DNA-based biosensors have played a huge role in many areas,especially in current global coronavirus outbreak.However,there is a great difficulty in the characterization of piezoelectric and flexoelectric coefficients ...DNA-based biosensors have played a huge role in many areas,especially in current global coronavirus outbreak.However,there is a great difficulty in the characterization of piezoelectric and flexoelectric coefficients of the nanoscale DNA film,because the existing experimental methods for hard materials are almost invalid.In addition,the relevant theoretical models for DNA films only consider a single effect without clarifying the difference between the two electromechanical effects on device detection signals.This work aims to present multiscale models for DNA-microcantilever experiments to clarify the competitive mechanism in piezoelectric and flexoelectric effects of DNA films on detection signals.First,a Poisson-Boltzmann(PB)equation is used to predict the potential distribution due to the competition between fixed phosphate groups and mobile salt ions in DNA films.Second,a macroscopic piezoelectric/flexoelectric constitutive equation of the DNA film and a mesoscopic free energy model of the DNA solution are combined to analytically predict the electromechanical coefficients of the DNA film and the relevant microcantilever signals by the deformation equivalent method and Zhang’s two-variable method.Finally,the effects of detection conditions on microscopic interactions,electromechanical coupling coefficients,and deflection signals are studied.Numerical results not only agree well with the experimental observations,but also reveal that the piezoelectric and flexoelectric effects of the DNA film should be equivalently modeled when interpreting microcantilever detection signals.These insights might provide opportunities for the microcantilever biosensor with high sensitivity.展开更多
BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis...BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.展开更多
Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which ...Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.展开更多
To explore the anticancer mechanism and DNA damages of hydroxyapatite ultrofine powder (HAUFP) on lymphocytes of rats, DNA damages in W 256 sarcoma cells and lymphocytes of rats were measured by single cell gel elec...To explore the anticancer mechanism and DNA damages of hydroxyapatite ultrofine powder (HAUFP) on lymphocytes of rats, DNA damages in W 256 sarcoma cells and lymphocytes of rats were measured by single cell gel electrophoresis (SCGE). The results showed that HAUFP damaged DNA of W 256 sarcoma cells obviously but only cause slight damage of DNA of lymphocytes in rats. It is suggested that HAUFP selectively damaged DNA of tumor cells with only mild damage of lymphocyte DNA. HAUFP has powerful anticancer effect and little genetic toxicity.展开更多
Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop respondi...Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.展开更多
Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as wel...Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.展开更多
Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attrac...Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.展开更多
Importance/Objective: Adverse Drug Reactions (ADRs) are unavoidable, but recognizing and addressing ADRs early can improve wellness and prevent permanent injury. We suggest that available medical information and digit...Importance/Objective: Adverse Drug Reactions (ADRs) are unavoidable, but recognizing and addressing ADRs early can improve wellness and prevent permanent injury. We suggest that available medical information and digital/electronic methods could be used to manage this major healthcare problem for individual patients in real time. Methods: We searched the available digital applications and three literature databases using the medical subject heading terms, adverse drug reaction reporting systems or management, filtered by clinical trial or systemic reviews, to detect publications with data about ADR identification and management approaches. We reviewed the reports that had abstract or summary data or proposed or implemented methods or systems with potential to identify or manage ADRs in clinical settings. Results: The vast majority of the 481 reports used retrospectively collected data for groups of patients or were limited to surveying one population group or class of medication. The reports showed potential and definite associations of ADRs for specific drugs and problems, mostly, but not exclusively, for patients in hospitals and nursing homes. No reports described complete methods to collect comprehensive data on ADRs for individual patients in a healthcare system. The digital applications have ADR information, but all are too cumbersome or incomplete for use in active clinical settings. Several studies suggested that providing information about potential ADRs to clinicians can reduce these problems. Conclusion and Relevance: Although investigators and government agencies agree with the need, there is no comprehensive ADR management program in current use. Informing the patient’s healthcare practitioners of potential ADRs at the point of service has the potential for reduction of these complications, which should improve healthcare and reduce unneeded costs.展开更多
Objective:This paper aims to analyze the analgesic effect of ultrasound-guided transversus abdominis plane block(TAPB)combined with non-steroidal anti-inflammatory analgesic drug lornoxicam on abdominal surgery in pat...Objective:This paper aims to analyze the analgesic effect of ultrasound-guided transversus abdominis plane block(TAPB)combined with non-steroidal anti-inflammatory analgesic drug lornoxicam on abdominal surgery in patients with a history of drug addiction.Methods:32 patients aged 18-60 who underwent lower abdominal surgery in the First People's Hospital of Liangshan Yi Autonomous Prefecture and Butuo County People's Hospital of Liangshan Yi Autonomous Prefecture from January 2022 to March 2023 were selected,the patients must have drug abuse history for more than 1 year,with a history of drug withdrawal and relapse.The patients were divided into observation group and control group by the envelope method,with 16 cases in the observation group and 16 cases in the control group.Two groups of patients underwent ultrasound-guided bilateral transversus abdominis plane block after the operation.The observation group was treated with dexmedetomidine hydrochloride 1μg/kg+0.25%ropivacaine hydrochloride 40ml,and the control group was treated with 40ml 0.9%sodium chloride injection,the two groups of patients returned to the ward after operation and given intravenous infusion of lornoxicam for relieving the pain.The visual analogue scale(VAS)score of postoperative pain,the times of rescue analgesia,the time of postoperative anal exhaust,the time of ambulation,nausea and vomiting,withdrawal symptoms,related adverse reactions,and hospitalization days were compared between the two groups.Results:The VAS score of postoperative pain in the observation group was significantly lower than that in the control group,P<0.05.Patients in the observation group used less postoperative rescue analgesics than those in the control group,P<0.05.For postoperative anal exhaust time,the difference between the two groups of patients was relatively small,and the time in the observation group was shorter,P>0.05.The time to get out of bed and the length of hospital stay were not significantly different between the control group and the observation group,P>0.05.The withdrawal symptoms of the patients in the observation group were better,P<0.05,nausea and vomiting,and other adverse reactions were lower in the control group,P<0.05.Conclusion:Ultrasound-guided transversus abdominis plane block combined with lornoxicam can be used to relieve pain in abdominal surgery for patients with drug addiction,which can effectively improve the therapeutic effect of patients and reduce the number of postoperative rescue analgesia.Thus,it has high clinical application value.展开更多
The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary an...The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary and alternative medicine (CAM). The study underscores the heightened susceptibility of elderly patients to DDIs due to the prevalence of polypharmacy and the widespread utilization of CAM among breast cancer patients. The potential ramifications of DDIs, encompassing adverse drug events and diminished treatment efficacy, are elucidated. The paper accentuates the imperative for healthcare providers to comprehensively understand both conventional and CAM therapies, enabling them to provide patients with informed guidance regarding safe and efficacious treatment options, culminating in enhanced patient outcomes.展开更多
Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical f...Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.展开更多
There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and s...There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials(RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios(HR) regarding the treatment effects of these drugs for cardiovascular disease(CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.展开更多
The activity of DNA topoisomerase Ⅱ prepared from either normal or tumor tissues were compared. It was found that the unknotting activity of the enzyme in malignant tumor cells was higher than that in normal cells. W...The activity of DNA topoisomerase Ⅱ prepared from either normal or tumor tissues were compared. It was found that the unknotting activity of the enzyme in malignant tumor cells was higher than that in normal cells. We selected some antitumor drugs including Chinese traditional medicine, and observed their effects on the unknotting activity of topoisomerase Ⅱ. The results showed that inhibition of the unknotting activity of the enzyme required very low concentrations of drugs, but much higher concentrations were required for other tested. Some antitumor drugs had no effect on the enzyme were also proved. It is interesting that carrageenan, an antiviral drug, strongly blocked the unknotting activity although its antitumor activity has not been reported.展开更多
The paper was to explore the preventive effects of five drugs on mycoplasma pneumonia of swine （MPS） and to provide reference for clinical medication of pig farms in Hainan Province. A total of 444 health piglets we...The paper was to explore the preventive effects of five drugs on mycoplasma pneumonia of swine （MPS） and to provide reference for clinical medication of pig farms in Hainan Province. A total of 444 health piglets were randomly divided into 6 groups, including five medication groups （72 piglets in group A, 74 pig- lets in group B, 72 piglets in group C, 76 piglets in group D, 76 piglets in group E） and one control group （74 piglets）. The piglets in experimental groups were treated drugs once a day for successive 5 days at 30, 60, 90, 120 and 150 of age. The piglets in control group were free of medication. At 70 and 140 days of age, 15 piglets of each group were randomly selected to collect their blood sermn. The Mycoplasma hyopneumoniae （M-Hyo） antibodies in serum were measured by en- zyme-linked immunosorbent assay （ELISA）. During the experiment, the incidence rates of respiratory disease, lung lesion, feed conversion rate, average daily gain （ADG）, and mortality rate of pigs were also observed and recorded. The results showed that the five drugs had significant difference in preventative effects. Group C （Zhiyuanjing group） received the best preventive effect and the highest economic benefits. Compared with control group, the ADG and feed conversion rate in group C were increased by 7.53% and 9.09%, respectively; the incidence rate of respiratory disease was reduced by 13.44% and lung lesion was alleviated by 81.43% ; and the earnings of each pig could rise by 132.70 yuan. The preventative effect and economic benefit of the drugs was sequenced by Chansu Kechuanling and Bingchan Kechuanwang. Wante Feilin and amoxicillin had weaker preventive effects against MPS but greatly influenced growth performance of pigs, so they should be used alternatively with other drugs.展开更多
基金Project supported by the National Natural Science Foundation of China(Nos.12172204,11772182,11272193,and 10872121)the Program of Shanghai Municipal Education Commission(No.2019-01-07-00-09-E00018)the Natural Science Foundation of Shanghai(No.22Z00142)。
文摘DNA-based biosensors have played a huge role in many areas,especially in current global coronavirus outbreak.However,there is a great difficulty in the characterization of piezoelectric and flexoelectric coefficients of the nanoscale DNA film,because the existing experimental methods for hard materials are almost invalid.In addition,the relevant theoretical models for DNA films only consider a single effect without clarifying the difference between the two electromechanical effects on device detection signals.This work aims to present multiscale models for DNA-microcantilever experiments to clarify the competitive mechanism in piezoelectric and flexoelectric effects of DNA films on detection signals.First,a Poisson-Boltzmann(PB)equation is used to predict the potential distribution due to the competition between fixed phosphate groups and mobile salt ions in DNA films.Second,a macroscopic piezoelectric/flexoelectric constitutive equation of the DNA film and a mesoscopic free energy model of the DNA solution are combined to analytically predict the electromechanical coefficients of the DNA film and the relevant microcantilever signals by the deformation equivalent method and Zhang’s two-variable method.Finally,the effects of detection conditions on microscopic interactions,electromechanical coupling coefficients,and deflection signals are studied.Numerical results not only agree well with the experimental observations,but also reveal that the piezoelectric and flexoelectric effects of the DNA film should be equivalently modeled when interpreting microcantilever detection signals.These insights might provide opportunities for the microcantilever biosensor with high sensitivity.
基金Supported by Science and Technology Plan Project of Shaoyang City,No.2022GX4139.
文摘BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.
基金supported by the Science and Technology Development Fund(Grant Nos.:0007/2020/A1 and 0020/2022/A1)the State Key Laboratory of Quality Research in Chinese Medicine,University of Macao(Grant No.:SKL-QRCM(UM)-2020-2022)+4 种基金the University of Macao(Grant Nos.:MYRG2019-00002-ICMS and MYRG2020-00017-ICMS)2022 Internal Research Grant of SKLQRCM(University of Macao)(Grant No.:QRCM-IRG2022-011)the National Natural Science Foundation of China(Grant No.:22101230)the Natural Science Basic Research Program of Shaanxi(Grant No.:2021JQ-089)the Natural Science Foundation of Chongqing,China(Grant No.:cstc2021jcyj-msxmX0659).
文摘Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.
文摘To explore the anticancer mechanism and DNA damages of hydroxyapatite ultrofine powder (HAUFP) on lymphocytes of rats, DNA damages in W 256 sarcoma cells and lymphocytes of rats were measured by single cell gel electrophoresis (SCGE). The results showed that HAUFP damaged DNA of W 256 sarcoma cells obviously but only cause slight damage of DNA of lymphocytes in rats. It is suggested that HAUFP selectively damaged DNA of tumor cells with only mild damage of lymphocyte DNA. HAUFP has powerful anticancer effect and little genetic toxicity.
文摘Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-026)the Beijing Natural Science Foundation(7202133)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-RW350-002)。
文摘Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.
基金the National Natural Science Foundation of China(Grant No.:51803120).
文摘Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.
文摘Importance/Objective: Adverse Drug Reactions (ADRs) are unavoidable, but recognizing and addressing ADRs early can improve wellness and prevent permanent injury. We suggest that available medical information and digital/electronic methods could be used to manage this major healthcare problem for individual patients in real time. Methods: We searched the available digital applications and three literature databases using the medical subject heading terms, adverse drug reaction reporting systems or management, filtered by clinical trial or systemic reviews, to detect publications with data about ADR identification and management approaches. We reviewed the reports that had abstract or summary data or proposed or implemented methods or systems with potential to identify or manage ADRs in clinical settings. Results: The vast majority of the 481 reports used retrospectively collected data for groups of patients or were limited to surveying one population group or class of medication. The reports showed potential and definite associations of ADRs for specific drugs and problems, mostly, but not exclusively, for patients in hospitals and nursing homes. No reports described complete methods to collect comprehensive data on ADRs for individual patients in a healthcare system. The digital applications have ADR information, but all are too cumbersome or incomplete for use in active clinical settings. Several studies suggested that providing information about potential ADRs to clinicians can reduce these problems. Conclusion and Relevance: Although investigators and government agencies agree with the need, there is no comprehensive ADR management program in current use. Informing the patient’s healthcare practitioners of potential ADRs at the point of service has the potential for reduction of these complications, which should improve healthcare and reduce unneeded costs.
基金supported by Liangshan Science and Technology Program(Project number:22ZDYF0100).
文摘Objective:This paper aims to analyze the analgesic effect of ultrasound-guided transversus abdominis plane block(TAPB)combined with non-steroidal anti-inflammatory analgesic drug lornoxicam on abdominal surgery in patients with a history of drug addiction.Methods:32 patients aged 18-60 who underwent lower abdominal surgery in the First People's Hospital of Liangshan Yi Autonomous Prefecture and Butuo County People's Hospital of Liangshan Yi Autonomous Prefecture from January 2022 to March 2023 were selected,the patients must have drug abuse history for more than 1 year,with a history of drug withdrawal and relapse.The patients were divided into observation group and control group by the envelope method,with 16 cases in the observation group and 16 cases in the control group.Two groups of patients underwent ultrasound-guided bilateral transversus abdominis plane block after the operation.The observation group was treated with dexmedetomidine hydrochloride 1μg/kg+0.25%ropivacaine hydrochloride 40ml,and the control group was treated with 40ml 0.9%sodium chloride injection,the two groups of patients returned to the ward after operation and given intravenous infusion of lornoxicam for relieving the pain.The visual analogue scale(VAS)score of postoperative pain,the times of rescue analgesia,the time of postoperative anal exhaust,the time of ambulation,nausea and vomiting,withdrawal symptoms,related adverse reactions,and hospitalization days were compared between the two groups.Results:The VAS score of postoperative pain in the observation group was significantly lower than that in the control group,P<0.05.Patients in the observation group used less postoperative rescue analgesics than those in the control group,P<0.05.For postoperative anal exhaust time,the difference between the two groups of patients was relatively small,and the time in the observation group was shorter,P>0.05.The time to get out of bed and the length of hospital stay were not significantly different between the control group and the observation group,P>0.05.The withdrawal symptoms of the patients in the observation group were better,P<0.05,nausea and vomiting,and other adverse reactions were lower in the control group,P<0.05.Conclusion:Ultrasound-guided transversus abdominis plane block combined with lornoxicam can be used to relieve pain in abdominal surgery for patients with drug addiction,which can effectively improve the therapeutic effect of patients and reduce the number of postoperative rescue analgesia.Thus,it has high clinical application value.
文摘The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary and alternative medicine (CAM). The study underscores the heightened susceptibility of elderly patients to DDIs due to the prevalence of polypharmacy and the widespread utilization of CAM among breast cancer patients. The potential ramifications of DDIs, encompassing adverse drug events and diminished treatment efficacy, are elucidated. The paper accentuates the imperative for healthcare providers to comprehensively understand both conventional and CAM therapies, enabling them to provide patients with informed guidance regarding safe and efficacious treatment options, culminating in enhanced patient outcomes.
文摘Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.
文摘There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials(RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios(HR) regarding the treatment effects of these drugs for cardiovascular disease(CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.
文摘The activity of DNA topoisomerase Ⅱ prepared from either normal or tumor tissues were compared. It was found that the unknotting activity of the enzyme in malignant tumor cells was higher than that in normal cells. We selected some antitumor drugs including Chinese traditional medicine, and observed their effects on the unknotting activity of topoisomerase Ⅱ. The results showed that inhibition of the unknotting activity of the enzyme required very low concentrations of drugs, but much higher concentrations were required for other tested. Some antitumor drugs had no effect on the enzyme were also proved. It is interesting that carrageenan, an antiviral drug, strongly blocked the unknotting activity although its antitumor activity has not been reported.
基金National Natural Science Foundation of China(31560696)Special Project of Enterprises-Universities-Researches Integration of Hainan Province(cxy20150008)Special Project of Technology Development in Scientific Research Institutes of Hainan Province(KYYS-2014-32)
文摘The paper was to explore the preventive effects of five drugs on mycoplasma pneumonia of swine （MPS） and to provide reference for clinical medication of pig farms in Hainan Province. A total of 444 health piglets were randomly divided into 6 groups, including five medication groups （72 piglets in group A, 74 pig- lets in group B, 72 piglets in group C, 76 piglets in group D, 76 piglets in group E） and one control group （74 piglets）. The piglets in experimental groups were treated drugs once a day for successive 5 days at 30, 60, 90, 120 and 150 of age. The piglets in control group were free of medication. At 70 and 140 days of age, 15 piglets of each group were randomly selected to collect their blood sermn. The Mycoplasma hyopneumoniae （M-Hyo） antibodies in serum were measured by en- zyme-linked immunosorbent assay （ELISA）. During the experiment, the incidence rates of respiratory disease, lung lesion, feed conversion rate, average daily gain （ADG）, and mortality rate of pigs were also observed and recorded. The results showed that the five drugs had significant difference in preventative effects. Group C （Zhiyuanjing group） received the best preventive effect and the highest economic benefits. Compared with control group, the ADG and feed conversion rate in group C were increased by 7.53% and 9.09%, respectively; the incidence rate of respiratory disease was reduced by 13.44% and lung lesion was alleviated by 81.43% ; and the earnings of each pig could rise by 132.70 yuan. The preventative effect and economic benefit of the drugs was sequenced by Chansu Kechuanling and Bingchan Kechuanwang. Wante Feilin and amoxicillin had weaker preventive effects against MPS but greatly influenced growth performance of pigs, so they should be used alternatively with other drugs.
