Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the"therapeutic module"of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Stroke imposes a tremendous burden on patients'families and society due to its high rates of mortality,disability,and recurrence.Advances in neuroimaging technologies have provided critical theoretical foundations for investigating the pathophysiological mechanisms of stroke,as well as enabling early clinical intervention and personalized rehabilitation.This article reviewed the application of five commonly used magnetic resonance imaging(MRI)techniques in acupuncture therapy for stroke,including functional MRI(fMRI)for cerebral blood oxygen metabolism,magnetic resonance spectroscopy(MRS),diffusion MRI(dMRI),perfusion MRI(pMRI),and structural MRI(sMRI).By examining functional,metabolic,structural,and hemodynamic aspects,these imaging modalities offer evidence to validate the multi-target effect and efficacy of acupuncture in stroke treatment.

Stroke imposes a tremendous burden on patients'families and society due to its high rates of mortality,disability,and recurrence.Advances in neuroimaging technologies have provided critical theoretical foundations for investigating the pathophysiological mechanisms of stroke,as well as enabling early clinical intervention and personalized rehabilitation.This article reviewed the application of five commonly used magnetic resonance imaging(MRI)techniques in acupuncture therapy for stroke,including functional MRI(fMRI)for cerebral blood oxygen metabolism,magnetic resonance spectroscopy(MRS),diffusion MRI(dMRI),perfusion MRI(pMRI),and structural MRI(sMRI).By examining functional,metabolic,structural,and hemodynamic aspects,these imaging modalities offer evidence to validate the multi-target effect and efficacy of acupuncture in stroke treatment.

ObjectiveBased on tumor necrosis factor alpha （TNF-α）/tumor necrosis factor receptor 1 （TNFR1）/receptor-interacting protein kinases （RIPKs） signaling pathway， this paper aims to study the effect of modified Erchentang on inflammation in rats with chronic obstructive pulmonary disease （COPD） and explore its mechanism of action. MethodA total of 60 SD rats were randomly divided into normal group， model group， high， medium， and low-dose groups （20， 10， 5 g·kg^-1·d^-1） of modified Erchentang， and Xiaokechuan group （3.5 mL·kg^-1·d^-1）， with 10 rats in each group. The COPD rat model was established by cigarette smoke combined with lipopolysaccharide （LPS）. The normal group and model group were given the same amount of normal saline for 21 days by gavage administration. The contents of TNF-α and TNFR1 in bronchoalveolar lavage fluid （BALF） of rats were detected by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expressions of RIPK1， RIPK3， and mixed lineage kinase domain-like （MLKL） in the lung tissue. The protein expressions of RIPK1， RIPK3， and MLKL in the lung tissue were detected by Western blot. The pathological changes in lung tissue were observed by hematoxylin-eosin （HE） staining. ResultCompared with the normal group， the contents of TNF-α and TNFR1 in BALF of the model group were significantly increased （P<0.01）， and the mRNA and protein expression levels of RIPK1， RIPK3， and MLKL in the lung tissue were significantly increased （P<0.01）. Compared with the model group， the contents of TNF-α and TNFR1 in BALF of high， medium， and low-dose groups of modified Erchentang and Xiaokechuan group were decreased （P<0.01）. The mRNA and protein expression levels of RIPK1， RIPK3， and MLKL in the lung tissue were decreased to different degrees （P<0.05， P<0.01）. ConclusionModified Erchentang can effectively improve the inflammatory response of lung tissue in COPD rats， and the mechanism may be by inhibiting the activation of the TNF-α/TNFR1/RIPKs signaling pathway.

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely 'overlooked' during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.

Objective To compare the clinical safety and efficacy of CT-guided hook-wire localization of≤10mm pulmonary ground-glass nodule(GGN)via different path ways before video-assisted thoracoscopic surgery(VATS).Methods The clinical data of a total of 128 patients with 10 mm pulmonary GGN,who received CT-guided hook wire localization before VATS at The Third Hospital of Mianyang of China between July 2018 and March 2023,were retrospectively analyzed.According to the puncturing localization path way mode,the patients were divided into vertical puncturing group(n=88)and non-vertical puncturing group(n=40).The number of puncturing times,the time spent for puncturing localization,the success rate of puncture,the operation time of VATS,and puncture-related complications of the two groups were recorded.Results No statistically significant differences in the gender,age,smoking history,GGN location,puncture position,nodule size,density characteristics of GGN,emphysema,and nodules-pleura distance existed between the two groups(all P＞0.05).Compared with non-vertical puncturing group,in vertical puncturing group the number of puncturing times was smaller,the time spent for localization was shorter,the incidence of pneumothorax was lower,and the operation time of VATS was shorter,the differences in all the above indexes between the two groups were statistically significant(all P＜0.05);and the subgroup analysis of patients whose GGN was overlapped with rib shadow obtained the same results.Binary logistic regression analysis revealed that non-vertical puncturing and the number of puncturing times were the independent risk factors for the occurrence of pneumothorax.Conclusion CT-guided hook-wire localization of≤10mm pulmonary GGN before VATS is clinically safe and effective.Under the condition when the lesion can be localized within the range of 2.0cm and the shadow overlapping of GGN with the rib and blood vessel can be effectively avoided,vertical puncturing path way mode should be preferred,which can effectively reduce the incidence of pneumothorax and shorten the operation time of VATS.

Objective:To systematically retrieve, evaluate and summarize the best evidence of exercise management for adolescents with type 2 diabetes mellitus (T2DM), so as provide reference for medical and nursing staff to guide patients and their families to exercise.Methods:Clinical decisions, recommended practices, evidence summaries, guidelines, expert consensuses, and systematic reviews on exercise management of adolescents with T2DM were electronically searched on BMJ Best Practice, UpToDate, Registered Nurses' Association of Ontario, National Guideline Clearinghouse, National Institute for Health and Clinical Excellence, Scottish Intercollegiate Guidelines Network, International Society for Pediatric and Adolescent Diabetes, Medlive, Joanna Briggs Institute Evidence-Based Health Care Center Database, Cochrane Library, PubMed, Web of Science, Embase, China National Knowledge Infrastructure, WanFang Data, Chinese Biology Medicine Disc, VIP and other databases. The search period was from database establishment to March 2023. After independent literature screening and quality evaluation by two researchers, evidence was extracted, summarized, and graded based on the theme.Results:A total of 10 articles were selected, including three guidelines, three systematic reviews, three expert consensuses, and one evidence summary. Finally, 22 pieces of best evidence of exercise management for adolescents with T2DM were summarized from seven aspects, including contraindications to exercise, exercise form, exercise intensity, exercise frequency, precautions, weight loss goals, family participation.Conclusions:This study summarizes the best evidence for exercise management in adolescents with T2DM. It is recommended that clinical medical and nursing staff should carry out personalized exercise management suitable for patients based on the wishes and preferences of patients and families, actual clinical situations, and support for exercise resources.

Objective Network Meta-analysis was used to compare and estimate the therapeutic effect and safety of oral Chinese patent drugs in treatment of diabetic peripheral neuropathy(DPN).Methods PubMed,Cochrane Library,EMbase,Web of Science,China National Knowledge Infrastructure(CNKI),Chinese Citation Database(CCD),China Science Periodical Database(CSPD)and SinoMed was retrieved to collect randomized controlled trials(RCTs),which were related to oral Chinese patent drugs in treatment of DPN.Cochrane Handbook 5.3 was used to assess the quality of the studies,and Stata 15 and ADDIS 1.16.5 were utilized to analyse data.Results 48 RCTs were included,including 4200 patients,involving 11 kinds of Chinese patent drugs.In terms of improving clinical total effective rate,the top three interventions were mecobalamin combined with Tangmaikang granules,Jinlida granules and Naoxintong capsules.The top three interventions for improving toronto clinical scoring system(TCSS)were mecobalamin combined with Mailuoning peroral liquids,Mudan granules and Xuefuzhuyu capsules.In the aspect of improving sensory conduction velocity(SCV)of median nerve,the top three interventions were mecobalamin combined with Tongxinluo capsules,Xuesaitong soft capsules and Fufangxueshuantong capsules.The top three interventions for improving SCV of peroneal nerve were mecobalamin combined with Xuefuzhuyu capsules,Jinlida granules and Mailuoning peroral liquids.In terms of improving motor conduction velocity(MCV)of median nerve,the top three interventions were mecobalamin combined with Tongxinluo capsules,Yindanxinnaotong soft capsules and Tangmaikang granules.The top three interventions for improving MCV of peroneal nerve were mecobalamin combined with Xuesaitong soft capsules,Yindanxinnaotong soft capsules and Tongxinluo capsules.In the terms of improving blood glucose,several studies reported that Tangmaikang granules and Tongmaijiangtang capsules combined with mecobalamin could improve the level of glycated hemoglobin(HbA1c),which was superior to mecobalamin alone.Compared with mecobalamin alone,mecobalamin combined with Chinese patent drugs did not increase the occurrence of adverse reactions.Conclusion Mecobalamin combined with Chinese patent drugs can improve the therapeutic effect,TCSS scores and nerve conduction velocity,and the safety is satisfactory,which can provide some reference for clinical medication.

Objective Network Meta-analysis was used to compare and estimate the therapeutic effect and safety of oral Chinese patent drugs in treatment of diabetic peripheral neuropathy(DPN).Methods PubMed,Cochrane Library,EMbase,Web of Science,China National Knowledge Infrastructure(CNKI),Chinese Citation Database(CCD),China Science Periodical Database(CSPD)and SinoMed was retrieved to collect randomized controlled trials(RCTs),which were related to oral Chinese patent drugs in treatment of DPN.Cochrane Handbook 5.3 was used to assess the quality of the studies,and Stata 15 and ADDIS 1.16.5 were utilized to analyse data.Results 48 RCTs were included,including 4200 patients,involving 11 kinds of Chinese patent drugs.In terms of improving clinical total effective rate,the top three interventions were mecobalamin combined with Tangmaikang granules,Jinlida granules and Naoxintong capsules.The top three interventions for improving toronto clinical scoring system(TCSS)were mecobalamin combined with Mailuoning peroral liquids,Mudan granules and Xuefuzhuyu capsules.In the aspect of improving sensory conduction velocity(SCV)of median nerve,the top three interventions were mecobalamin combined with Tongxinluo capsules,Xuesaitong soft capsules and Fufangxueshuantong capsules.The top three interventions for improving SCV of peroneal nerve were mecobalamin combined with Xuefuzhuyu capsules,Jinlida granules and Mailuoning peroral liquids.In terms of improving motor conduction velocity(MCV)of median nerve,the top three interventions were mecobalamin combined with Tongxinluo capsules,Yindanxinnaotong soft capsules and Tangmaikang granules.The top three interventions for improving MCV of peroneal nerve were mecobalamin combined with Xuesaitong soft capsules,Yindanxinnaotong soft capsules and Tongxinluo capsules.In the terms of improving blood glucose,several studies reported that Tangmaikang granules and Tongmaijiangtang capsules combined with mecobalamin could improve the level of glycated hemoglobin(HbA1c),which was superior to mecobalamin alone.Compared with mecobalamin alone,mecobalamin combined with Chinese patent drugs did not increase the occurrence of adverse reactions.Conclusion Mecobalamin combined with Chinese patent drugs can improve the therapeutic effect,TCSS scores and nerve conduction velocity,and the safety is satisfactory,which can provide some reference for clinical medication.