The phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity of Forsythiae Fructus: An updated systematic review.

Forsythiae Fructus (FF), the dried fruit of F. suspensa, is commonly used to treat fever, inflammation, etc in China or other Asian countries. FF is usually used as the core herb in traditional Chinese medicine preparations for the treatment of influenza, such as Shuang-huang-lian oral liquid and Yin-qiao powder, etc. Since the wide application and core role of FF, its research progress was summarized in terms of traditional uses, phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity. Meanwhile, the anti-influenza substances and mechanism of FF were emphasized. Till now, a total of 290 chemical components are identified in F. suspensa, and among them, 248 components were isolated and identified from FF, including 42 phenylethanoid glycosides, 48 lignans, 59 terpenoids, 14 flavonoids, 3 steroids, 24 cyclohexyl ethanol derivatives, 14 alkaloids, 26 organic acids, and 18 other types. FF and their pure compounds have the pharmacological activities of anti-virus, anti-inflammation, anti-oxidant, anti-bacteria, anti-tumor, neuroprotection, hepatoprotection, etc. Inhibition of TLR7, RIG-I, MAVS, NF-κB, MyD88 signaling pathway were the reported anti-influenza mechanisms of FF and phenylethanoid glycosides and lignans are the main active groups. However, the bioavailability of phenylethanoid glycosides and lignans of FF in vivo was low, which needed to be improved. Simultaneously, the un-elucidated compounds and anti-influenza substances of FF strongly needed to be explored. The current quality control of FF was only about forsythoside A and phillyrin, more active components should be taken into consideration. Moreover, there are no reports of toxicity of FF yet, but the toxicity of FF should be not neglected in clinical applications.

Multi-omics and chemical profiling approaches to understand the material foundation and pharmacological mechanism of sophorae tonkinensis radix et rhizome-induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sophorae tonkinensis Radix et Rhizoma (STR) is an extensively applied traditional Chinese medicine (TCM) in southwest China. However, its clinical application is relatively limited due to its hepatotoxicity effects. AIM OF THE STUDY: To understand the material foundation and liver injury mechanism of STR. MATERIALS AND METHODS: Chemical compositions in STR and its prototypes in mice were profiled by ultra-performance liquid chromatography coupled quadrupole-time of flight mass spectrometry (UPLC-Q/TOF MS). STR-induced liver injury (SILI) was comprehensively evaluated by STR-treated mice mode. The histopathologic and biochemical analyses were performed to evaluate liver injury levels. Subsequently, network pharmacology and multi-omics were used to analyze the potential mechanism of SILI in vivo. And the target genes were further verified by Western blot. RESULTS: A total of 152 compounds were identified or tentatively characterized in STR, including 29 alkaloids, 21 organic acids, 75 flavonoids, 1 quinone, and 26 other types. Among them, 19 components were presented in STR-medicated serum. The histopathologic and biochemical analysis revealed that hepatic injury occurred after 4 weeks of intragastric administration of STR. Network pharmacology analysis revealed that IL6, TNF, STAT3, etc. were the main core targets, and the bile secretion might play a key role in SILI. The metabolic pathways such as taurine and hypotaurine metabolism, purine metabolism, and vitamin B6 metabolism were identified in the STR exposed groups. Among them, taurine, hypotaurine, hypoxanthine, pyridoxal, and 4-pyridoxate were selected based on their high impact value and potential biological function in the process of liver injury post STR treatment. CONCLUSIONS: The mechanism and material foundation of SILI were revealed and profiled by a multi-omics strategy combined with network pharmacology and chemical profiling. Meanwhile, new insights were taken into understand the pathological mechanism of SILI.

[Economic evaluation of Annao Pills combined with antihypertensive drugs in treatment of primary hypertension: a study based on decision tree model].

The purpose of this study was to evaluate the economics of Annao Pills combined with antihypertensive drugs in the treatment of primary hypertension in the Chinese medical setting. TreeAge pro 2018 was used for cost-effect analysis and sensitivity analysis of the two treatment regimens. The intervention time of the simulation model was 2 weeks. The cost parameters were derived from Yaozhi.com, and the effect parameters were based on Meta-analysis of randomized controlled trial(RCT) involving Annao Pills. The experimental group was treated with Annao Pills combined with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets), and the control group was treated with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets). The basic analysis showed that the incremental cost-effect ratio(ICER) of the two groups was 2 678.67 yuan, which was less than 7.26% of the per capita disposable income in 2022. That is, compared with anti-hypertensive drugs alone, Annao Pills combined with antihypertensive drugs cost 2 678.67 yuan more for each additional patient with primary hypertension. The results of sensitivity analysis verified the robustness of the basic analysis results. The probability sensitivity results showed that when the patient's personal willingness to pay the price was higher than 2 650 yuan, the probability of the regimen in the experimental group was higher, which was consistent with the results of the basic analysis. In conclusion, when the price was higher than 2 650 yuan, Annao Pills combined with anti-hypertensive drugs was more economical than anti-hypertensive drugs alone in terms of improving the response rate of the patients with primary hypertension.

Impact of age, sex, and thyroid autoimmunity on the association between selenium intake and type 2 diabetes mellitus.

BACKGROUND: The association between dietary selenium(Se) intake and type 2 diabetes mellitus (T2DM) remains controversial. The present study aimed to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2007-2012. METHODS: Three thousand seventy three individuals aged 20 years and above were eligible for inclusion in this cross-sectional study. The average age of the participants was 50.74 years and the proportions of males and females were nearly equal (49.12% vs. 50.88%). The odds ratios (OR) of the association between dietary Se intake (log2-transformed) and T2DM were examined through the multivariate logistic regression model. Subgroup analyses were conducted based on age, sex, and thyroid autoimmunity to assess the potential impact of these variables on the relationship. Fitted smoothing curves and threshold effect analysis were conducted to describe the nonlinear relationship. RESULTS: In the fully adjusted model, a significant positive association between Se intake and T2DM was observed (OR = 1.49, 95% CI: 1.16, 1.90, p = 0.0017). After stratifying the data by age, sex, and thyroid autoimmunity, a significant positive association between Se intake and T2DM was observed in individuals under 65 years of age, males, and those with negative thyroid autoimmunity. A two-segment linear regression model was analyzed for sex stratification, revealing a threshold effect in males with an inflection point of 90.51 µg, and an inverted U-shaped relationship in females with an inflection point of 109.90 µg, respectively. CONCLUSIONS: The present study found a positive relationship between Se intake and the prevalence of T2DM. This association is particularly significant in younger individuals, males, and those with negative thyroid autoimmunity. Our results should be validated in future large prospective studies in different populations.

A review of the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology of Abri Herba (Ji-Gu-Cao).

Abri Herba (AH, known as 'Ji-Gu-Cao' in China) has a long-term medicinal history of treating cholecystitis, acute and chronic hepatitis and non-alcoholic fatty liver (NAFL) in China or other Asian countries. This review aimed to provide a comprehensive analysis of AH in terms of ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology. The information involved in the study was collected from a variety of electronic resources, and >100 scientific studies have been used since 1962. Until now, 95 chemical compounds have been isolated and identified from AH and the seeds of Abrus cantoniensis Hance (ACH), including 47 terpenoids, 26 flavonoids and 4 alkaloids. The pharmacological activities of AH extracts and their pure compounds have been explored in the aspects of anti-hyperlipidaemia, hepatoprotection, anti-tumour, anti-viral, anti-bacterial, anti-inflammatory and analgesic, immunomodulation, antioxidant and others. The pharmacokinetics and excretion kinetics of AH in vivo and 15 traditional and clinical prescriptions containing AH have been sorted out, and the potential therapeutic mechanism and drug metabolism pattern were also summarised. The pods of ACH are toxic, with a median lethal dose (LD50) of 10.01 ± 2.90 g/kg (i.g.) in mice. Interestingly, the toxicity of ACH's pods and seeds decreased after boiling. However, the toxicity mechanism of pods of ACH is unclear, limiting its clinical application. Clinical trials in the future should be used to explore its safety. Meanwhile, as one of the relevant pharmacological activities, the effects and mechanism of AH on anti-hyperlipidaemia and hepatoprotection should be further studied, which is of great significance for understanding its mechanism of action in the treatment of NAFL disease and improving its clinical application.

Epicoccum sorghinum Causing Leaf Spot on Polygonatum cyrtonema in China.

Polygonatum cyrtonema Hua (family Asparagaceae) is a traditional Chinese medicinal plant that is widely cultivated in various parts of China, including Hunan Province. In summer 2022, a leaf spot disease was observed in 10% of the P. cyrtonema plants (Huang jing) in 18 hectares of this crop in the Hongjiang District (27°18'4″N, 110°11'1″E) of Hunan Province. The initial symptoms of the disease were brown spots on young leaves, and adjacent tissues gradually changed from green to yellow. The entire leaf then became yellow, withered, and eventually exhibited a thn and black appearance. In total, 12 diseased plants from four sampling sites (three plants per site) were collected for laboratory analysis to address the concerns of P. cyrtonema growers. Symptomatic leaf samples were selected, and the leaf fragments containing infected parts of the plants were disinfected with 75% ethanol for 1 min, then immersed in 2.5% hypochlorite for 45 s. After disinfection, symptomatic leaf samples were rinsed three times with sterile water, placed on potato saccharose agar containing 50 µg/ml kanamycin and incubated at 25°C for 2 days. Subsequently, 12 fungal isolates were isolated from various leaf samples through hyphal tip transferring. Ten of the 12 fungal isolates had similar morphological features, and one of them (isolate hjh) was used as the representative isolate for the study. With a growth rate of 6.3 mm per day, its white colonies transformed into red concentric rings in five days; they gradually became black after 10 days of growth. The chlamydospores were round (4.0-9.9 × 3.1-9.3 µm, n = 30), whereas the conidia were ovate (8.0-12.1 × 3.2-6.5 µm, n = 30). The morphological features of the isolate hjh were similar to the features of Epicoccum spp. (Aveskamp et al. 2010). The internal transcribed spacer (ITS) region (including the partial ITS1 sequence and the 5.8S and ITS2 complete sequences), ß-tubulin (tub) gene, and large subunit (LSU) rRNA gene, were amplified from the isolate hjh using the primer pairs ITS5/ITS4, Bt2a/Bt2b, and LROR/LR5, respectively (Taguiam et al. 2021). BLASTn analysis showed that the ITS (OR253745), tub (OR253764), and LSU (OR253746) sequences generated from the isolate hjh were 98-99% similar to the sequences of E. sorghinum strains CBS 179.80 and CBS 627.68. Subsequently, the ITS, tub, and LSU sequences were combined using Sequence Matrix software; phylogenetic analysis via Bayesian and maximum likelihood methods (Vaidya et al. 2011; Li et al. 2021) classified the isolate hjh into the E. sorghinum clade. To fulfill Koch's postulates, pathogenicity tests were conducted on healthy (lesion-free and disease-free) 2-year-old P. cyrtonema plants. Three healthy plants were inoculated by spraying whole plant until run-off with a spore suspension of the isolate hjh (1 × 106 conidia/ml); Three other healthy plants were sprayed with sterile water as controls. The inoculated plants were incubated in a growth chamber at 25 ± 2°C with 85% humidity for 28 days(Chen et al. 2021). Leaves from the inoculated plants gradually became brown within 15 days. Finally, the plants died 28 days after inoculation. The control plants showed no symptoms throughout the experimental period. Isolates (isolate hjh1, hjh2 and hjh3) that were reisolated from the inoculated plants exhibited morphologically similar characteristics and molecularly identical to the original isolate hjh. To our knowledge, this is the first report of E. sorghinum causing leaf spot disease on P. cyrtonema. The results of this study may facilitate the production of P. cyrtonema in China.

Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.

Acupuncture and moxibustion for irritable bowel syndrome: An umbrella systematic review.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional bowel disease characterized by abdominal pain or discomfort associated with altered bowel habits. Several clinical studies have demonstrated the effectiveness of acupuncture and moxibustion for IBS. Many systematic reviews of acupuncture and moxibustion for IBS have been published in recent years, but their results are not entirely consistent. OBJECTIVE: To evaluate the methodological, reporting, and evidence quality of systematic reviews of acupuncture and moxibustion for IBS. SEARCH STRATEGY: Systematic reviews of acupuncture and moxibustion for IBS published before February 20, 2023 were searched in eight databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data, VIP Database for Chinese Technical Periodicals, and China Biology Medicine. The keywords used for literature search were acupuncture, moxibustion, systematic review, meta-analysis, and irritable bowel syndrome. INCLUSION CRITERIA: Systematic reviews and meta-analyses of randomized controlled trials of acupuncture and moxibustion for IBS were included. DATA EXTRACTION AND ANALYSIS: Relevant information was independently extracted by two investigators. The A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020), and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were used to evaluate the methodological quality, reporting quality and evidence quality, respectively. RESULTS: A total of 342 studies were retrieved and 15 systematic reviews were included. The results of AMSTAR 2 showed low methodological quality in 2 studies and very low methodological quality in the remaining 13 studies, with main issues being failure to register a protocol, incomplete search strategy, not providing a list of excluded studies, incomplete consideration of the risk of bias in the included studies, and a failure to assess the publication bias. The results of PRISMA 2020 showed seriously deficient reporting quality of 2 studies, somewhat deficient reporting quality of 12 studies, and relatively complete reporting quality of 1 study, with the main problems being lack of a complete search strategy, non-availability of a list of excluded studies with justification for their exclusion, not conducting heterogeneity and sensitivity analyses, not evaluating the credibility of the evidence, and not registering the protocol. The results of GRADE showed that the quality of the evidence is low or very low. CONCLUSION: Most included systematic reviews interpreted findings to suggest that acupuncture and moxibustion have benefits for IBS. However, there is a need to improve the methodological, reporting and evidence quality of the systematic reviews. Larger, multicenter, rigorously designed randomized controlled trials and high-quality systematic reviews are required to obtain more robust evidence. PLEASE CITE THIS ARTICLE AS: Ma YY, Hao Z, Chen ZY, Shen YX, Liu HR, Wu HG, Bao CH. Acupuncture and moxibustion for irritable bowel syndrome: An umbrella systematic review. J Integr Med. 2024; 22(1): 22-31.

The comparative analysis of Lonicerae Japonicae Flos and Lonicerae Flos: A systematical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae Japonicae Flos (LJF) and Lonicerae Flos (LF) were once used as the same herb in China, but they were distinguished by Chinese Pharmacopoeia in 2005 in terms of their medicinal history, plant morphology, medicinal properties and chemical constituents. However, their functions, flavor, and meridian tropism are the same according to the Chinese pharmacopoeia 2020 edition, making researchers and customers confused. AIM OF THE REVIEW: This review aimed to provide a comparative analysis of LJF and LF in order to provide a rational application in future research. MATERIALS AND METHODS: The information was gathered from China National Knowledge Infrastructure (CNKI), SciFinder, Google Scholar, PubMed, Web of Science, and Chinese Masters and Doctoral Dissertations (all chosen articles were reviewed attentively from 1980.1 to 2023.8). RESULTS: Till now, 507 chemical compounds have been isolated and identified in LJF, while 223 ones (79 overlapped compounds) are found in LF, including organic acids and derivatives, flavonoids, triterpenoids, iridoids, and essential oil components, etc. In addition, the pharmacological activities of LJF and LF, especially for their anti-influenza efficacy and mechanism, and their difference in terms of pharmacokinetic parameters, toxicology, and clinical applications were also summarized. CONCLUSION: The current work offers comparative information between LJF and LF in terms of botany, traditional uses, phytochemistry, ethnopharmacology, pharmacokinetics, toxicology, and pharmacology, especially their anti-influenza activities. Despite the same clinical applications and similar chemical components in LJF and LF, differentiated components were still existed, resulting in differentiated pharmacological activities and pharmacokinetics parameters. Moreover, the research about anti-influenza mechanism and functional substances of LJF and LF is dramatically limited, restricting their clinical applications. In addition, few studies have investigated the metabolism feature of LF in vivo, which is one of the important bases for revealing the pharmacological mechanism of LF. At the same time, the toxicity of LJF and LF is not fully studied, and the toxic compounds of LJF and LF need to be screened out in order to standardize the drug use and improve their rational applications.

Target Design of Multinary Metal-Organic Frameworks for Near-Infrared Imaging and Chemodynamic Therapy.

Imaging-guided chemodynamic therapy is widely considered a promising modality for personalized and precision cancer treatment. Combining both imaging and chemodynamic functions in one system conventionally relies on the hybrid materials approach. However, the heterogeneous, ill-defined, and dissociative/disintegrative nature of the composites tends to complicate their action proceedings in biological environments and thus makes the treatment imprecise and ineffective. Herein, a strategy to employ two kinds of inorganic units with different functions─reactive oxygen species generation and characteristic emission─has achieved two single-crystalline metal-organic frameworks (MOFs), demonstrating the competency of reticular chemistry in creating multifunctional materials with atomic precision. The multinary MOFs could not only catalyze the transformation from H2O2 to hydroxyl radicals by utilizing the redox-active Cu-based units but also emit characteristic tissue-penetrating near-infrared luminescence brought by the Yb4 clusters in the scaffolds. Dual functions of MOF nanoparticles are further evidenced by pronounced cell imaging signals, elevated intracellular reactive oxygen species levels, significant cell apoptosis, and reduced cell viabilities when they are taken up by the HeLa cells. In vivo NIR imaging is demonstrated after the MOF nanoparticles are further functionalized. The independent yet interconnected modules in the intact MOFs could operate concurrently at the same cellular site, achieving a high spatiotemporal consistency. Overall, our work suggests a new method to effectively accommodate both imaging and therapy functions in one well-defined material for precise treatment.

Study on after-effect of electroacupuncture with different time intervals on corticospinal excitability in primary motor cortex. / ä¸åŒé—´éš”æ—¶é—´ç”µé’ˆå¯¹åˆçº§è¿åŠ¨çš®å±‚çš®è´¨è„Šé«“å ´å¥‹æ€§çš„åŽæ•ˆåº”ç ”ç©¶.

OBJECTIVES: To compare the effects of electroacupuncture (EA) with different time intervals on corticospinal excitability of the primary motor cortex (M1) and the upper limb motor function in healthy subjects and observe the after-effect rule of acupuncture. METHODS: Self-comparison before and after intervention design was adopted. Fifteen healthy subjects were included and all of them received three stages of trial observation, namely EA0 group (received one session of EA), EA6h group (received two sessions of EA within 1 day, with an interval of 6 h) and EA48h group (received two sessions of EA within 3 days, with an interval of 48 h). The washout period among stages was 1 week. In each group, the needles were inserted perpendicularly at Hegu (LI 4) on the left side, 23 mm in depth and at a non-acupoint, 0.5 cm nearby to the left side of Hegu (LI 4), separately. Han's acupoint nerve stimulator (HANS-200A) was attached to these two needles, with continuous wave and the frequency of 2 Hz. The stimulation intensity was exerted higher than the exercise threshold (local muscle twitching was visible, and pain was tolerable by healthy subjects, 1-2 mA ). The needles were retained for 30 min. Using the single pulse mode of transcranial magnetic stimulation (TMS) technique, before the first session of EA (T0) and at the moment (T1), in 2 h (T2) and 24 h (T3) after the end of the last session of EA, on the left first dorsal interosseous muscle, the amplitude, latency (LAT), resting motor threshold (rMT) of motor evoked potentials (MEPs) and the completion time of grooved pegboard test (GPT) were detected. Besides, in the EA6h group, TMS was adopted to detect the excitability of M1 (amplitude, LAT and rMT of MEPs) before the last session of EA (T0*). RESULTS: The amplitude of MEPs at T1 and T2 in the EA0 group, at T0* in the EA6h group and at T1, T2 and T3 in the EA48h group was higher when compared with the value at T0 in each group separately (P<0.001). At T1, the amplitude of MEPs in the EA0 group and the EA48h group was higher than that in the EA6h group (P<0.001, P<0.01); at T2, it was higher in the EA0 group when compared with that in the EA6h group (P<0.01); at T3, the amplitude in the EA0 group and the EA6h group was lower than that of the EA48h group (P<0.001). The LAT at T1 was shorter than that at T0 in the three groups (P<0.05), and the changes were not obvious at the rest time points compared with that at T0 (P > 0.05). The GPT completion time of healthy subjects in the EA0 group and the EA48h group at T1, T2 and T3 was reduced in comparison with that at T0 (P<0.001). The completion time at T3 was shorter than that at T0 in the EA6h group (P<0.05); at T2, it was reduced in the EA48h group when compared with that of the EA6h group (P<0.05). There were no significant differences in rMT among the three groups and within each group (P>0.05). CONCLUSIONS: Under physiological conditions, EA has obvious after-effect on corticospinal excitability and upper limb motor function. The short-term interval protocol (6 h) blocks the after-effect of EA to a certain extent, while the long-term interval protocol (48 h) prolongs the after-effect of EA.

Cost-effectiveness of pemigatinib as a second-line treatment for advanced intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 fusions in Taiwan: from the evidence of the phase II trial and the perspective of Taiwan's National Health Insurance Administration.

BACKGROUND: In December 2022, the Taiwan National Health Insurance Administration (NHIA) announced the reimbursement of three dosages of pemigatinib 4.5 mg, 9 mg, and 13.5 mg for treating advanced intrahepatic cholangiocarcinoma (ICC) with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and set the reimbursement price for pemigatinib 4.5 mg at NT$6600. This study aims to analyze the cost-effectiveness of pemigatinib 13.5 mg as a second-line treatment compared to mFOLFOX and 5-FU chemotherapy for advanced ICC patients with FGFR2 fusions/rearrangements from the perspective of Taiwan's NHIA. METHODS: This study used a 3-state partitioned survival model to analyze the 5 year cost-effectiveness of pemigatinib as a second-line treatment for advanced ICC patients in whom first-line gemcitabine-based chemotherapy failed and to compare the results with those for the mFOLFOX and 5-FU chemotherapy regimens. Overall survival and progression-free survival were estimated from the FIGHT-202 trial (pemigatinib), ABC-06 trial (mFOLFOX), and NIFTY trial (5-FU). The price of pemigatinib 13.5 mg was set at the potentially highest listing price (NT$17,820). Other parameters of utility, disutility, and costs related to advanced ICC were obtained from the published literature. The willingness-to-pay threshold was three times the forecasted gross domestic product per capita in 2022 (NT$2,928,570). A 3% discount rate was applied to quality-adjusted life-years (QALYs) and costs. Several scenario analyses were performed, including a gradual price reduction for pemigatinib. Deterministic sensitivity analysis, probabilistic sensitivity analysis (PSA), and value of information were performed to assess uncertainty. RESULTS: Pemigatinib was not cost-effective compared to mFOLFOX or 5-FU in the base-case analysis. When the price of pemigatinib was reduced by 50% or more, pemigatinib gained a positive net monetary benefit (mFOLFOX: NT$55,374; 5-FU: NT$92,437) and a 72% (mFOLFOX) and 77.1% (5-FU) probability of being cost-effective. Most of the uncertainty came from the medication cost of pemigatinib, health state utility, and the overall survival associated with pemigatinib. CONCLUSIONS: According to the NCCN guidelines, the daily use of pemigatinib 13.5 mg at the hypothesized NHIA price of NT$17,820/13.5 mg was not cost-effective compared to mFOLFOX or 5-FU. The price reduction scenario suggested a 50% price reduction, NT$8910 per 13.5 mg, for advanced ICC patients with FGFR2 fusions/rearrangements.

This study performed a cost-effectiveness analysis on the use of targeted therapy pemigatinib 13.5 mg daily in second-line treatment for Taiwanese patients with intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusions/rearrangements. This regimen was approved by the U.S. Food and Drug Administration in 2020 and recommended by the National Comprehensive Cancer Network (NCCN). Taiwan's National Health Insurance Administration (NHIA) has announced the reimbursement of three pemigatinib dosages of 4.5 mg, 9 mg, and 13.5 mg to be listed in the NHI coverage in 2022. However, as of the middle of April 2023, only the listing price for pemigatinib 4.5 mg has been determined, while pricing for the other two dosages remains pending. Based on a hypothesized NHIA price of NT$17,820/13.5 mg, this study evaluated the cost-effectiveness of pemigatinib 13.5 mg as a second-line treatment for advanced ICC with FGFR2 fusions/rearrangements compared to mFOLFOX (a regimen recommended by NCCN) and 5-FU (a regimen fully covered by Taiwan NHIA) and recommended a listing price for NHIA as reference. Our study showed that the hypothesized price of NT$17,820/13.5 mg was not cost-effective compared to mFOLFOX or 5-FU. The price reduction scenario suggested a 50% reduction (NT$8910) in the hypothesized NHIA price for advanced ICC patients with FGFR2 fusions/rearrangements.

Acupoint Thread Embedding Combined With Wenshen Bugu Decoction for the Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptom Among Postmenopausal Breast Cancer Patients: Study Protocol of a Randomized Controlled Trial.

BACKGROUND: Aromatase inhibitors (AIs) are recommended as the preferred therapy for postmenopausal women with hormone receptor-positive (HR+) breast cancer. As a result, aromatase inhibitor-associated musculoskeletal symptom (AIMSS) have become a major problem leading to therapy discontinuation and decreased quality of life in patients receiving adjuvant AIs treatment. Multiple therapies have been attempted, but have yielded limited clinical results. This study will be performed to determine whether acupoint thread embedding (ATE) combined with Wenshen Bugu Decoction can effectively treat AIMSS, so as to improve the AIs medication compliance of postmenopausal breast cancer patients. METHODS: This study will utilize a randomized, 2 parallel groups controlled trial design. A total of 128 eligible postmenopausal breast cancer women with AIMSS will be randomized to receive a 12-week treatment with Wenshen Bugu Decoction alone (control group) or in combination with ATE (treatment group) in a 1:1 ratio. The primary outcome will be the 12 week Brief Pain Inventory Worst Pain (BPI-WP) score. The secondary outcome measures will include response rate, Brief Pain Inventory-Short Form (BFI-SF), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Functional Assessment of Cancer Therapy-Endocrine Symptom (FACT-ES), Functional Assessment of Cancer Therapy-Breast (FACT-B), bone marrow density (BMD), blood markers of bone metabolite, Morisky medication adherence scale-8 (MMAS-8), credibility and expectancy, and survival outcomes. DISCUSSION: This trial may provide clinical evidence that ATE combined with Wenshen Bugu Decoction can be beneficial for treating AIMSS among postmenopausal breast cancer survivors. Our findings will be helpful to enhance the quality of life and reduce the occurrence of AIs withdrawal.

Biomechanics of a Plant-Derived Sealant for Corneal Injuries.

Purpose: The corneal epithelium has a glycocalyx composed of membrane-associated glycoproteins, mucins, and galactin-3. Similar to the glycocalyx in visceral tissues, the corneal glycocalyx functions to limit fluid loss and minimize frictional forces. Recently, the plant-derived heteropolysaccharide pectin has been shown to physically entangle with the visceral organ glycocalyx. The ability of pectin to entangle with the corneal epithelium is unknown. Methods: To explore the potential role of pectin as a corneal bioadhesive, we assessed the adhesive characteristics of pectin films in a bovine globe model. Results: Pectin film was flexible, translucent, and low profile (80 µm thick). Molded in tape form, pectin films were significantly more adherent to the bovine cornea than control biopolymers of nanocellulose fibers, sodium hyaluronate, and carboxymethyl cellulose (P < 0.05). Adhesion strength was near maximal within seconds of contact. Compatible with wound closure under tension, the relative adhesion strength was greatest at a peel angle less than 45 degrees. The corneal incisions sealed with pectin film were resistant to anterior chamber pressure fluctuations ranging from negative 51.3 ± 8.9 mm Hg to positive 214 ± 68.6 mm Hg. Consistent with these findings, scanning electron microscopy demonstrated a low-profile film densely adherent to the bovine cornea. Finally, the adhesion of the pectin films facilitated the en face harvest of the corneal epithelium without physical dissection or enzymatic digestion. Conclusions: We conclude that pectin films strongly adhere to the corneal glycocalyx. Translational Relevance: The plant-derived pectin biopolymer provides potential utility for corneal wound healing as well as targeted drug delivery.

[Research advances in mechanism of lipid infiltration of coronary heart disease and simultaneous treatment of phlegm and blood stasis based on phlegm-blood stasis correlation theory].

Atherosclerosis(AS) is the key pathological basis of coronary heart disease(CHD), and lipid infiltration is a classical theory to explain the pathological mechanism of AS. The theory highlights that the occurrence and development of AS are closely related to abnormal lipid metabolism, with the essence of the pathological reaction caused by the invasion of lipids into arterial intima from plasma. Phlegm and blood stasis are physiologically homologous and subject to pathological co-existence. Phlegm-blood stasis correlation is the basic theory to explain the pathogenesis characteristics of CHD and has important guiding significance for revealing the mecha-nism of lipid infiltration of CHD. Phlegm is the pathological product of abnormal metabolism of Qi, blood, and body fluid, and a gene-ral summary of a series of abnormally expressed lipid substances. Among them, turbid phlegm invades the heart vessels, gradually accumulates, and condenses to achieve the qualitative change from "invisible pathogen" to "tangible pathogen", which corresponds to the mechanism of lipid migration and deposition in the intima of blood vessels, and is the starting factor of the disease. Blood stasis is the continuous development of phlegm, and it is a result of pathological states such as decreased blood fluidity, increased blood coagulation, and abnormal rheology. The fact that blood stasis caused by phlegm accords with the pathological process of "lipid abnormality-circulatory disturbance" and is the central link of the disease. Phlegm and blood stasis aggravate each other and lead to indissoluble cementation. The phlegm-blood stasis combination serves as common pathogen to trigger the disease, which is the inevitable outcome of the disease. Based on the phlegm-blood stasis correlation theory, the simultaneous treatment of phlegm and blood stasis is established. It is found that this therapy can simultaneously regulate blood lipid, reduce blood viscosity, and improve blood circulation, which can fundamentally cut off the biological material basis of the reciprocal transformation between phlegm and blood stasis, thus exerting a significant curative effect.

Growth hormone supplementation ameliorates blastocyst euploidy rates and improves pregnancy outcomes in women undergoing preimplantation genetic testing for aneuploidy cycles.

Background: Growth hormone (GH) supplementation has been shown to improve oocyte quality and live birth, but few studies have examined whether GH can reduce embryonic aneuploidy. Chromosomal abnormalities in preimplantation embryos have been regarded as the principal cause of implantation failure and miscarriage, and an increased percentage of aneuploid embryos has been observed in patient cohorts with unexplained recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and advanced maternal age. Methods: This prospective cohort study was conducted on women whose previous PGT-A cycle ended up with no transferrable blastocysts, or the aneuploidy rate was above 50% and no live birth was acquired. The participants were divided into GH co-treatment and comparison groups according to whether GH was administered in the subsequent PGT-A cycle. In addition, within the GH co-treatment group, the previous failed cycle constituted the self-control group. Results: 208 women were recruited in the study (GH co-treatment group: 96 women, comparison group: 112 women). Compared to the self-control and comparison groups, the rate of euploid blastocysts was significantly higher in the GH co-treatment group (GH vs self-control: 32.00% vs 9.14%, odds ratio [OR]: 4.765, 95% confidence interval [CI]: 2.420-9.385, P < 0.01; GH vs comparison: 32.00% vs. 21.05%, OR: 1.930, 95% CI: 1.106-3.366, P = 0.021), and their frozen embryo transfers resulted in more pregnancies and live births. In the subgroup analysis, for the <35 and 35-40 years groups, the euploidy rate in the GH co-treatment group was significantly higher than those in the self-control and comparison groups, but in the >40 years group, there was no difference in euploidy rate. Conclusion: Our study presents preliminary evidence that GH supplementation may ameliorate blastocyst aneuploidy and improve pregnancy outcomes in women who have previously experienced pregnancy failures along with high aneuploidy rates, particularly in those younger than 40 years. Therefore, the use of GH in such women should be considered. However, considering the limited sample size and mixed indications for PGT-A, further scientific research on the underlying mechanism as well as clinical trials with larger sample sizes are needed to confirm the effects and optimal protocols.

Synthesis and biological evaluation of ruthenium complexes containing phenylseleny against Gram-positive bacterial infection by damage membrane integrity and avoid drug-resistance.

Compounds modified with selenium atom as potential antibacterial agents have been exploited to combat the nondrug-resistant bacterial infection. In this study, we designed and synthesized four ruthenium complexes retouching of selenium-ether. Fortunately, those four ruthenium complexes shown excellent antibacterial bioactive (MIC: 1.56-6.25 µg/mL) against Staphylococcus aureus (S. aureus), and the most active complex Ru(II)-4 could kill S. aureus by targeting the membrane integrity and avoid the bacteria to evolve drug resistance. Moreover, Ru(II)-4 was found to significantly inhibit the formation of biofilms and biofilm eradicate capacity. In toxicity experiments, Ru(II)-4 exhibited poor hemolysis and low mammalian toxicity. To illustrate the antibacterial mechanism: we conducted scanning electron microscope (SEM), fluorescent staining, membrane rupture and DNA leakage assays. Those results demonstrated that Ru(II)-4 could destroy the integrity of bacterial cell membrane. Furthermore, both G. mellonella wax worms infection model and mouse skin infection model were established to evaluate the antibacterial activity of Ru(II)-4 in vivo, the results indicated that Ru(II)-4 was a potential candidate for combating S. aureus infections, and almost non-toxic to mouse tissue. Thus, all the results indicated that introducing selenium-atom into ruthenium compounds were a promising strategy for developing interesting antibacterial agents.

[Current status and our consideration on clinical transformation of acupuncture research].

It has become one of the major strategic directions to develop translational medicine and realize the stride leap from basic research to clinical application in the national biomedical field. In recent years, both basic and clinical researches of acupuncture and moxibustion have made landmark progress. However, the transformation of acupuncture and moxibustion techniques still faced with many difficulties, such as low conversion rate and high difficulty of transformation. In this article, we mainly made a preliminary discussion on the current situations of acupuncture and moxibustion transformation from the aspects of basic research content, evidence-based medicine and clinical trials, evaluation criteria for the conclusion of scientific research projects and transformation mode, put forward some existing problems in the transformation process, and proposed some corresponding countermeasures to the problems.

[Clinical research of acupuncture therapy combined with domperidone in treatment of diabetic gastroparesis of liver stagnation and spleen deficiency].

OBJECTIVE: To observe the clinical efficacy of shuanggu yitong acupuncture therapy (the therapy for both replenishment and unblocking) combined with domperidone on diabetic gastroparesis (DGP) of liver stagnation and spleen deficiency pattern and explore its effect mechanism. METHODS: DGP patients differentiated as liver stagnation and spleen deficiency pattern were divided into a control group (n=42) and an observation group (n=42) according to the random number table. The patients in the control group took domperidone tablets orally, 10 mg each time, 3 times a day for 28 days. In the observation group, on the base of the treatment as the control group, shuanggu yitong acupuncture therapy was applied to Baihui (GV20), Shenting (GV24), Zhongwan (CV12), bilateral Zusanli (ST36), Hegu (LI4)and Taichong (LR3), stimulated for 30 min in each treatment. Acupuncture was given once daily, 3 times a weeks for 28 days consecutively. Fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PBG) and glycosylated hemoglobin (HbA1c) were detected before and after treatment in the patients of two groups separately. The score of symptom severity index of gastroparesis (GCSI), traditional Chinese medicine (TCM) syndrome score and gastric emptying rate were assessed in the patients of two groups. Using ELISA, radioimmunoassay and colorimentry methods, the contents of motilin in plasma, gastrin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and interferon-gamma (INF-γ) in serum, as well as the activity of superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA) in the serum were determined in the two groups. The clinical curative effect was evaluated. RESULTS: After treatment, the levels of FBG, 2 h PBG and HbA1c, the scores of GCSI and TCM syndrome, the contents of motilin in plasma, gastrin, TNF-α and MDA, as well as the activity of ROS in serum were all reduced when compared with those before treatment in each group (P<0.05, P<0.01), while gastric emptying rate and SOD activity in the serum were higher than those before treatment (P<0.05, P<0.01). After treatment, the serological content of INF-γ was lower than that before treatment in the control group (P<0.05), and the contents of IL-6 and IL-1ß were reduced than those before treatment in the observation group (P<0.05). Compared with the control group, the levels of FBG, 2 h PBG and HbA1c, the scores of GCSI and TCM symptoms, the contents of motilin in plasma, gastrin, TNF-α, MDA, IL-6 and IL-1ß, and the activity of ROS in serum in the observation group were all lower significantly (P<0.05, P<0.01), while the SOD activity and gastric emptying rate in the observation group were higher than those in the control group (P<0.05, P<0.01). The total effective rate was 90.5% (38/42) in the observation group, better than the control group (73.8%, 31/42, P<0.05). CONCLUSION: Shuanggu yitong acupuncture therapy combined with domperidone remarkably relieves the clinical symptoms and improves the gastric emptying rate, effectively reduces motilin and gastrin and regulates oxidative stress and inflammatory responses in the patients with DGP of liver stagnation and spleen deficiency.

Structurally diverse sulphur-containing amides from Glycosmis craibii with their potential antiproliferative activities.

Fourteen new sulphur-containing amides, glycocramides A-N (1-14), as well as nine known analogues (15-23) were isolated and characterized from Glycosmis craibii Tanaka. The chemical structures of new sulphur-containing amides 1-14 were ambiguously elucidated by extensive spectroscopic methods, while the known compounds 15-23 were identified by the comparison of their experimental spectral data with those described data in the literatures. The antiproliferative effects of all isolated sulphur-containing amides were evaluated in vitro. As a result, part of sulphur-containing amides showed remarkable inhibitory effects against MGC-803 cell line with IC50 values ranging from 13.12 ± 0.10 to 20.03 ± 0.13 µM. These research results suggest that the sulphur-containing amides are potentially to be developed as a new natural anti-tumor drugs.