BACKGROUND: Growing evidence suggests that long non-coding RNAs (lncRNAs) exert pivotal roles in fostering chemoresistance across diverse tumors. Nevertheless, the precise involvement of lncRNAs in modulating chemoresistance within the context of gallbladder cancer (GBC) remains obscure. This study aimed to uncover how lncRNAs regulate chemoresistance in gallbladder cancer, offering potential targets to overcome drug resistance. METHODS: To elucidate the relationship between gemcitabine sensitivity and small nucleolar RNA host gene 1 ( SNHG1 ) expression, we utilized publicly available GBC databases, GBC tissues from Renji Hospital collected between January 2017 and December 2019, as well as GBC cell lines. The assessment of SNHG1, miR-23b-3p, and phosphatase and tensin homolog (PTEN) expression was performed using in situ  hybridization, quantitative real-time polymerase chain reaction, and western blotting. The cell counting kit-8 (CCK-8) assay was used to quantify the cell viability. Furthermore, a GBC xenograft model was employed to evaluate the impact of SNHG1 on the therapeutic efficacy of gemcitabine. Receiver operating characteristic (ROC) curve analyses were executed to assess the specificity and sensitivity of SNHG1. RESULTS: Our analyses revealed an inverse correlation between the lncRNA SNHG1 and gemcitabine resistance across genomics of drug sensitivity in cancer (GDSC) and Gene Expression Omnibus (GEO) datasets, GBC cell lines, and patients. Gain-of-function investigations underscored that SNHG1 heightened the gemcitabine sensitivity of GBC cells in both in vitro and in vivo  settings. Mechanistic explorations illuminated that SNHG1 could activate PTEN -a commonly suppressed tumor suppressor gene in cancers-thereby curbing the development of gemcitabine resistance in GBC cells. Notably, microRNA (miRNA) target prediction algorithms unveiled the presence of miR-23b-3p binding sites within SNHG1 and the 3'-untranslated region (UTR) of PTEN . Moreover, SNHG1 acted as a sponge for miR-23b-3p, competitively binding to the 3'-UTR of PTEN , thereby amplifying PTEN expression and heightening the susceptibility of GBC cells to gemcitabine. CONCLUSION The SNHG1/miR-23b-3p/PTEN axis emerges as a pivotal regulator of gemcitabine sensitivity in GBC cells, holding potential as a promising therapeutic target for managing GBC patients.
Humans ; Deoxycytidine/pharmacology* ; PTEN Phosphohydrolase/genetics* ; Gemcitabine ; RNA, Long Noncoding/metabolism* ; MicroRNAs/genetics* ; Gallbladder Neoplasms/genetics* ; Cell Line, Tumor ; Animals ; Mice ; Drug Resistance, Neoplasm/genetics* ; Mice, Nude ; Antimetabolites, Antineoplastic ; Gene Expression Regulation, Neoplastic

The iridoid glycosides from Veronica anagallis-aquatica L. alleviate heart failure by modulating the gut microbiota and influencing the production of two metabolites with potential antihypertrophic effects, HVA and 2OH-VA.Image 1.

OBJECTIVES: To evaluate the protective effect of Schistosoma japonicum cystatin (rSj-Cystatin) in a mouse mode of "two-hit" sepsis. METHODS: Sixty male C57BL/6 mice randomized equally into sham-operated group, protein group, "two-hit" modeling group, and protein intervention group. In the former two groups, the mice received an intraperitoneal injection of 100 μL PBS followed by exposure of the cecum and then by intraperitoneal injection of 100 μL PBS or 25 μg rSj-Cystatin 30 min later; In the latter two groups, 100 μL PBS containing LPS (5 mg/kg) was injected intraperitoneally 24 h before cecal ligation and puncture (CLP), and 100 μL PBS or 25 μg rSj-Cystatin were injected 30 min after CLP. At 12 h after rSj-Cystatin treatment, 6 mice from each group were sacrificed for detection of TNF-α, IL-6, IL-10, TGF-β, iNOS and Arg-1 in the serum, spleen, liver, lung and kidney tissues using ELISA, for examinations of liver, lung and kidney pathologies with HE staining, and for analysis of CD3⁺CD4⁺CD25⁺Foxp3⁺ T cell percentage in the spleen using flow cytometry. The remaining mice were observed for general condition and 72-h survival. RESULTS: The 72-h survival rates in the 4 groups were 100%, 100%, 0% and 20%, respectively, showing significant differences between the latter two groups. The mouse models of "two-hit" sepsis exhibited obvious tissue pathologies and significant elevations of TNF-α and IL-6 in both the serum and tissue homogenate, which were significantly ameliorated by rSj-Cystatin treatment. Treatment with rSj-Cystatin also increased IL-10 and TGF-β levels and spleen CD3⁺CD4⁺CD25⁺Foxp3⁺ T cell percentage. The septic mouse models also showed increased iNOS levels in all the detected tissues and a decreased Arg-1 level in the kidney, and these changes were obviously improved by rSj-Cystatin treatment. CONCLUSIONS rSj-Cystatin has a protective effect against "two-hit" sepsis in mice by regulating the inflammatory microenvironment.
Animals ; Mice ; Sepsis/drug therapy* ; Male ; Schistosoma japonicum/chemistry* ; Mice, Inbred C57BL ; Cystatins/therapeutic use* ; Interleukin-10/metabolism* ; Interleukin-6/blood* ; Tumor Necrosis Factor-alpha/blood* ; Disease Models, Animal ; Transforming Growth Factor beta/metabolism*

Recommendations for Chinese patent medicine （CPM） based on key information on rational drug use are one of the important conditions for enhancing guideline enforceability as well as facilitating guideline implementation. In this study， we discussed in detail of the key information on the rational use of CPM in five aspects， which are dosage， drug discontinuation， drug-drug and drug-food interactions， safety and economy. Following the process of multi-source search， synthesis and prioritization， it is suggested to collect key information on the rational use of CPM from a multi-source search of drug instructions， policy documents， literature， and clinical experts' experiences. Then the searched information should be summarized and prioritized with the principle that taking drug instructions as the basis and other-sources information for check and supplementation. Finally， methodological recommendations for the retrieval and synthesis of key information on rational drug use in guideline recommendations has been formed.

Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

As a supplement to randomized controlled trials， observational studies can provide evidence for the effectiveness of traditional Chinese medicine （TCM） treatment measures. They can also study influencing factors of diseases， etiology， and prognosis. However， there is a confounding effect due to the lack of randomization， which seriously affects the causal inference between the study factors and the outcome， resulting in confounding bias. Therefore， identifying and controlling confounding factors are key issues to be addressed in TCM observational studies. According to the causal network and the characteristics of TCM theory， confounding factors can be categorized into measured and unmeasured confounding factors. In addition， attention must be paid to identifying confounding factors and intermediate variables， as well as the interaction between confounding factors and study factors. For methods of controlling confounding factors， measured confounding factors can be controlled by stratification， multifactor analysis， propensity scores， and disease risk scores. Unmeasured and unknown confounding factors can be corrected using instrumental variable methods， difference-in-difference methods， and correction for underlying event rate ratios. Correcting and controlling confounding factors can ensure a balance between groups， and confounding bias can be reduced. In addition， methods such as sensitivity analysis and determination of interactions make the control of confounding factors more comprehensive. Due to the unique characteristics of TCM， observational studies of TCM face unique challenges in identifying and controlling confounding factors， including the ever-changing TCM treatment measures received by patients， the often-overlooked confounding effects in the four diagnostic information of TCM， and the lack of objective criteria for TCM evidence-based diagnosis. Some scholars have already conducted innovative explorations to address these issues， providing a methodological basis for conducting higher-quality TCM observational studies， so as to obtain more rigorous real-world evidence of TCM and gradually develop quality evaluation criteria for OS that are consistent with the characteristics of TCM.

ObjectiveTo investigate the possible mechanism of electroacupuncture at Fengchi （GB 20）， Yanglingquan （GB 34） and Waiguan （TE 5） for acute migraine attacks by peroxisome proliferator-activated receptor γ/ nuclear transcription factor-κB pathway in the trigeminal neurovascular system. MethodsForty SD rats were randomly divided into blank group， model group， electroacupuncture group， electroacupuncture plus inhibitor group， and agonist group， 8 rats in each group. Except for the blank group， rats were injected with inflammation decoction intracranial catheter to establish rat models of acute migraine. Thirty minutes after modelling， the electroacupuncture group was given 0.9% NaCl solution by intraperitoneal injection and then electroacupuncture at "Fengchi" （GB 20）， "Yanglingquan" （GB 34）， and "Waiguan" （TE 5） for 30 mins； the electroacupuncture plus inhibitor group was given PPARγ inhibitor T0070907 （1.5 mg/kg） and eclectroacupuncture as the above for 30 mins； the agonist group was given PPARγ inhibitor pioglitazone hydrochloride （10 mg/kg） for 30 mins. Rats in the blank group and the model group were injected intraperitoneally with 0.9% NaCl solution and then bound and restrained for 30 mins. Behavioural scores were evaluated before modelling， 30 mins after modelling （pre-intervention） and post-intervention； after the last behavioural test， PPARγ， NF-κB p65 mRNA content in rat dura mater was detected by real-time fluorescence quantitative PCR； protein expression of PPARγ， NF-κB p65， interleukin 6 （IL-6）， tumour necrosis factor α （TNF-α） in spinal trigeminal nucleus of rats was detected by protein blotting； immunofluorescence double-labelling method was used to detect the fluorescence intensity of PPARγ， NF-κB p65 in spinal trigeminal nucleus of rats. ResultsCompared with the blank group at the same time， the behavioural scores of rats in the remaining groups increased after modelling and after intervention （P＜0.01）. Compared with the model group at the same time， the beha-vioural scores of rats in the electroacupuncture group， electroacupuncture plus inhibitor group， and agonist group decreased after the intervention （P＜0.01）. Compared with the electroacupuncture group at the same time， beha-vioural scores reduced in the agonist group and elevated in the electroacupuncture plus inhibitor group after intervention （P＜0.01）. Compared with the blank group， expression of PPARγ and NF-κB p65 mRNA elevated in the dura mater of rats in the model group， and expression of PPARγ， NF-κB p65， IL-6， and TNF-α protein enhanced in spinal trigeminal nucleus， and the fluorescence intensity of PPARγ and NF-κB p65 enhanced （P＜0.01）. Compared with the model group， PPARγ mRNA expression in dura mater elevated and NF-κB p65 mRNA expression reduced in each intervention group， PPARγ protein expression in spinal trigeminal nucleus enhanced， and NF-κB p65， IL-6， and TNF-α protein expression weakened； in the electroacupuncture group and the agonist group， PPARγ fluorescence intensity enhanced， and the fluorescence intensity of NF-κB p65 weakened in each intervention group （P＜0.05 or P＜0.01）. Compared with the electroacupuncture group， in the electroacupuncture plus inhibitor group， PPARγ mRNA， protein expression and fluorescence intensity reduced， NF-κB p65 mRNA， protein expression and fluorescence intensity elevated， and IL-6 and TNF-α protein expression enhanced； in the agonist group， PPARγ mRNA and protein expression elevated， NF-κB p65 mRNA and protein expression reduced， and IL-6 and TNF-α protein expression decreased （P＜0.05 or P＜0.01）. ConclusionElectroacupuncture at "Fengchi" （GB 20）， "Yanglingquan" （GB 34） and "Waiguan" （TE 5） can can reduce the symptoms of acute migraine attacks in rats， and its mechanism may be related to the up-regulation of PPARγ expression and the reduction of NF-κB expression， thus inhibiting the neurogenic inflammatory response.

Epicardial adipose tissue (EAT) is a fat reservoir close to the myocardium and visceral pericardium. It has special anatomical and physiological characteristics. The volume and deposition site of EAT are closely related to the occurrence and development of atrial fibrillation (AF). This article discusses the connotation of the traditional Chinese medicine theory," yang transforming qi and yin shaping up the body",and holds that the essence of abnormal accumulation of EAT is "yang transforming qi deficiency and yin constituting form too much". Yin pathogen gradually accumulates,local yin and yang imbalance occurs,and abnormal secretion occurs. With the extension of time,the intrinsic yang heat is accompanied and becomes increasingly exuberant. Finally,yin is difficult to control yang,resulting in EAT infiltrating normal tissues,inducing and promoting the occurrence and progression of AF. Under the guidance of this theory,when distinguishing the amount of yin and yang between the body and EAT,considering the ability of "yang transforming qi" and "yin constituting form" in the whole and part,the method of supporting yang and eliminating yin should be reasonably selected. At the beginning of the disease,it is mainly to restore "yang transforming qi". By avoiding the accumulation of evil from the yin,it dissipates the body of the yin that has become. When the disease progresses,it is necessary to " eliminate pathogenic factor",supplemented by different treatment methods such as eliminating dampness,activating qi,and promoting blood circulation. Furthermore,the whole course of the disease should take care of the patient's deficiency,pay attention to strengthening yang and tonifying the healthy qi,and eliminate yin and evil promptly to improve clinical efficacy.

Objective:To analyze the distribution of clopidogrel metabolism-related gene variability in Kawasaki disease (KD) children with coronary artery lesions (CAL) across different age groups and the impact of genetic variability on the efficacy of clopidogrel antiplatelet therapy.Methods:A retrospective cohort study was conducted. Clinical data were collected from 46 KD children with CAL who were hospitalized in the Cardiovascular Center of Children′s Hospital of Fudan University between January 2021 and August 2022 and were treated with clopidogrel, including gender, age, body mass index, course of KD, CAL severity grade, and baseline platelet count. According to their age, the children were divided into ≥2-year-old group and <2-year-old group. Their platelet responsiveness was assessed by adenosine diphosphate-induced platelet inhibition rate (ADPi) calculated via thromboelastography, and children were categorized into high on-treatment platelet reactivity (HTPR) and normal on-treatment platelet reactivity (NTPR) groups. Genotypes of CYP2C19, PON1 and ABCB1 were detected. The t test, one-way analysis of variance and Chi-square test were used for intergroup comparison. Results:Among the 46 KD children with CAL, 34 were male and 12 were female; 37 were ≥2-year-old and 9 were <2-year-old; 25 cases were in the HTPR group and 21 cases were in the NTPR group, with 19 HTPR and 18 NTPR in the ≥2-year-old group, and 6 HTPR and 3 NTPR in the <2-year-old group. Genetic analysis showed that 92 alleles among the 46 children, with frequencies of CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*17, PON1 192Q, PON1 192R, ABCB1 3435C, ABCB1 3435T at 59% (54/92), 32% (29/92), 9% (8/92), 1% (1/92), 36% (36/92), 64% (59/92), 63% (58/92) and 37% (34/92), respectively. Analysis of the impact of genotype on ADPi revealed that in children aged ≥2 years, those with CYP2C19*1/*3 genotype had significantly lower ADPi than those with CYP2C19*1/*1 genotype ((34±15)% vs. (61±29)%, t=2.18, P=0.036). There were also no significant difference in ADPi among children with PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes ((40±22)% vs. (52±33)% vs. (65±27)%, F=2.17, P=0.130), or among those with ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((55±34)% vs. (60±27)% vs. (49±24)%, F=0.33, P=0.719). In <2-year-old group, there were no significant differences in ADPi across CYP2C19*1/*1, CYP2C19*1/*2 and CYP2C19*2*2 genotypes ((40±20)% vs. (53±37)% vs. (34±16)%, F=0.37, P>0.05). There were no significant differences in ADPi across CYP2C19*1/*1 and CYP2C19*1/*3 genotypes ((44±27)% vs. (42±20)%, t=0.08, P>0.05). There were no significant differences in ADPi across PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes (45% vs. (55±27)% vs. (24±5)%, F=1.83, P>0.05). There were no significant differences in ADPi across ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((36±16)% vs. (50±35)% vs. 45%, F=0.29, P>0.05). The risk analysis of HTPR in different genotypes revealed that in children aged ≥2 years, carrying at least 1 or 2 loss-of-function alleles of CYP2C19 was a risk factor for HTPR ( OR=4.69, 10.00, 95% CI 1.11-19.83, 0.84-119.32, P=0.033, 0.046, respectively), and PON1 192R homozygosity and carrying at least one PON1 192R allele were protective factors against HTPR ( OR=0.08, 0.13, 95% CI 0.01-0.86, 0.01-1.19, P=0.019, 0.043, respectively). Conclusion:KD children aged ≥2 years carrying CYP2C19 loss-of-function alleles and PON1 192Q are more likely to develop HTPR.

Diabetic retinopathy(DR)is one of the most common microvascular complications of diabetes and has become one of the leading causes of blindness and visual impairment in diabetes patients.The pathogenesis of DR is multifaceted,involving inflammation,oxidative stress,neurovascular abnormalities,and other factors that present potential targets for disease management interventions.Currently,anti-vascular endothelial growth factor(VEGF)drugs serve as the primary treatment for advanced stages of DR when irreversible neurovascular damage and visual impairment have occurred.Additionally,some patients show poor or no response to anti-VEGF treatment.There is a lack of early intervention options for the initial phases of the disease.Therefore,there is an urgent need to develop novel local or systemic therapies based on the underlying mechanisms of DR to enable early prevention and treatment with the aim of preserving patients' vision.Medications targeting various pathways including anti-inflammatory agents(corticosteroids and nonsteroidal anti-inflammatory drugs),neurotrophic and neuroprotective drugs,drugs modulating biochemical pathways,antioxidant phytochemicals,and gene therapy can complement each other in terms of therapeutic effects to benefit a larger number of individuals affected by DR.This article reviews previous research reports on the pathogenesis,drug treatment methods,and potential therapeutic targets associated with DR in order to provide guidance for clinical practice.