdrawal].

OBJECTIVE: To compare the therapeutic effect between Tiaoshen acupuncture combined with psychotherapy and simple psychotherapy on anxiety after methamphetamine withdrawal. METHODS: A total of 78 patients were randomized into an observation group (39 cases, 2 cases dropped off) and a control group (39 cases, 1 case dropped off). Psychotherapy was given in the control group. On the basis of the treatment in the control group, Tiaoshen acupuncture was applied at Baihui (GV 20), Shenting (GV 24), Benshen (GB 13), Neiguan (PC 6) and Shenmen (HT 7) in the observation group. The treatment was given once a day, 6 days were as one course and totally 4 courses were required in both groups. The scores of Hamilton anxiety scale (HAMA), quality of life for drug addicts (QOL-DA) and Pittsburgh sleep quality index (PSQI) before and after treatment were observed in both groups. RESULTS: After treatment, the various scores and the total scores of HAMA, QOL-DA and PSQI were decreased compared before treatment in both groups (P<0.05), and the scores of somatic anxiety factor, the psychic anxiety factor and the total score of HAMA, each various score and the total score of QOL-DA as well as the scores of sleep quality, time to fall asleep, sleep time, daytime dysfunction and the total score of PSQI in the observation group were lower than those in the control group (P<0.05). CONCLUSION: Tiaoshen acupuncture combined with psychotherapy can relieve the anxiety in patients with anxiety after methamphetamine withdrawal, improve the quality of life and sleep, the therapeutic effect is superior to the simple psychotherapy.

Treatment for overactive bladder: A meta-analysis of transcutaneous tibial nerve stimulation versus percutaneous tibial nerve stimulation.

BACKGROUND: We aim to compare the safety and effectiveness of transcutaneous tibial nerve stimulation (TTNS) versus percutaneous tibial nerve stimulation (PTNS) in treating overactive bladder. METHODS: A systematical search on PubMed, Embase, clinicalTrial.gov, and Cochrane Library Central Register of Controlled Trials from January 1, 1999 to November 1, 2020 was performed. The primary outcomes were the changes in a 3-day voiding diary. Quality of life scores were also evaluated. Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) was applied to conduct all statistical analyses. RESULTS: A total of 4 trials (2 randomized controlled trials, 1 retrospective study, and 1 before-after study) with 142 patients were eventually enrolled. Compared with PTNS, TTNS had a similar performance in the voiding frequency in 24 hours (mean difference [MD] = -0.65, 95% confidence interval [CI]: -1.35 to 0.05, P = .07), the number of urgency episodes in 24 hours (MD = 0.13, 95% CI: -0.36 to 0.62, P = .60), the number of incontinence episodes in 24 hours (MD = 0.01, 95% CI: -0.13 to 0.14, P = .93), as well as in the nocturia frequency (MD = -0.14, 95% CI: -0.52 to 0.24, P = .47). Moreover, comparable results were observed regarding HRQL scores (P = .23) and incontinence quality of life scores (P = .10) in both groups. The total complication rate in the current study was 2.1% (3/142). No adverse events were identified in the TTNS group. CONCLUSION: Current data supported that TTNS is as effective as PTNS for the treatment of overactive bladder, moreover, with no reported adverse events. However, the evidence is low-grade and well-designed prospective studies with a large sample size are warranted to verify our findings.

Gu-Ben-Fang-Xiao decoction modulates lipid metabolism by activating the AMPK pathway in asthma remission.

Gu-Ben-Fang-Xiao decoction (GBFXD), derived from the traditional Chinese medicine Yu-Ping-Feng-San, is widely used in clinical settings and has obvious curative effects in respiratory diseases. GBFXD regulates cholesterol transport and lipid metabolism in chronic persistent asthma. There is evidence for its beneficial effects in the remission stage of asthma; however, its metabolic regulatory effects and underlying mechanisms during asthma remission are unclear. In the present study, we used liquid chromatography-mass spectrometry (LC-MS) to analyse the metabolic profile of mouse serum during asthma remission. The acquired LC-MS data were subjected to a multivariate analysis for identification of significantly altered metabolites. In total, 42 metabolites were significantly differentially expressed among the control, model, and GBFXD groups. In particular, levels of fatty acids, acylcarnitines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, and diacylglycerols were altered during asthma remission. GBFXD may maintain lipid homeostasis on the lung surface by modulating lipid metabolism and may thereby alleviate asthma. We further quantified hypogeic acid (FA 16:1) based on targeted metabolomics and found that GBFXD may regulate fatty acid metabolism by activating the AMP-activated protein kinase (AMPK) pathway. These results support the use of GBFXD in patients with asthma remission.

Effect of total saponins from Panax japonicus on non-alcoholic steatohepatitis by regulating autophagy / 中国中药杂志

Non-alcoholic steatohepatitis(NASH) was induced by high-sugar and high-fat diet in mice to investigate the intervention effect of total saponins from Panax japonicus(TSPJ) and explore its possible mechanism. Mice were fed with high-sugar and high-fat diet to establish NASH model, and intervened with different doses of TSPJ(15, 45 mg·kg~(-1)). The animals were fed for 26 weeks. The histomorphology and pathological changes of liver tissues were observed by HE staining. The transcriptional expression levels of miR-199 a-5 p, autophagy related gene 5(ATG5) and inflammatory cytokines interleukin-6(IL-6), interleukin-1β(IL-1β) and tumor necrosis factor α(TNF-α) in mouse liver were measured by quantitative Real-time polymerase chain reaction(qRT-PCR). Western blot was used to detect the expression of autophagy-related proteins ATG5, P62/SQSTM1(P62), and microtubule-associated protein light chain 3(LC3)-I/Ⅱ proteins in mouse liver. The expression of P62 protein was detected by immunofluorescence staining. In order to verify the targeting regulation relationship between miR-199 a-5 p and ATG5, miR mimic/inhibitor NC and miR-199 a-5 p mimic/inhibitor were transfected into Hepa 1-6 cells, and the expression of ATG5 mRNA and protein was detected. pMIR-reportor ATG5-3'UTR luciferase reporter gene plasmid was constructed and co-transfected with miR mimic/inhibitor NC and miR-199 a-5 p mimic/inhibitor into Hepa 1-6 cells to detect luciferase activity. In vivo, HE staining in the model group showed typical fatty degeneration and inflammatory infiltration, with increased expression of miR-199 a-5 p and decreased expression of ATG5 mRNA and protein. The expression of autophagy-associated protein P62 increased significantly, the ratio of LC3Ⅱ/Ⅰ decreased, and the transcriptional expression of inflammatory factors increased significantly. After the intervention by TSPJ, the pathological performance of liver tissue was significantly improved, the expression of miR-199 a-5 p decreased and the expression of ATG5 mRNA and protein increased, the expression of autophagy-associated protein P62 decreased significantly, the ratio of LC3Ⅱ/Ⅰ increased, and the transcriptional expression of inflammatory cytokines IL-6, IL-1β and TNF-α decreased significantly. In vitro, it was found that the expression of ATG5 mRNA and protein and luciferase activity decreased significantly in miR-199 a-5 p overexpression cells, while after inhibition of miR-199 a-5 p expression, the expression level of ATG5 mRNA and protein and luciferase activity increased. The results showed that TSPJ can improve NASH in mice fed with high-sugar and high-fat diet, and its mechanism may be related to the regulation of miR-199 a-5 p/ATG5 signal pathway, the regulation of autophagy activity and the improvement of inflammatory response of NASH.

A polyoxyethylene sorbitan oleate modified hollow gold nanoparticle system to escape macrophage phagocytosis designed for triple combination lung cancer therapy via LDL-R mediated endocytosis.

Presently, a combination of chemotherapy, radiotherapy, thermotherapy, and other treatments has become a hot topic of research for the treatment of cancer, especially lung cancer. In this study, novel hollow gold nanoparticles (HGNPs) were used as drug carriers, and in order to improve the targeting ability of HGNPs to a lung tumor site, polyoxyethylene sorbitol oleate (PSO) was chosen here as a target ligand since it can be specifically recognized by the low-density lipoprotein (LDL) receptor which is usually over expressed on A549 lung cancer cells. In this way, a PSO-modified doxorubicin-loaded HGNP drug delivery system (PSO-HGNPs-DOX) was constructed and its physicochemical properties, photothermal conversion ability, and drug release of PSO-HGNPs-DOX was investigated. Further, the effects of triple combination therapy, the intracellular uptake, and the ability to escape macrophage phagocytosis of PSO-HGNPs-DOX were also studied using A549 cells in vitro. In addition, an in vivo mouse model was also used to study the targeting of PSO-HGNPs-DOX to lung cancer. PSO-HGNPs-DOX demonstrated a good triple therapeutic effect for lung cancer (A549 cell viability was only 10% at 500 µM) by LDL receptor mediated endocytosis and was able to escape macrophage phagocytosis to enhance its accumulation at the target site. Therefore, PSO-HGNPs-DOX is a novel, safe, promising, and targeted drug carrier designed for triple combination lung cancer therapy which should be further studied for such applications.

Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility.

The neuraminidase (NA) inhibitor (NAI) oseltamivir (OST) is the most widely used influenza antiviral drug. Several NA amino acid substitutions are reported to reduce viral susceptibility to OST in in vitro assays. However, whether there is a correlation between the level of reduction in susceptibility in vitro and the efficacy of OST against these viruses in vivo is not well understood. In this study, a ferret model was utilised to evaluate OST efficacy against circulating influenza A and B viruses with a range of in vitro generated 50% inhibitory concentrations (IC50) values for OST. OST efficacy against an A(H1N1)pdm09 and an A(H1N1)pdm09 virus with the H275Y substitution in neuraminidase was also tested in the macaque model. The results from this study showed that OST had a significant impact on virological parameters compared to placebo treatment of ferrets infected with wild-type influenza A viruses with normal IC50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC50 values. Differing pathogenicity of the viruses made evaluation of clinical parameters difficult, although some effect of OST in reducing clinical signs was observed with influenza A(H1N1) and A(H1N1)pdm09 (H275Y) viruses. Viral titres in macaques were too low to draw conclusive results. Analysis of the ferret data revealed a correlation between IC50 and OST efficacy in reducing viral shedding but highlighted that the current WHO guidelines/criteria for defining normal, reduced or highly reduced inhibition in influenza B viruses based on in vitro data are not well aligned with the low in vivo OST efficacy observed for both wild-type influenza B viruses and those with reduced OST susceptibility.

Oral Colon-Targeted Konjac Glucomannan Hydrogel Constructed through Noncovalent Cross-Linking by Cucurbit[8]uril for Ulcerative Colitis Therapy.

Orally administered colon-targeted formulations of drugs are of great importance in managing diseases in the colon. However, it is often challenging to maintain the integrity of such formulations during delivery, particularly in the gastric environment, which may lead to premature drug release before reaching the targeted colon. Herein, an oral colon-targeted drug delivery hydrogel (OCDDH) was developed through cucurbit[8]uril (CB[8])-mediated noncovalent cross-linking of phenylalanine (Phe)-modified Konjac glucomannan (KGM), in which berberine (BBR), a natural anti-inflammatory product originating from Chinese medicine, was loaded into the hydrogel matrix. With the strong host-guest complexation mediated cross-linking and the inherent reversibility of such interactions, KGM-Phe@CB[8] hydrogel exhibited a readily tunable degree of cross-linking and an excellent self-healing capability, and therefore the hydrogel retained ultrahigh stability in the gastric environment, which is important for orally administered formulations to target the colon. In the colon, KGM may get degraded by colon-specific enzymes, ß-mannanase or ß-glucosidase, resulting in burst release of the loaded cargoes on site. The structure and specific payload release of the hydrogel, with and without BBR, have been fully characterized in vitro, and the therapeutic effect of BBR-loaded KGM-Phe@CB[8] hydrogel was evaluated against dextran sulfate sodium (DSS) induced ulcerative colitis (UC) in a mouse model. Very interestingly, the BBR-loaded KGM-Phe@CB[8] hydrogel exhibited significantly improved therapeutic efficacy in treating colitis, without causing any systemic toxicity, when compared with free BBR. This strategy may pave a new way in the development of advanced supramolecular OCDDH.

[Regulation and Mechanism of a Dregs Biochar Matrix Combined with Maifanite on a Soil-Ryegrass System].

An indoor pot experiment and isothermal adsorption experiment were used to examine the regulation of soil-ryegrass system treatments. For the treatments, Banlangen dregs were selected as a raw material alongside two kinds of biochar (BC300, BC500) prepared by pyrolysis at 300℃ and 500℃ under anoxic conditions. Fe was modified by BC500 (Fe-BC500), which was then combined with maifanite (MFS) as a passivating agent[BC500:MFS (1:1) and Fe-BC500:MFS (1:1)]. Surface pore distribution (BET), scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR) were used in the analyses. The results showed that treatment with BC300, BC500, Fe-BC500, MFS, BC500:MFS (1:1), and Fe-BC500:MFS (1:1) significantly reduced the Cu and Cd content (2% content in soil) of ryegrass (P<0.05) and significantly increased the biomass of ryegrass. This effect could have resulted from the enhanced chlorophyll content and root activity of the ryegrass. The effect of BC300 was better than the other treatments, which reduced the content of Cu and Cd in the roots of ryegrass by 44.78% and 63.89%, respectively, and in the aboveground biomass by 76.34% and 53.40%, respectively. The biomass of roots was also increased by 327.22%, and the aboveground biomass increased by 504.11%. The Langmuir equation produced the best fit for adsorption effects of BC300, BC500, and Fe-BC500, for which the maximum adsorption capacity for Cu was 8.02, 9.20, and 8.82 mg·g-1, respectively. The maximum adsorption capacity for Cd was 7.97, 8.51, and 7.70 mg·g-1, respectively. The Freundlich equation gave a better fit for the adsorption of MFS. In this case, the maximum adsorption capacity for Cu and Cd was 7.03 mg·g-1 and 6.10 mg·g-1, respectively. BC300 and BC500 mainly passes through their surface hydroxyl, carboxyl, carbonyl, and ester groups; Fe-BC500 mainly passes through its surface hydroxyl group and iron hydroxyl group; MFS mainly passes through its silicon hydroxyl group, hydroxyl group, and carboxyl group on the surface of NaAlSi3O8 and Al2Si2O5(OH)4 and then to repair passivated Cu and Cd contaminated soil effect. Therefore, Banlangen dregs biochar, iron-modified Banlangen dregs biochar, maifanite, and the combination of these materials can be used for the remediation of Cu and Cd contaminated soils, although the mechanism of remediation is different.

Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy.

One of the main challenges for immune checkpoint blockade antibodies lies in malignancies with limited T-cell responses or immunologically "cold" tumors. Inspired by the capability of fever-like heat in inducing an immune-favorable tumor microenvironment, mild photothermal therapy (PTT) is proposed to sensitize tumors to immune checkpoint inhibition and turn "cold" tumors "hot." Here we present a combined all-in-one and all-in-control strategy to realize a local symbiotic mild photothermal-assisted immunotherapy (SMPAI). We load both a near-infrared (NIR) photothermal agent IR820 and a programmed death-ligand 1 antibody (aPD-L1) into a lipid gel depot with a favorable property of thermally reversible gel-to-sol phase transition. Manually controlled NIR irradiation regulates the release of aPD-L1 and, more importantly, increases the recruitment of tumor-infiltrating lymphocytes and boosts T-cell activity against tumors. In vivo antitumor studies on 4T1 and B16F10 models demonstrate that SMPAI is an effective and promising strategy for treating "cold" tumors.

[Correlation analysis of quality,origin and phenotypic characters of Paris polyphylla var. yunnanensis].

In order to provide guidance for the protection and utilization of resources,quality control and breeding of improved varieties,we compared the main phenotypic characters and quality of wild and transplanted Paris polyphylla var. yunnanensis collected from different producing areas. Seven phenotypic characters of 33 samples of P. polyphylla var. yunnanensis collected from Yunnan,Guizhou and Sichuan were determined by conventional methods,and the principal component analysis and cluster analysis were used to analyze the diversity of the samples. The parissaponin( polyphyllin Ⅰ,Ⅱ,Ⅵ,Ⅶ) content of the samples were detected by HPLC,and analyzed by cluster analysis. Correlation analysis of the phenotypic characters and the parissaponin content was performed. There were significant differences in seven phenotypic characters between wild and transplanted samples of P. polyphylla var. yunnanensis from different habitats,with high phenotypic diversity and abundant genetic variation. The results of principal component analysis showed that leaf shape index was the main factor of morphological variation of P. polyphylla var. yunnanensis. Cluster analysis showed that the phenotypic characters of wild and transplanted P. polyphylla var. yunnanensis could not be completely separated. The content of saponins in wild and transplanted samples from different habitats was quite different. Saponins content of 93. 94% samples met the criterion of Chinese Pharmacopoeia 2015 edition,and the overall quality was relatively steady. The results of independent sample t-test showed that there was no significant difference of all the active ingredient between wild and transplanted samples,and it couldn't be used to distinguish between wild and transplanted samples. It is the same as the results of cluster analysis. The results of correlation analysis showed that the phenotypic traits of P. polyphylla var. yunnanensis were correlated with its medicine quality,and the total content of saponins was positively correlated with leaf length and leaf shape index( r = 0. 389,0. 441; P<0. 05). Yunnan,Guizhou and Sichuan are suitable for the growth of P. polyphylla var. yunnanensis. And the transplaned P. polyphylla var. yunnanensis can be used as the same as the wild ones completely. The results provide reference for the protection and selective breeding of P. polyphylla var. yunnanensis.

[Clinical observation of mild to moderate lumbodorsal fascitis treated with distal acupoints along meridian plus exercising combined with penetration needling on yang meridians of back].

OBJECTIVE: To compare the therapeutic effect between distal acupoints along meridian plus exercising combined with penetration needling on yang meridians of back and simple penetration needling on yang meridians of back for mild to moderate lumbodorsal fascitis. METHODS: A total of 60 patients with mild to moderate lumbodorsal fascitis were randomized into an observation group and a control group, 30 cases in each one. In the control group, penetration needling on yang meridians of back was applied at acupoints of the Governor vessel (T2-L5) and the first line of bladder meridian, penetration needling was performed from the top down along the governor vessel and the first line of bladder meridian of the lumbar back pain (from one acupoint down to another acupoint), until there was no pain. In the observation group, distal acupoints along meridian plus exercising were adopted on the base of treatment in the control group. The distal acupoints along meridian plus exercising was applied at Cuanzhu (BL 2) for 30 min, at the same time, lumbar back anteflexion, hypsokinesis and turning sides were used in combination for 10 min. And then penetration needling on yang meridians of back was performed. The treatments were given once a day, 5 consecutive treatments a week, 1 week as a course and 2 courses were required. The visual analogue scale (VAS) score and Oswestry disability index (ODI) before treatment, after treatment and 1-month in follow-up were observed in the two groups, and the clinical effects were compared. RESULTS: Compared before treatment, the VAS score and ODI were reduced after treatment in the two groups (P<0.01). The changes of the VAS score and ODI in the observation group were larger than those in the control group (P<0.01, P<0.05). In follow-up, the VAS score and ODI in the observation group were lower than those in the control group (P<0.05). The total effective rate in the observation group was 90.0% (27/30), which was superior to 83.3% (25/30) in the control group (P<0.05). CONCLUSION: Distal acupoints along meridian plus exercising combined with penetration needling on yang meridians of back have a better therapeutic effect than simple penetration needling on yang meridians of back in the treatment of mild to moderate lumbodorsal fascitis.

Improved effects of saponins from Panax japonicus on decline of cognitive function in natural aging rats via NLRP3 inflammasome pathway / 中国中药杂志

The aim of this paper was to investigate the effect of total saponins from Panax japonicus( SPJ) on cognitive decline of natural aging rats and its mechanism. Thirty male SD rats of eighteen month old were randomly divided into three groups: aged group,10 mg·kg~(-1) SPJ-treated group and 30 mg·kg~(-1) SPJ-treated group. The SPJ-treated groups were given SPJ at the dosages of 10 mg·kg~(-1) and 30 mg·kg~(-1),respectively,from the age of 18 to 24 months. Aged group were lavaged the same amount of saline,10 six-month-old rats were used as control group,with 10 rats in each group. The open field test,novel object recognition and Morris water maze were performed to detect the changes of cognitive function in each group. The changes of synaptic transmission of long-term potentiation( LTP) in hippocampal CA1 region were detected by field potential recording. Western blot was used to detect the protein levels of NLRP3,ASC,caspase-1 and the changes of Glu A1,Glu A2,CAMKⅡ,CREB and phosphorylation of CAMKⅡ,CREB in each group.The results showed that SPJ could improve the decline of cognitive function in aging rats,reduce the damage of LTP in the hippocampal CA1 region of aged rats,and decrease the expression of NLRP3,ASC,caspase-1 in aging rats. At the same time,SPJ could enhance the membrane expression of AMPA receptor( Glu A1 and Glu A2),and increase the expression of p-CAMKⅡand p-CREB in aging rats.SPJ could improve cognitive decline of natural aging rats,and its mechanism may be related to regulating NLRP3 inflammasome,thus regulating the membrane expression of AMPA receptor,and enhancing the expression phosphorylation of CAMKⅡ and CREB.