Isosteviol is a tetracyclic diterpenoid compound obtained by hydrolysis of natural stevia glycoside under acidic conditions. It has many pharmacological activities, such as anti-tumor, hypoglycemic, anti-inflammatory and antibacterial. Due to its low water solubility, low activity and low bioavailability, isosteviol has poor performance. In order to overcome these shortcomings, scholars have obtained a large number of isosteviol derivatives with novel structures and excellent activity. In this paper, we review the recent progress in the research on the structure modification, biological activity, structure-activity relationship and microbial transformation of isosteviol, in order to provide a reference for the development of new drugs of isosteviol and its derivatives.

ObjectiveTo investigate the effects of Pinelliae Rhizoma Praeparatum （PRP） on lung tissue， gut microbiota， and short-chain fatty acid （SCFA） metabolism in a model of mice with cold fluid retention in the lung and explore its mechanism of action in resolving dampness and phlegm based on the interconnection between the lung and large intestine. MethodsFifty female ICR mice were randomly divided into a normal group， model group， positive control group （Xiaoqinglong granules， 6.5 g·kg^-1）， and high-dose and low-dose PRP decoction groups （3.0， 1.5 g·kg^-1）， with 10 mice in each group. A model of mice with cold fluid retention in the lung was established using ovalbumin （OVA） sensitization combined with cold-water immersion. Drug interventions were conducted from day 18 to day 33 for 15 consecutive days. The airway resistance value of the mice was measured using a non-invasive pulmonary function analyzer. Phlegm-resolving effects were evaluated via a microplate reader. Eosinophil and neutrophil counts in bronchoalveolar lavage fluid （BALF） were analyzed using an automated hematology analyzer. Serum levels of total immunoglobulin E （IgE）， interferon-γ （IFN-γ）， interleukin-4 （IL-4）， and BALF levels of interleukin-6 （IL-6） and interleukin-8 （IL-8） were quantified by enzyme-linked immunosorbent assay （ELISA）. Lung histopathology was assessed using hematoxylin-eosin （HE） staining. Immunohistochemistry （IHC） was employed to detect mucin 5AC （MUC5AC） and aquaporin 5 （AQP5） protein expression in lung tissue. Gut microbiota composition was analyzed via agarose gel electrophoresis， and fecal SCFA levels were measured by gas chromatography-mass spectrometry （GC-MS）. ResultsCompared with the normal group， the model group exhibited significantly increased airway resistance value （RI） （P<0.05）， elevated eosinophil and neutrophil counts and IL-6 and IL-8 levels in BALF （P<0.05）， increased serum IgE and IL-4 levels （P<0.05）， with reduced IFN-γ levels （P<0.05）. It also showed thickened bronchial walls， widened alveolar septa， narrowed lumens， and mucus plugs in lung tissue， upregulated MUC5AC protein expression and downregulated AQP5 protein expression （P<0.05）， decreased relative abundance of beneficial gut microbiota （Firmicutes， Clostridia， Clostridiales， Lactobacillaceae， and Lactobacillus）， and increased abundance of harmful microbiota （Bacteroidetes， Bacteroidia， Bacteroidales， Muribaculaceae， and Muribaculum）. In addition， the model group presented reduced fecal SCFA levels （acetate， propionate， and butyrate） （P<0.05）. After the intervention of PRP decoction， compared to the model group， all drug administration groups showed decreased RI （P<0.05）， increased phenol red excretion， declined eosinophil and neutrophil counts and IL-6， IL-8， IgE， and IL-4 levels （P<0.05）， and improved IFN-γ levels （P<0.05） and lung pathology improved. The MUC5AC protein expression decreased （P<0.05）， and the AQP5 protein expression increased （P<0.05）. The disorder of gut microbiota was improved， and the diversity of gut microbiota was restored， with a significantly increased relative abundance ratio of beneficial microbiota （P<0.05） and a significantly reduced relative abundance ratio of harmful microbiota （P<0.05）. The SCFA levels （acetate， propionate， and butyrate） increased （P<0.05）. The efficacy indicators of serum inflammatory factors （IgE， IL-4， and IFN-γ）， phlegm-resolving effect， airway resistance， total pathological score， and the protein expression of MUC5AC and AQP5 were correlated with gut microbiota and SCFAs. ConclusionPRP decoction alleviates cold-phlegm syndrome by modulating the gut-lung axis， promoting beneficial gut microbiota， enhancing SCFA production， restoring the balance of gut microbiota， and suppressing respiratory inflammation. This study provides novel insights into the TCM theory of interconnection between the lung and large intestine.

ObjectiveTo investigate the effects of Pinelliae Rhizoma Praeparatum （PRP） on lung tissue， gut microbiota， and short-chain fatty acid （SCFA） metabolism in a model of mice with cold fluid retention in the lung and explore its mechanism of action in resolving dampness and phlegm based on the interconnection between the lung and large intestine. MethodsFifty female ICR mice were randomly divided into a normal group， model group， positive control group （Xiaoqinglong granules， 6.5 g·kg^-1）， and high-dose and low-dose PRP decoction groups （3.0， 1.5 g·kg^-1）， with 10 mice in each group. A model of mice with cold fluid retention in the lung was established using ovalbumin （OVA） sensitization combined with cold-water immersion. Drug interventions were conducted from day 18 to day 33 for 15 consecutive days. The airway resistance value of the mice was measured using a non-invasive pulmonary function analyzer. Phlegm-resolving effects were evaluated via a microplate reader. Eosinophil and neutrophil counts in bronchoalveolar lavage fluid （BALF） were analyzed using an automated hematology analyzer. Serum levels of total immunoglobulin E （IgE）， interferon-γ （IFN-γ）， interleukin-4 （IL-4）， and BALF levels of interleukin-6 （IL-6） and interleukin-8 （IL-8） were quantified by enzyme-linked immunosorbent assay （ELISA）. Lung histopathology was assessed using hematoxylin-eosin （HE） staining. Immunohistochemistry （IHC） was employed to detect mucin 5AC （MUC5AC） and aquaporin 5 （AQP5） protein expression in lung tissue. Gut microbiota composition was analyzed via agarose gel electrophoresis， and fecal SCFA levels were measured by gas chromatography-mass spectrometry （GC-MS）. ResultsCompared with the normal group， the model group exhibited significantly increased airway resistance value （RI） （P<0.05）， elevated eosinophil and neutrophil counts and IL-6 and IL-8 levels in BALF （P<0.05）， increased serum IgE and IL-4 levels （P<0.05）， with reduced IFN-γ levels （P<0.05）. It also showed thickened bronchial walls， widened alveolar septa， narrowed lumens， and mucus plugs in lung tissue， upregulated MUC5AC protein expression and downregulated AQP5 protein expression （P<0.05）， decreased relative abundance of beneficial gut microbiota （Firmicutes， Clostridia， Clostridiales， Lactobacillaceae， and Lactobacillus）， and increased abundance of harmful microbiota （Bacteroidetes， Bacteroidia， Bacteroidales， Muribaculaceae， and Muribaculum）. In addition， the model group presented reduced fecal SCFA levels （acetate， propionate， and butyrate） （P<0.05）. After the intervention of PRP decoction， compared to the model group， all drug administration groups showed decreased RI （P<0.05）， increased phenol red excretion， declined eosinophil and neutrophil counts and IL-6， IL-8， IgE， and IL-4 levels （P<0.05）， and improved IFN-γ levels （P<0.05） and lung pathology improved. The MUC5AC protein expression decreased （P<0.05）， and the AQP5 protein expression increased （P<0.05）. The disorder of gut microbiota was improved， and the diversity of gut microbiota was restored， with a significantly increased relative abundance ratio of beneficial microbiota （P<0.05） and a significantly reduced relative abundance ratio of harmful microbiota （P<0.05）. The SCFA levels （acetate， propionate， and butyrate） increased （P<0.05）. The efficacy indicators of serum inflammatory factors （IgE， IL-4， and IFN-γ）， phlegm-resolving effect， airway resistance， total pathological score， and the protein expression of MUC5AC and AQP5 were correlated with gut microbiota and SCFAs. ConclusionPRP decoction alleviates cold-phlegm syndrome by modulating the gut-lung axis， promoting beneficial gut microbiota， enhancing SCFA production， restoring the balance of gut microbiota， and suppressing respiratory inflammation. This study provides novel insights into the TCM theory of interconnection between the lung and large intestine.

Objective To determine the relationship between methylenetetrahydrofolate reductase(MTHFR)C677T,A1298C and multidrug resistance 1(ABCB1)C3435T gene polymorphisms and the adverse reactions of high-dose methotrexate(HD-MTX)in children with acute lymphoblastic leukemia(ALL).Methods Blood samples of ALL children treated with HD-MTX chemotherapy were collected,and the polymorphic polymorphism of MTHFR C677T,A1298C and ABCB1 C3435T genes were detected by sequencing method.The adverse drug reactions after MTX chemotherapy were evaluated according to the common adverse drug reaction grading criteria.The relationship between MTHFR C677T,A1298C and ABCB1 C3435T gene polymorphisms and HD-MTX adverse drug reactions was analyzed.Results The risk of MTHFR A1298C AC+CC type hepatic injury(grade 2)was higher than AA type[odds ratio(OR)2.350,95％confidence interval(CI)=1.038-5.320,P＜0.05],no correlations were found between MTHFR A1298C and myelosuppression,mucositis,gastrointestinal reaction and acute renal impair(all P＞0.05).ABCB1 C3435T CT type hepatic injury(grade 2)was higher than TT type(OR 5.161,95％CI 1.371-19.424,P＜0.05),ABCB1 C3435T CC+CT type hepatic injury(grade 2)was higher than TT type(OR 4.231,95％CI 1.165-15.362,P＜0.05);no correlations were found between ABCB1 C3435T and myelosuppression,mucositis,gastrointestinal reaction and acute renal impair(all P＞0.05).No correlations wre found between MTHFR C677T and HD-MTX adverse drug reactions(all P＞0.05).Conclusion When treating ALL with HD-MTX,adverse drug reactions can be predicted by detecting MTHFR A1298C and ABCB1 C3435T genotypes,so as to implement more scientific individualized medication.

Most patients with differentiated thyroid cancer have a good prognosis after radioiodine-131 therapy,but a small number of patients are insensitive to radioiodine-131 therapy and even continue to develop disease.At present,some targeted drugs can improve progression-free survival in patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC),such as sorafenib and levatinib,have been approved for the treatment of RAIR-DTC.However,due to the presence of primary and acquired drug resistance,drug efficacy in these patients is unsatisfactory.This review introduces the acquired drug resistance mechanism of sorafenib in the regulation of mitogen-activated protein kinase(MAPK)and phosphatidylinositol-3-kinase(PI3K)pathways and proposes related treatment strategies,in order to provide a reference for similar drug resistance mechanism of sorafenib and effective treatment of RAIR-DTC.

OBJECTIVE To introduce a case of interstitial pneumonia induced by vedolizumab （VDZ）， summarize and analyze the characteristics of the occurrence of VDZ-associated lung toxicity， and provide a reference for the clinically safe use of drugs. METHODS From the perspective of clinical pharmacists， the diagnosis and treatment of a case of VDZ-induced interstitial pneumonia were retrospectively analyzed， and the association of adverse drug reactions （ADR） was analyzed. Retrieving from Chinese and English databases such as CNKI， VIP， PubMed and Web of Science， case reports of VDZ-associated lung toxicity were summarized and analyzed. RESULTS The patient developed interstitial pneumonia during the use of VDZ and empirical anti- infective therapy with antibiotics was ineffective. After withdrawal of VDZ and treatment with methylprednisolone， symptoms and imaging examinations improved， but interstitial pneumonia still existed. According to Naranjo’s ADR evaluation scale and based on China Adverse Drug Reaction Reporting and Monitoring Manual， the association between VDZ and interstitial pneumonia was “very likely”. Results of the literature analysis showed that among 29 involved patients （including the patient reported in this article）， there were 19 males and 10 females， with an average age of （49.24±17.06） years. Lung toxicity mainly included VDZ- associated pneumonia， eosinophilic pneumonia， pulmonary granulomas or necrobiotic nodules， interstitial lung injury， etc.， which mostly occurred ≤24 weeks after medication （58.62%）. The main clinical manifestations included cough， dyspnea and fever. The vast majority of patients improved or recovered after drug withdrawal and/or glucocorticoid treatment， but one patient died of respiratory failure. CONCLUSIONS Lung toxicity is a rare ADR of VDZ with insidious onset and nonspecific symptoms. Once patients experience symptoms such as cough and dyspnea， early diagnosis，timely drug withdrawal，and symptomatic treatment measures such as glucocorticoid should be taken to ensure medication safety.

ObjectiveTo evaluate the effect and safety of Jiuxin Pill （救心丸） on exercise tolerance and quality of life in patients with stable angina pectoris （SAP）. MethodsA randomised， double-blind， placebo-controlled， multicentre study design was used to enroll 170 patients of SAP from nine centres， which were divided into 85 patients each in the trial group and control group with 1∶1 ratio. Both groups maintained the original western medicine treatment plan， and added Jiuxin Pill or placebo respectively， 2 pills （0.05 g） each time twicely for 28 days. The main outcomes were total exercise time （TED） in the exercise treadmill test and Seattle Angina Questionnaire （SAQ） scores including physical limitation （PL）， angina stability （AS）， angina frequency （AF）， treatment satisfaction （TS）， and disease perception （DP）. The secondary outcomes were exercise treadmill test indicators including heart rate recovery in 1 min （HRR1）， metabolic equivalents （METs）， maximum magnitude of ST-segment depression， and the Borg rating of perceived exertion scale， the average number of angina attacks per week， withdrawal and reduction rate of nitroglycerin， traditional Chinese medicine syndrome scores， incidence of major adverse cardiovascular events. Safety indicators were evaluated and the occurrence of adverse events during the trial was recorded. Data was collected before treatment， day 28±2 in treatment period， and follow-up at day 56 which is 28±2 days after treatment period finished. ResultsEighty-four and eighty-five patients respectively from trial group and control group were included to the full analysis set （FAS） and safety analysis set （SS）. Compared with the group before treatment and with the control group after treatment， the trial group had higher TED， HRR1， and METs， and lower maximum magnitude of ST-segment depression and Borg rating of perceived exertion scores after treatment （P＜0.01）. Compared with the group before treatment and with the control group after treatment and at follow-up， the total SAQ score and scores of AS， AF， TS and DP of the trial group after treatment and at follow-up elevated， while the average number of angina attacks per week and traditional Chinese medicine syndrome scores reduced （P＜0.01）. There was no statistically significant difference in the withdrawal and reduction rate of nitroglycerin between groups （P＞0.05）. Major adverse cardiovascular events occurred in 1 case （1/84， 1.19%） in the trial group and 1 case （1/85， 1.18%） in the control group， and the difference between groups was not statistically significant （P＞0.05）. A total of 3 cases of adverse events occurred in the trial group （3/84， 3.57%）， and a total of 6 cases of adverse events occurred in the control group （6/85， 7.06%）， and there was no statistically significant difference in the incidence of adverse events between groups （P＞0.05）. ConclusionIn the treatment of SAP， Jiuxin Pill combined with conventional western medicine can further enhance exercise tolerance， improve quality of life， and demonstrate great safety.

Objective To investigate the effect and mechanism of transplantation of neuregulin1(NRG1)gene-modified bone marrow mesenchymal stem cells(BMSCs)on the repair of hemi-transected spinal cord injury(SCI)in rats.Methods Isolated and cultured rat BMSCs,followed by transfection with the NRG1 gene.The levels of NRG1 in BMSCs lysate and culture supernatant was deected by ELISA method,and the proliferation activity of the BMSCs was detected by cell counting method.Forty-three healthy 8-week-old SD rats were randomly divided into control group(n=10),SCI model group(n=10),BMSCs group(n=10),and NRG1-BMSCs group(n=13).After establishing the spinal cord hemisection model,animals received in-situ transplantation of BMSCs or NRG1-BMSCs.On the 1,7,14,21,and 28 days after transplantation,the hind limb motor function was evaluated using BBB score and inclined plate test;on the 7th day after transplantation,the migration and distribution of transplanted cells was monitored using a fluorescence microscope;on the 28th day after transplantation,the pathological changes of rat spinal cord tissues was examined using HE staining and Nissl staining;cell apoptosis using TUNEL staining,and levels of endoplasmic reticulum stress-related proteins[X-box binding protein 1(XBP1),C/EBP homologous protein(CHOP),activating transcription factor 4(ATF4),ATF6,glucose-regulated protein 78(GRP78)]and apoptosis-related proteins[B-cell lymphoma-2(Bcl-2)and Bcl-2-associated protein X(Bax)]in rat spinal cord tissues using Western blotting.Results BMSCs were successfully isolated,cultured,and transfected with the NRG1 gene.ELISA method results showed that the NRG1 contents in the NRG1-BMSCs lysate and culture supernatant were significantly higher than that of BMSCs in a time-dependent manner(P<0.05).The proliferation activity of NRG1-BMSCs was significantly higher than that of BMSCs(P<0.05).On the 21 and 28 days after transplantation,the BBB score and the slope angle of the inclined plate in NRG1-BMSCs group were higher than those in SCI model group or BMSCs group(P<0.05).However,it did not reverse to the level in control group(P<0.05).On the 28th day after transplantation,compared with the SCI model group and BMSCs group,neuronal pyknosis reduced,the Nissl body density increased,the expression levels of XBP1,CHOP,ATF4,ATF6,GRP78,and Bax,and the rate of TUNEL-positive cells significantly reduced in NRG1-BMSCs group(P<0.05),and the expression level of Bcl-2 significantly increased(P<0.05).Conclusion Transplantation of NRG1 gene-modified BMSCs can alleviate SCI and improve the recovery of motor function in rats.The mechanism may be related to promoting the proliferation activity of BMSCs,inhibiting cell apoptosis,and mitigating endoplasmic reticulum stress.

Cryoablation therapy with explicit anti-tumor mechanisms and histopathological manifestations has a long history.A large number of clinical practice has shown that cryoablation therapy is safe and effective,making it an ideal tumor treatment method in theory.Previously,its efficacy and clinical application were constrained by the limitations of refrigerants and refrigeration equipment.With the development of the new generation of cryoablation equipment represented by argon helium knives,significant progress has been made in refrigeration efficien-cy,ablation range,and precise temperature measurement,greatly promoting the progression of tumor cryoablation technology.This consensus systematically summarizes the mechanism of cryoablation technology,indications for oral mucosal melanoma(OMM)cryotherapy,clinical treatment process,adverse reactions and management,cryotherapy combination therapy,etc.,aiming to provide reference for carrying out the standardized cryoablation therapy of OMM.

AIM: To explore the neuro-ophthalmological characteristics of acute macular neuroretinopathy(AMN)after SARS-CoV-2 infection.METHODS: A total of 8 patients(14 eyes), including 6 females and 2 males, who were diagnosed with AMN in the neuro-ophthalmology department of Xi'an No.1 Hospital(The First Affiliated Hospital of Northwest University)from December 27, 2022 to February 1, 2023 were included in the study. All patients had a history of SARS-CoV-2 infection before the disease, and the results of best corrected visual acuity(BCVA), non-contact indirect intraocular pressure measurement, fundus color photography, near infrared(IR), spectral-domain optical coherence tomography(SD-OCT), OCT angiography(OCTA), fundus fluorescein angiography(FFA), indocyanine green angiography(ICGA), visual field, visual evoked potential(VEP), and electroretinogram(ERG)were collected. Furthermore, the neuro-opthalmology characteristics of the included patients were analyzed and summarized.RESULTS: The included 8 patients aged from 20 to 43, with an average age of(30±6.63)years old. The patients had a history of SARS-CoV-2 infection 3 to 11(mean 5±3.51)d before the disease, and 6 out of 8 patients developed visual symptoms within 5 d of infection with SARS-CoV-2, with manifestated with decreased vision or visual scotoma. The visual acuity varied from 0.08 to 1.0, with visual field defect characterized by central, paracentral or peripheral scotoma. VEP showed prolongation latency of P100 or P2, and ERG revealed impaired function of retinal photoreceptor cell. In the early stage of the disease, the size and shape of early visual acuity, visual field, and extraretinal lesions in patients with AMN associated with SARS-CoV-2 infection may not match, and the lower the visual acuity, the later the VEP peaks.CONCLUSION: The neuro-ophthalmic features of SARS-CoV-2 infection-associated AMN require the attention of clinicians. In addition to multi-mode fundus imaging, clinicians should use a variety of methods to comprehensively evaluate visual function and prognosis of patients.