Growing attention on the toxicity of Chinese herbal medicine: a bibliometric analysis from 2013 to 2022.

Introduction: Despite the clinical value of Chinese herbal medicine (CHM), restricted comprehension of its toxicity limits the secure and efficacious application. Previous studies primarily focused on exploring specific toxicities within CHM, without providing an overview of CHM's toxicity. The absence of a quantitative assessment of focal points renders the future research trajectory ambiguous. Therefore, this study aimed to reveal research trends and areas of concern for the past decade. Methods: A cross-sectional study was conducted on publications related to CHM and toxicity over the past decade from Web of Science Core Collection database. The characteristics of the publication included publication year, journal, institution, funding, keywords, and citation counts were recorded. Co-occurrence analysis and trend topic analysis based on bibliometric analysis were conducted on keywords and citations. Results: A total of 3,225 publications were analyzed. Number of annal publications increased over the years, with the highest number observed in 2022 (n = 475). The Journal of Ethnopharmacology published the most publications (n = 425). The most frequently used toxicity classifications in keywords were hepatotoxicity (n = 119) or drug-induced liver injury (n = 48), and nephrotoxicity (n = 40). Co-occurrence analysis revealed relatively loose connections between CHM and toxicity, and their derivatives. Keywords emerging from trend topic analysis for the past 3 years (2019-2022) included ferroptosis, NLRP3 inflammasome, machine learning, network pharmacology, traditional uses, and pharmacology. Conclusion: Concerns about the toxicity of CHM have increased in the past decade. However, there remains insufficient studies that directly explore the intersection of CHM and toxicity. Hepatotoxicity and nephrotoxicity, as the most concerned toxicity classifications associated with CHM, warrant more in-depth investigations. Apoptosis was the most concerned toxicological mechanism. As a recent increase in attention, exploring the mechanisms of ferroptosis in nephrotoxicity and NLRP3 inflammasome in hepatotoxicity could provide valuable insights. Machine learning and network pharmacology are potential methods for future studies.

Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

Exploring the boost of steaming with wine on Ligustri Lucidi Fructus in treating postmenopausal osteoporosis based on superior "multi-component structure" and iron/bone metabolism coregulation.

BACKGROUND: Clinical studies indicated that postmenopausal osteoporosis (PMOP) often accompanied by iron overload risk factor, which exacerbated bone metabolism disorders and accelerated PMOP. Previous research found that multicomponent in Ligustri Lucidi Fructus (FLL) or wine-steamed FLL (WFLL) acted on the common targets of iron overload and PMOP simultaneously, which indicated that FLL and WFLL probably regulated iron/bone metabolism dually. Additionally, WFLL had more superior effect according to the theory of Chinese medicine for thousands of years. PURPOSE: To reveal the "superior multi-component structure (SMCS)" and its molecular mechanisms in parallelly down-regulating iron overload and rescuing bone metabolism by WFLL. DESIGNS AND METHODS: HPLC fingerprinting was established to compare the chemical profiles of FLL and WFLL; Then, the chemical compositions and quality markers of FLL and WFLL were analyzed by UPLC-Orbitrap-MS/MS coupled with OPLS-DA; the dynamic contents of quality markers and the multi-component structure at different wine steaming times (WST) were simultaneously determined by HPLC-DAD. Meanwhile, the dynamic efficacy of FLL at different WST were hunt by systematic zebrafish model. Subsequently, potential mechanism of WFLL in treating PMOP accompanied with iron overload was obtained from network pharmacology (NP) and molecular docking (MD). Finally, zebrafish and ovariectomy rat model were carried out to validate this potential mechanism. RESULTS: HPLC fingerprints similarity of 15 batches in FLL and WFLL were among 0.9-1.0. 126 compositions were identified, including 58 iridoids, 25 terpenes, 30 phenylethanoids, 7 flavonoids and 6 others. 20 quality markers associated with WFLL was revealed, and the ratio of phenylethanols: Iridoids: Triterpenes (P/I/T) was converted from 1: 15: 4.5 to 1: 0.8: 0.9 during steaming (0 - 24 h) calculated by the quantification of 11 quality markers; the bone mineralization and motor performance of zebrafish larvae indicated that the optimum efficacy of WFLL at 12 h (p < 0.05) in which the SMCS of P/I/T was converted to 1: 4: 1.8. NP discovered that BMP-Smad pathway is one of the potential mechanisms of FLL in anti PMOP and then regulated bone formation and iron overload simultaneously. MD revealed that 17 active ingredients and 10 core targets genes could spontaneously bind with appropriate affinity. Rats model verified that FLL and WFLL significantly reversed PMOP, based on the improvement in bone formation indexes (ALP, OPG, OGN), iron metabolism indicators (hepcidin, ferritin), bone microstructure (BMD, BV/TV, Tb. Th, Tb. N); Moreover, WFLL significant enhanced reversal effect in anti-PMOP compared to FLL (p < 0.05). FLL and WFLL increased genes and proteins expression (Hep, BMP-6, p-Smad1/5, Smad4) related to BMP-Smad pathway compared with model group, and WFLL was more superior than FLL (p< 0.05). CONCLUSION: The SMCS of FLL was optimized by wine-steam, WFLL represented a dual effect in downregulating iron overload and promoting bone formation, and the BMP-Smad pathway is one of the potential molecular mechanisms.

A rs-fMRI study of functional connectivity changes between thalamus and postcentral gyrus in patients with neuropathic pain after brachial plexus avulsion.

BACKGROUND: The neuropathic pain (NPP) after brachial plexus avulsion (BPA) is common and difficult to cure, and thalamus and postcentral gyrus have been accepted to be the key nodes of mechanisms and pathways for pain. However, little attention has been paid on the thalamus-postcentral gyrus functional connectivity changes in NP patients after BPA. METHODS: Eighteen patients with NPP after BPA and twenty age and gender matched healthy controls were enrolled and underwent resting-state functional MRI (rs-fMRI) scans in this study. The Pearson's r-value of functional connection (bilateral thalamus and postcentral gyrus as regions of interest) was generated and examined using two sample t-test. The linear regression analysis was used to select possible related factors, and multiple linear regression of the possible predictors was used to identify the variables that significantly predicted Visual Analogue Score (VAS). RESULTS: The standardized Pearson r-values of the left thalamus-right thalamus, left thalamus-left postcentral gyrus, left thalamus-right postcentral gyrus, right thalamus-left postcentral gyrus and right thalamus-right postcentral gyrus in the control group were 0.759 ± 0.242, 0.358 ± 0.297, 0.383 ± 0.270, 0.317 ± 0.295 and 0.333 ± 0.304, respectively. And the corresponding standardized Pearson r-values in patients group were 0.510 ± 0.224,0.305 ± 0.212,0.281 ± 0.225,0.333 ± 0.193 and 0.333 ± 0.210, respectively. The functional connectivity strength of the left thalamus-right thalamus in control group was significantly higher than that in the patients group (P < 0.05). Linear regression analysis showed that the functional connectivity strength of the left thalamus-right thalamus was negatively correlated with the patients' VAS score (P < 0.05). CONCLUSIONS: NPP patients after BPA had a significant pain-related bilateral thalamus functional connection reorganization, with the purpose to limit the pain signal inputs within the unilateral cerebral hemisphere.

Effectiveness of Zhenqi Buxue Oral Liquid Combined with Progesterone for Treatment of Oligomenorrhea and Hypomenorrhea with Qi-Blood and Kidney (Shen) Essence Deficiency: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effectiveness and safety of Zhenqi Buxue Oral Liquid (ZQ), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea with qi-blood and Kidney (Shen) essence deficiency. METHODS: This was a prospective, randomized, multi-center controlled trial between June 2022 to December 2022. Ninety-six oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency were randomly assigned to receive ZQ (ZQ group, 29 cases), progesterone capsules (PG group, 32 cases), or the combined Chinese and Western medicine (COM group, 31 cases) at a ratio of 1:1:1. Patients in the ZQ or PG group took daily 10 mL twice a day of ZQ or 200 mg once a day of progesterone capsules for 10 consecutive days on day 15 of the menstrual cycle respectively, and patients in the COM group received the same ZQ combined with progesterone capsules. The treatment course lasted for 3 months and follow-up was performed at 1 and 3 months after the end of treatment. Primary endpoint was the menstrual Traditional Chinese Medicine Syndrome Scale (TCMSS) scores. Secondary endpoints included pictorial blood loss assessment chart (PBAC) scores, clinical efficacy rate, 36-item Short Form Health Survey (SF-36) scores, sex hormones and thickness of endometrium. Adverse events (AEs) were recorded. RESULTS: TCMSS scores after 1- and 3-month treatment in all groups were significantly lower than those at baseline (P<0.05). Only TCMSS scores after 3-month treatment in the ZQ and COM groups continuously decreased compared with those after 1-month treatment in the same group (P<0.01). TCMSS scores after 3-month treatment in the ZQ and COM groups were significantly lower than those in the PG group (P<0.05, P<0.01). Compared with baseline, PBAC scores in the ZQ and COM groups after 3 months of treatment were also significantly higher (both P<0.01). The total effective rates of TCM syndrome of 3-month treatment were significantly improved in all groups compared with that after 1 month of treatment (P<0.05). The total effective rate of the COM group was the highest in the 3rd month of treatment and significantly higher than that of PG group alone (P<0.05). Compared with baseline, only the SF-36 scores of COM group were significantly improved after 3 months of treatment (P<0.05). No serious adverse reactions were observed after treatment. CONCLUSIONS: The combination of ZQ and PG, or ZQ only had better effects on reducing TCMSS scores compared with PG, and COM showed the higher total effective rate compared with monotherapy. Besides, COM could effectively improve menstrual blood loss and quality of life. ZQ combined with PG may be an effective and safe option for oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency.

Shifting of nutrient limitation dominates the recovery of aboveground net primary productivity of mixed forests in northeastern China after selective logging.

The primary productivity of temperate forests is commonly limited by nitrogen (N) supply, which may be aggravated by the removal of trees. After selective logging, whether and the mechanism by which the N limitation can be alleviated by the rapidly increasing nutrient turnover during the recovery processes, which is important for improving carbon sequestration in temperate forests, remain unclear. We investigated the effect of nutrient limitation (leaf N:Pcom: the leaf N:P ratio at the community level) on plant community productivity by selecting 28 forest plots including seven forest recovery periods (at the sites logged 6, 14, 25, 36, 45, 55, and 100 years ago) following low-intensity selective logging (13-14 m3/ha) and one unlogged treatment by measuring the soil N concentration, soil phosphorus (P) concentration, leaf N concentration, leaf P concentration, and the aboveground net primary productivity (ANPP) of 234 plant species. The plant growth in temperate forests was limited by N, but the P limitation was observed at the sites logged 36 years ago, which showed a transition pattern of plant growth from N limitation to P limitation during the forest recovery process. Meanwhile, a robust linear trend in the community ANPP was observed with the increase in the community leaf N:P ratio, which suggests the enhancement in community ANPP with the release of N limitation after selective logging. Nutrient limitation (leaf N:Pcom) had a significant direct effect (56.0 %) on the community ANPP and showed a higher independent contribution (25.6 %) to the variation in the community ANPP than the soil nutrient supply and even the changes in species richness. Our results suggested that selective logging alleviated the N limitation, but a shift toward P limitation should also be highly regarded in learning the changes in carbon sequestration during the recovery processes.

Synthetic Antibacterial Quaternary Phosphorus Salts Promote Methicillin-Resistant Staphylococcus aureus-Infected Wound Healing.

Background: Drug-resistant microbes pose a global health concern, requiring the urgent development of effective antibacterial agents and strategies in clinical practice. Therefore, there is an urgent need to explore novel antibacterial materials to effectively eliminate bacteria. The synthesis of quaternary phosphonium salt in haloargentate systems, wherein the phosphorus atom is represented in a cationic form, is a possible strategy for the development of antibacterial materials. Methods: Using (triphenyl)phosphonium-based quaternary phosphorus salts with different spacer lengths (n=2, 4, 6) as a template, we designed three kinds of quaternary phosphorus salts as effective antibacterial agents against drug-resistant bacteria. Results: The synthesized quaternary phosphorus salt of (1,4-DBTPP)Br2 effectively prevented the formation of the bacterial biofilms, and degraded bacterial membranes and cell walls by promoting the production of reactive oxygen species, which exhibited effective therapeutic effects in a rat model of a superficial wound infected with methicillin-resistant Staphylococcus aureus. Conclusion: The quaternary phosphorus salt (1,4-DBTPP)Br2 demonstrated hemocompatibility and low toxicity, revealing its potential in the treatment of clinical infections.

Mitochondrial pyruvate carrier influences ganoderic acid biosynthesis in Ganoderma lucidum.

Mitochondrial pyruvate carriers (MPCs), located in the inner membrane of mitochondria, are essential carriers for pyruvate to enter mitochondria. MPCs regulate a wide range of intracellular metabolic processes, such as glycolysis, the tricarboxylic acid cycle (TCA cycle), fatty acid metabolism, and amino acid metabolism. However, the metabolic regulation of MPCs in macrofungi is poorly studied. We studied the role of MPCs in Ganoderma lucidum (GlMPC) on ganoderic acid (GA) biosynthesis regulation in G. lucidum. In this study, we found that the mitochondrial/cytoplasmic ratio of pyruvate was downregulated about 75% in GlMPC1- and GlMPC2-silenced transformants compared with wild type (WT). In addition, the GA content was 17.72 mg/g and increased by approximately 50% in GlMPC1- and GlMPC2-silenced transformants compared with WT. By assaying the expression levels of three key enzymes and the enzyme activities of isocitrate dehydrogenase (IDH) and α-ketoglutarate dehydrogenase (α-KGDH) of the TCA cycle in GlMPC1- and GlMPC2-silenced transformants, it was found that the decrease in GlMPCs activity did not significantly downregulate the TCA cycle rate, and the enzyme activity of IDH increased by 44% compared with WT. We then verified that fatty acid ß-oxidation (FAO) supplements the TCA cycle by detecting the expression levels of key enzymes involved in FAO. The results showed that compared with WT, the GA content was 1.14 mg/g and reduced by approximately 40% in co-silenced transformants. KEY POINTS: • GlMPCs affects the distribution of pyruvate between mitochondria and the cytoplasm. • Acetyl-CoA produced by FAO maintains the TCA cycle. • Acetyl-CoA produced by FAO promotes the accumulation of GA.

The neural representations underlying asymmetric cross-modal prediction of words.

Cross-modal prediction serves a crucial adaptive role in the multisensory world, yet the neural mechanisms underlying this prediction are poorly understood. The present study addressed this important question by combining a novel audiovisual sequence memory task, functional magnetic resonance imaging (fMRI), and multivariate neural representational analyses. Our behavioral results revealed a reliable asymmetric cross-modal predictive effect, with a stronger prediction from visual to auditory (VA) modality than auditory to visual (AV) modality. Mirroring the behavioral pattern, we found the superior parietal lobe (SPL) showed higher pattern similarity for VA than AV pairs, and the strength of the predictive coding in the SPL was positively correlated with the behavioral predictive effect in the VA condition. Representational connectivity analyses further revealed that the SPL mediated the neural pathway from the visual to the auditory cortex in the VA condition but was not involved in the auditory to visual cortex pathway in the AV condition. Direct neural pathways within the unimodal regions were found for the visual-to-visual and auditory-to-auditory predictions. Together, these results provide novel insights into the neural mechanisms underlying cross-modal sequence prediction.

MiR-19b-3p Attenuates Chondrocytes Injury by Inhibiting MAPK/NF-Κb Axis via Targeting SOCS1.

In this study, miR-19b-3p was downregulated in osteoarthritic cartilage tissues and IL-1ß-stimulated primary chondrocytes, and miR-19b-3p overexpression reversed the inhibitory effect of IL-1ß on cell viability, the promotion effects of apoptosis, inflammatory factor secretion and extracellular matrix degradation, whereas the opposite effect was observed with miR-19b-3p inhibitor. Moreover, SOCS1 is a target gene of miR-19b-3p. Furthermore, SOCS1 overexpression enhanced cell injury compared with IL-1ß alone treatment, whereas knockdown of SOCS1 restored cell damage caused by IL-1ß. Further studies revealed that miR-19b-3p promoted chondrocyte injury repair by suppressing SOCS1 expression, and we found that was mediated by blocking the MAPK/NF-κB axis. Taken together, our findings may provide a new therapeutic strategy for osteoarthritis.

[Chemical Forms and Spatial Distribution of Phosphorus in the Sediment of Sihe River].

Based on the study of the content, forms, and spatial distribution of phosphorus (P) in the surface and columnar sediments of the Sihe River, the relationships between the total phosphorus (TP) and various forms of P and the basic physical and chemical properties of sediment and their ecological significance were deeply discussed. The forms of P in the sediment were defined including soluble and loosely bound P (S/L-P), Al-bound P (Al-P), Fe-bound P (Fe-P), reductant soluble P (RS-P), Ca-bound P (Ca-P), and residual P (RES-P) using the method of selectively sequential extraction. The results indicated that ω (TP) was 421.84-1188.65 mg·kg-1 in the surface sediment. Among the six forms of P, the content of Ca-P was the highest, accounting for more than 40% of TP, followed by the content of Fe-P, accounting for more than 20% of TP. The content of S/L-P was the lowest, which only accounted for approximately 0.4% of TP. The contents of TP and various forms of P in the surface sediments of the downstream area of the Sihe River were higher than those of the upstream area of the river, which was induced by the discharge of industrial wastewater and domestic sewage in the urban areas nearby the downstream portion of the Sihe River. The contents of TP in the upper samples of the two sediment profiles were obviously higher than those in the bottom samples, indicating that the P pollution in the water environment of the Sihe River has been intensifying in recent years. Among all forms of P in the sediment profiles, Ca-P accounted for the largest proportion, followed by Res-P. The correlation analysis results showed that significant correlations were observed between Fe and Fe-P, Al and Al-P, Ca and Ca-P, and TOC and RS-P in the surface sediments; the same correlations had not been found in the sediment profiles. The calculated results of Fe and TP molar ratio indicated that the sediments of the Sihe River could further accumulate P. The percentage of bioavailable P (BAP) in sediment was 25%-50%.

[Clinical anatomical study on the treatment of tarsal tunnel syndrome with four-point vertical acupotomy].

OBJECTIVE: To explore safety and accuracy of four-point acupotomy for the treatment of tarsal tunnel syndrome regarding release of ankle tunnel flexor retinaculum to provide an anatomical basis of clinical treatment. METHODS: Twenty-nine adult specimens (15 males and 14 females) fixed with 10% formalin, aged from 47 to 98 years old with an average age of (81.10±11.14) years old, 29 on the right side and 29 on the left side, which were selected for the study from September 2020 to October 2020. Simulate the operation of loosening flexor retinaculumt with a needle knife on the human specimen, and place the specimen on the frog position of lower limbs with medial malleolus upward to determine the center of medial malleolus. Choose 4 different positions near the flexor retinaculum to insert the needle so that the needle body was perpendicular to skin and cutting edge direction was perpendicular to the running direction of the flexor retinaculum. The needle knife penetrates the skin and explores slowly. When the flexor retinaculum was reached, the needle tip may touch the tough tissue. At this time, the cutting is loosened for 4 times. After acupotomy release operation was completed, make a lateral incision on the skin surface along acupotomy direction, open the area of the exposed flexor retinaculum, dissecting layer by layer, observe and record the needle knife and its surrounding anatomical structure. The length of acupotomy cutting marks of flexor retinaculum was measured by electronic vernier caliper. The safety and accuracy of acupotomy loosening of ankle canal flexor retinaculum were evaluated by observing the number and degree of ankle canal contents such as tendons and nerves injured by needle knife. The safety is to count the number of cases of acupotomy injury to the contents of the ankle canal, and to calculate the injury rate, that is, the number of injury cases/total cases × 100%. The effective release was defined as the release length L ≥ W/2(W is the width of the flexor retinaculum, defined as 20 mm). RESULTS: For safety, there were no acupotomy injuries to nerves or blood vessels in 58 cases, 26 cases injuried to posterior tibial tendon which 17 of these tendon injury cases, the tendon was penetrated and severely injured, and flexor digitorum longus tendon was injured in 12 cases. Among these cases, tendon was penetrated and severely injured in 4 cases, and total injury rate was 32.14%. No nerve and vessel injury on c3 and c4 point. For accuracy, 58 specimens were successfully released. The length Lc of releasing trace for acupotomy was (10.40±1.36) cm, and length range 6.38 to 12.88 cm. Among all cases, the length of releasing trace was ≥10 mm in 37 cases. The overall success rate of release was 100.00%. Layered structure of ankle tube flexor retinaculumt:fiber diaphragm from flexor retinaculum divides contents of ankle tube into different chambers inward, and fiber diaphragm meets here to synthesize a complete flexor retinaculum at the midpoint of the line between the medial malleolus tip and calcaneal tubercle(above the neurovascular course). CONCLUSION: Four-point needle-knife method of releasing flexor retinaculum for the treatment of tarsal tunnel syndrome is performed at the attachment of the two ends of flexor retinaculum;the tendon, but not the nerves and blood vessels, is easily damaged. It is safe to insert needle on the side of calcaneus. The extent of release is relatively complete, but due to the "layered" structure of the flexor retinaculum, classic surgical technique could only release one layer of flexor retinaculum when a needle is inserted at the edge of the bone and cannot achieve complete release of the full thickness of the flexor. Therefore, it remains to be determined whether the desired effect can be achieved clinically.

Antitumour effects of apatinib in progressive, metastatic differentiated thyroid cancer (DTC).

PURPOSE: Management of progressive, metastatic radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has been a great challenge due to its poor prognosis and limited treatment options. Recently, apatinib, an orally anti-angiogenic tyrosine kinase inhibitor (TKI) is reported to be useful for treatment of progressive RAIR-DIC. The aim of this study was to evaluate the antitumour effect of apatinib and the combination therapy with radioactive iodine (RAI) in patients with progressive metastatic DTC. METHODS: Five patients (all female, mean age 62 ± 8 years, ranged from 51 to 69 years) with distant metastatic DTC (dmDTC) after total thyroidectomy (TTE) and neck lymph node dissection were treated with apatinib at a dose 500 mg per day after 18F-Fluorodeoxyglucose (18F-FDG) PET/CT. The effects of apatinib on DTC were evaluated at 4 ± 1 months after treatment with apatinib. RAI therapy was then initiated. The response to apatinib and the combination therapy with RAI treatment was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) and metabolic activity using serum thyroglobulin (Tg) and 18F-FDG PET/CT. RESULTS: Positive 18F-FDG PET/CT results were found in all patients before apatinib therapy. The immunohistochemical analysis of primary tumour tissues showed high expression of vascular endothelial growth factor receptor-2 (VEGFR-2). Four patients with follicular thyroid carcinoma (FTC) showed partial response (PR) with significant decrease in tumour size and maximum standardized uptake value (SUVmax) after 4 ± 1 month's treatment with apatinib. Further significant reduction of tumour size and SUVmax were observed in three patients after combination therapy with apatinib and RAI. Only one patient with both FTC and papillary thyroid cancer (PTC) demonstrated progressive disease (PD) after treatment with apatinib alone, however, a decrease in tumour size and SUVmax as well as serum Tg levels was achieved after the combination with RAI therapy and apatinib. CONCLUSIONS: Apatinib had significant antitumour effects on progressive distant metastatic DTC. Moreover, beneficial synergistic and complementary effects were shown when apatinib combined with RAI therapy. CLINICAL TRIAL REGISTRATION: NCT04180007, Registered November 26, 2019.

2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside ameliorates NAFLD via attenuating hepatic steatosis through inhibiting mitochondrial dysfunction dependent on SIRT5.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming more and more common in clinic in the world, and the study on its mechanism and treatment strategy has already been a research hotspot. Natural chemical compound 2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-d-glucoside (TSG) is isolated from Polygonum multiflorum Thunb. that has already been reported to have the lipid-lowering activity. PURPOSE: The purpose of this research was to observe the improvement of TSG on methionine and choline deficient (MCD) diet-induced NAFLD in mice and to further elucidate its engaged mechanism. METHODS: NAFLD was induced in mice fed by MCD diet for 6 weeks. The accumulation of lipids in hepatocytes was induced by 0.5 mM non-esterified fatty acid (NEFA). Biochemical parameters in serum or livers from mice were tested. Protein and mRNA expression and stability were measured. Mitochondrial dysfunction was analyzed both in vivo and in vitro. The Label-free quantitative proteomic analysis was used to find potential involved key molecules. RESULTS: TSG attenuated hepatic parenchymal cells injury, liver inflammatory responses and hepatic fibrosis, and markedly ameliorated liver steatosis in mice from MCD group. In vitro results indicated that TSG reduced the accumulation of cellular lipids in hepatocytes induced by NEFA. TSG reduced reactive oxygen species (ROS) formation and attenuated mitochondrial dysfunction both in vivo and in vitro. The label-free quantitative proteomic analysis predicted the crucial participation of NAD-dependent protein deacylase sirtuin-5 (SIRT5). Next experimental results further evidenced that TSG enhanced SIRT5 expression in mitochondria both in vitro and in vivo. The TSG-supplied inhibition on ROS formation and mitochondrial dysfunction in hepatocytes was disappeared after the application of SIRT5 siRNA. TSG increased the expression and enzymatic activity of carnitine palmitoyltransferase 1A (CPT1A), but this enhance was diminished in hepatocytes transfected with SIRT5 siRNA. Additionally, the TSG-provided inhibition on cellular lipids accumulation was also disappeared in hepatocytes transfected with SIRT5 siRNA. Further results demonstrated that TSG increased SIRT5 expression by regulating its mRNA stability through enhancing the binding of SIRT5 mRNA with serine/arginine-rich splicing factor 2 (SRSF2), which is an RNA-binding protein (RBP). CONCLUSION: TSG attenuated liver steatosis and inhibited NAFLD progression through preventing oxidative stress injury and improving mitochondrial dysfunction, and SIRT5 played a key role in this process.

Inhibitory effect of main phenolic acid components of Jacobaea cannabifolia (Less.) on inflammation caused by PM2.5.

PM2.5 is an important environmental problem threatening human health at present, which poses serious harm to human body after inhalation. J. cannabifolia is a traditional Chinese medicine which exhibits anti-inflammatory effect. This study aimed to investigate the inhibitory effect of main phenolic acid components of J. cannabifolia on inflammation caused by PM2.5. Effect of PM2.5 on cell activity and apoptosis were determined by MTT, flow cytometry and calcein AM/PI staining. PHBA, PHPAA, and mixture of PHBA and PHPAA of different concentrations were given to RAW264.7 cells pretreated with PM2.5. The effect of drugs on cellular inflammatory factors was detected by ELISA. The expressions of TLRs related signal pathway at protein and gene levels were detected by western blot and qRT-PCR. The results showed that PM2.5 had no effect on cell activity and apoptosis within the determined concentration range. PHBA and PHPAA could markly inhibit the level of IL-1ß, IL-6, and TNF-α in RAW264.7 cells. Furthermore, the expressions of TLR2, TLR4, MyD88, IRAK1, TRAF6, TAK1, IKKß, and NF-κB induced by PM2.5 were markedly inhibited by PHBA and PHPAA at protein and gene levels. This study demonstrated that PHBA and PHPAA could attenuated inflammation caused by PM2.5 through suppressing TLRs related signal pathway.

Seed oil of Brucea javanica induces apoptosis through the PI3K/Akt signaling pathway in acute lymphocytic leukemia Jurkat cells.

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3ß was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.

Seed oil of Brucea javanica induces apoptosis through the PI3K/Akt signaling pathway in acute lymphocytic leukemia Jurkat cells / 中国天然药物

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3β was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.

Comparable efficacy of 100 mg aspirin twice daily and rivaroxaban for venous thromboembolism prophylaxis following primary total hip arthroplasty: a randomized controlled trial / 中华医学杂志(英文版)

BACKGROUND@#Aspirin has demonstrated safety and efficacy for venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA); however, inconsistent dose regimens have been reported in the literature. This study aimed to evaluate and compare the safety and efficacy of 100 mg aspirin twice daily with rivaroxaban in VTE prophylaxis following THA.@*METHODS@#Patients undergoing elective unilateral primary THA between January 2019 and January 2020 were prospectively enrolled in the study and randomly allocated to receive 5 weeks of VTE prophylaxis with either oral enteric-coated aspirin (100 mg twice daily) or rivaroxaban (10 mg once daily). Medication safety and efficacy were comprehensively evaluated through symptomatic VTE incidence, deep vein thrombosis (DVT) on Doppler ultrasonography, total blood loss (TBL), laboratory bloodwork, Harris hip score (HHS), post-operative recovery, and the incidence of other complications.@*RESULTS@#We included 70 patients in this study; 34 and 36 were allocated to receive aspirin and rivaroxaban prophylaxis, respectively. No cases of symptomatic VTE occurred in this study. The DVT rate on Doppler ultrasonography in the aspirin group was not significantly different from that in the rivaroxaban group (8.8% vs. 8.3%, χ2 = 0.01, P = 0.91), confirming the non-inferiority of aspirin for DVT prophylaxis (χ2 = 2.29, P = 0.01). The calculated TBL in the aspirin group (944.9 mL [658.5-1137.8 mL]) was similar to that in the rivaroxaban group (978.3 mL [747.4-1740.6mL]) (χ2 = 1.55, P = 0.12). However, there were no significant inter-group differences in HHS at post-operative day (POD) 30 (Aspirin: 81.0 [78.8-83.0], Rivaroxaban: 81.0 [79.3-83.0], χ2 = 0.43, P = 0.67) and POD 90 (Aspirin: 90.0 [89.0-92.0], Rivaroxaban: 91.5 [88.3-92.8], χ2 = 0.77, P = 0.44), the incidence of bleeding events (2.9% vs. 8.3%, χ2 = 0.96, P = 0.33), or gastrointestinal complications (2.9% vs. 5.6%, χ2 = 1.13, P = 0.29).@*CONCLUSION@#In terms of safety and efficacy, the prophylactic use of 100 mg aspirin twice daily was not statistically different from that of rivaroxaban in preventing VTE and reducing the risk of blood loss following elective primary THA. This supports the use of aspirin chemoprophylaxis following THA as a less expensive and more widely available option for future THAs.@*TRIAL REGISTRATION@#Chictr.org, ChiCTR18000202894; http://www.chictr.org.cn/showproj.aspx?proj=33284.

[Clinical anatomical study on the treatment of carpal tunnel syndrome with classic Acupotomy].

OBJECTIVE: To explore the safety of classic Acupotomy in the treatment of carpal tunnel syndrome. METHODS: Twenty six adult specimens (15 males and 11 females), aged 60 to 95(82.54±6.94) years old, were selected from 10% formalin antiseptic fixation. There were 52 sides(two of them could not be tested). The study period was from November 2017 to May 2018. The specimens were collected from the body donation center of the school of basic medicine, Peking University. The operation of releasing the transverse carpal ligament on the human body specimen was simulated by the classic acupotomy, and the distance from the four points to the surrounding anatomical structure was measured to calculate the direct injury rate to the nerve and blood vessels, and the shortest distance between the acupotomy and the nerve and blood vessels was defined as ≥2 mm as safety. RESULTS: In the experimental operation, the direct injury rate of nerve and blood vessel was 14% and 12% respectively. There was significant difference in the rate of direct nerve injury between the four injection points (P<0.05). There was no significant difference in the rate of direct vascular injury between the four injection points (P>0.05). Among the four points, there was a statistically significant difference in the safety of nerves(P<0.05), and the safety of point 1 and point 3 of radial injection was higher than that of point 2 and point 4 of ulnar injection(P<0.05). There was significant difference in the safety of blood vessels between the four points(P<0.05), and the safety of radial point 1 was higher than that of ulnar point 2 and point 4 (P<0.05). CONCLUSION: The safety of the classic Acupotomy for carpal tunnel syndrome is related to the location of the needle entry point, and the safety of theradial proximal end of the needle is the highest.