Cholesterol plays a key role in the molecular and mesoscopic organisation of lipid membranes and it is expected that changes in its molecular structure  may affect adversely membrane properties and function. In this study, we present evidence that oxidation of cholesterol has significant effects on the mechanical properties, molecular and mesoscopic organisation and lipid–sterol interactions in condensed monolayers composed of the main species found in the inner leaflet of the erythrocyte membrane. Using a combination of experimental methods  and atomistic molecular dynamics simulations, we show that oxidation of cholesterol to 7-ketocholesterol leads to stiffening of the monolayer (under both static and dynamic conditions), significant changes in the monolayer microdomain organisation, disruption in the van der Waals, electrostatic and hydrophobic interactions between the sterol and the other lipid species, and the lipid membrane hydration. Surface sensitive X-ray techniques reveal that, whilst the molecular packing mode is not significantly affected by cholesterol oxidation in these condensed phases, there are subtle changes in membrane thickness and a significant decrease in the coherence length in monolayers containing 7-ketocholesterol. Erythrocytes are responsible for delivering oxygen to tissues. Over its lifetime of 120 days, an 8 diameter ,5,6. UndThe mammalian plasma membrane is comprised of hundreds of different lipid species, but most contain only a single sterol type, cholesterol . CholestIt has been known for a long time that cholesterol can alter the molecular order, lateral organisation and mechanical properties of lipid membranes and experiments with model lipid systems of varying composition have provided important insights ,9,10,11.lesterol . Under olesterol . All healesterol ,5. The plesterol . Howeverlesterol ,14,15. Ilesterol ,17,18. Olesterol ,20 as welesterol ,22. Intet impact . We demot impact . It has Much work has been undertaken to understand the differences between healthy and oxidised red blood cell membranes ,15,25,26A few words about the choice of systems. The vast molecular diversity of lipid species in the membrane makes it virtually impossible to predict its exact macrodomain lateral organisation and physical properties. On the other hand, reducing the system to only two or three components, as often done in model membrane studies, may fail to capture a number of relevant effects resulting from potential synergistic interactions. Our choice for this study is to include the main lipid species found in the mammalian plasma membrane, with a focus on the inner leaflet, a total of five compounds (including cholesterol). As a first step in this approximation, we chose to work with saturated chain lipids for two reasons. Firstly, cholesterol is known to interact with saturated-chain lipids to form raft-like phases, so this system can be seen as probing such interactions and condensed phases. Secondly, including lipids with a wider distribution of chain saturations would significantly complicate the interpretation of results even for a five-component system. Once we clarify the effect of cholestrol oxidation in this system, it could readily be upgraded to include a more realistic distribution of chain lengths and saturations.We have used a combination of all-atom molecular dynamics simulations and a range of experimental biophysical techniques to investigate the effect of cholesterol oxidation on the inner leaflet of red blood cell model membranes (RBC IL). We use the atomistic simulations to provide an insight into the molecular mechanisms that govern the organisation and properties of the membrane, thus helping the interpretation of experimental observations.sn-glycero-3-phosphoethanolamine), DPPC , PSM , the sodium salt of DPPS  and cholesterol (Chol)  . To deteAll lipids were purchased from Avanti Polar Lipids Inc.  as 1 g/L stock solution in chloroform  and used without further treatment.2 (Sigma Aldrich Co.) in a Teflon trough , ammonium salt), a fluorescent lipid. The monolayers were prepared and treated as described above. The subphase temperature was kept at Lipid mixture stock solutions were mixed with 2 and a single movable barrier, mounted on an active antivibration system. After spreading the film, the trough was sealed with a hood filled with He. The trough temperature was kept constant at X-ray Reflectivity (XRR) and Grazing Incidence X-ray Diffraction (GIXD) were used to resolve the lateral and transverse molecular organisation in the lipid monolayers. We used the synchrotron source at the ID10 beamline Surface Scattering Station of the European Synchrotron Radiation Facility (ESRF) in Grenoble, France (experiment number SC-4816) . Both XRz-direction , as the wave vector transfer of the reflected X-ray will be entirely along this direction. The monolayer reflectivity, z-direction can be extracted [For the XRR experiments, the sample was irradiated under the glancing angle, xtracted ,38.z-direction, and For the GIXD experiments, the film was irradiated at an incidence angle of mponents :qxy≃4πλsrection) ,39,40,41A series of all-atom molecular dynamics (MD) simulations have been used to study the effects of cholesterol oxidation on the structural and interfacial properties of the model RBC plasma membrane inner leaflet described above. Simulations of three systems have been performed: one with no cholesterol (RBC NChol), a second with 20 ids each B.The CHARMM-GUI Bilayer Builder was used to generate symmetric RBC Chol and RBC NChol bilayers with 200 lipids per leaflet . The RBCat 293 K . During ectively . During ermostat ,46 and aermostat .x and y dimensions. As such, to produce a pseudo-2D Ewald summation, force and potential corrections were applied in the z dimension [The bilayers were then split at the hydrophobic core to produce two monolayers separated by water B. The mof 1.2 nm ,52. For imension . All simimension ,54,55. TAnalysis ,57, LiPyAnalysis , and FreAnalysis . The hydAnalysis .z-axis. sn-1 and sn-2 tails of each lipid. The values of 3 to C17  elasticity of the Langmuir monolayers. For all three monolayers, the static compression moduli pressure b. Even fressures b. When cWe used surface dilatational rheology  to probeant area a, and frDilatational rheology experiments were performed at For the the RBC Chol system, there is a fast pressure relaxation in the first 30 s–40 s a, which For all three systems studied, Similar stress relaxation experiments for all three monolayers were performed also at target pressures of A comparison of the static and dynamic elastic moduli shows that the three systems exhibit different behaviour. For RBC NChol, the values of The target pressure of Static compressibility and dynamic dilatational viscoelasticity measurements reported above serve to inform on the monolayer behaviour as a whole as they produce values averaged over the entire film. However, these monolayers are complex mixtures in which lipid–lipid interactions may drive phase separation on mesoscopic scales. Such microdomain structures are conveniently visualised by epifluorescence microscopy coupled to the Langmuir trough, which allows the recording of images during a continuous compression of the monolayer. For this, a small amount of a rhodamine labelled lipid  was incorporated into the lipid monolayers, as detailed in the Methods section. As the dye moiety is bulky and inflexible, it will be excluded from more densely-packed domains of the lipid film, which in turn will appear dark on the micrographs . Less orpersists b. Upon ce formed c. To some formed d until tWhen cholesterol is removed from the mixture, similar structures are seen at low pressure, i.e., bright domains, 1 ckground i. This pRBC Chol b. When tRBC Chol j,k. ThisRBC Chol a and theRBC Chol d which dRBC KChol monolayer presents a very different microdomain organisation. At low surface pressures, dark microdomains, 2 rographs e. The incent dye f. Upon fcent dye g. On clo modulus d. We sees . Synchrotron X-ray experiments were performed at 5, 15 and 30 Electron density profiles were obtained experimentally using surface-sensitive X-ray reflectivity on Langmuir films at the air/buffer interface. For this, we used the soft surfaces and interfaces, high-brilliance undulator beamline (ID10-EH1) at ESRF in Grenoble, France. It should be noted that the X-ray data were obtained using TRIS buffer subphase at pH = 7.4, 150 ab model ,69,70, iWe focus our discussion on X-ray data at 30 features a. The po/dT+dH/2 . For RBCz, along the normal to the plane of the film. The three monolayers show similar electron density profiles  profiles were recorded using synchrotron radiation. All three films show one distinct peak in the GIXD patterns d, indicafor DPPC .−5 )Å, −5 )Å, and −4 )Å. This indicates the same d-spacing of the unit cells  and thus similar packing modes. From the full width half maximum (fwhm) of the peaks, information on the average domain size can be obtained. Using the Scherrer formula, The peak positions are very similar for all three films (9 ± 2) Å e. When il chains . At π= 1 visible  indicatiThe results from this study provide evidence that cholesterol oxidation could have significant implications in terms of membrane organisation (on both molecular and mesoscopic levels), membrane physical properties, and degree of lateral order in lipid monolayers akin to the inner leaflet of the red blood cell. On a molecular level, these effects appear to stem from alterations in the distribution of hydrophilic (headgroup) and hydrophobic (tail) regions of the lipid monolayer containing different sterols as revealed by surface sensitive X-ray techniques. Complementary MD simulations of the same systems suggest that these alterations originate in the significant differences in which cholesterol and its oxidised variant, 7-ketocholesterol, interact with neighbouring lipid species. 7-ketocholesterol, due to its increased hydrophilicity, is able to draw water deeper in the headgroup region of the monolayer thus increasing its size. Oxidation of cholesterol also results in a decrease of the coherence length for these monolayers.As a first step in understanding of these effects, we chose to work with mixtures of saturated-chain lipid species in order to emulate condensed lipid phases. Whilst our model lipid systems cannot capture the full molecular diversity of the mammalian plasma membrane, they should be representative of the condensed phases in the inner leaflet of the erythrocyte membrane, which are thought to form between cholesterol and saturated-chain lipids. Modifications of their properties as a result of oxidative stress may therefore have effects on such phases if they indeed exist in the inner leaflet, and lead to altered biological function. The obvious example is the membrane mechanical properties, which are of crucial importance especially for the erythrocyte. Increased membrane stiffness in terms of area compressibility (both static and dynamic) reported here complement existing studies that have shown that oxidative stress leads to increase of the membrane bending and shear stiffness  and lipi


Finally, the confusion matrix was used to validate the model for a dose regimen of 1,250 mg lapatinib , and for a dose regimen of 1,000 mg lapatinib . To conclude, we established a deep learning model to predict lapatinib dose based on important influencing variables selected from real-world evidence, to achieve an optimal individualized dose regimen with good predictive performance.Lapatinib is used for the treatment of metastatic HER2(+) breast cancer. We aim to establish a prediction model for lapatinib dose using machine learning and deep learning techniques based on a real-world study. There were 149 breast cancer patients enrolled from July 2016 to June 2017 at Fudan University Shanghai Cancer Center. The sequential forward selection algorithm based on random forest was applied for variable selection. Twelve machine learning and deep learning algorithms were compared in terms of their predictive abilities . As a result, TabNet was chosen to construct the prediction model with the best performance (accuracy = 0.82 and AUC = 0.83). Afterward, four variables that strongly correlated with lapatinib dose were ranked  What is the current knowledge on the topic?Lapatinib was approved in China to treat patients with HER2(+) metastatic breast cancer in combination with capecitabine based on a single-arm, open-label study (EGF10949). Two dose regimens are commonly recommended for lapatinib, 1,250 mg of lapatinib in combination with capecitabine and 1,000 mg of lapatinib in combination with trastuzumab. Under the recommended dose regimen, lapatinib can be well tolerated with minimal avoidance of drug toxicities.2. What question did this study address?In this study, we established a deep learning model to predict the lapatinib dose based on important influencing variables from real-world evidence, resulting in getting the optimal individualized dose regimen.3. What does this study add to our knowledge?This study provides a new perspective and guidance for lapatinib dose administration where few studies focused on individualized lapatinib dose treatment in breast cancer patients previously.4. How might this change clinical pharmacology or translational science?Models based on machine learning and deep learning methods could help clinicians treat breast cancer patients with individualized lapatinib dose regimens to get the optimal effect and reduce adverse events.Lapatinib is a selective inhibitor of the tyrosine kinase receptor and human epidermal growth factor receptor-2 (HER2) and has activity in HER2-overexpressing breast cancer –3. By biWith the rapid development of information technology, real-world study has become an important data source for clinical research . Most reIn order to achieve a balance of drug efficacy and toxicities, an appropriate dose regimen is important for patients’ treatment outcome. In this study, we aim to establish a model based on machine learning and deep learning techniques to predict the lapatinib dose based on important influencing variables from real-world evidence, resulting in getting the optimal individualized dose regimen.This is a retrospective, real-world study. Patients who were diagnosed with breast cancer and treated with lapatinib were included from July 2016 and June 2017 at Fudan University Shanghai Cancer Center (FUSCC). One hundred fifty-four patients were enrolled, including 55 at the initial dose of 1,000 mg, 94 at the initial dose of 1,250 mg, and 5 at the initial dose of 500 mg. This study mainly considered patients with commonly recommended dose regimens, namely, 1,000 mg and 1,250 mg. Therefore, after excluding patients with an initial dose of 500 mg, 149 patients remained. This study was approved by the ethics committee (No. 2016-106-1159-K1), and informed consents were included.All data were collected from electronic medical records. Demographic information included continuous variables, such as age, height, and weight, and binary variables, such as age ≥52 years or not. Combination medication information included the prior use of anthracycline, taxane, platinum, fluorouracil, and trastuzumab. Physiopathological conditions indicated that patients had hypertension, diabetes, heart disease, other underlying diseases , and postmenopausal or not. Treatment protocol information included number of previous chemotherapy regiments, Ki-67, prior endocrine therapy, estrogen receptors (ER), progesterone receptors (PR), disease stage, operation, Eastern Cooperative Oncology Group (ECOG), number of metastases, lung metastases, liver metastases, bone metastases, brain metastases, protocol_1 (combination regimen of lapatinib + capecitabine), protocol_2 (combination regimen of paclitaxel + carboplatin + herceptin + lapatinib), protocol_3 (combination regimen of vinorelbine + lapatinib), and protocol_4 (other combination regimens).There were two initial dose regimens of lapatinib, 1,000 and 1,250 mg, which were converted to binary variables, where 1,250 mg corresponds to “1” and 1,000 mg corresponds to “0.” According to the National Cancer Institute Common Terminology Criteria for Adverse Events , patients with adverse drug reactions of grade ≤ 2 were considered to have drug safety. In addition, according to a previous study on lapatinib in breast cancer patients at FUSCC, the median progression-free survival (PFS) was 8.1 months; therefore, patients with PFS >8.1 months were considered to have drug effectiveness herein , random forest (RF), Adaboost, XGBoost, gradient-boosted decision tree, LightGBM, CatBoost, TabNet, Artificial Neural Network (ANN), Super TML, and Wide&Deep, respectively. As a novel deep learning architecture, we implemented the TabNet model exactly as described in Arik and Pfister, used a sparsemax attention, and included the sparsification term in the loss function . The modSubsequently, based on the selected important variables, the evaluation metrics for model performance were calculated, including precision, recall, f1_score, accuracy, and area under the curve (AUC). The model with the best predictive performance in the test cohort was selected to predict the lapatinib dose regimen. The specific formula of evaluation metrics are as follows:Accuracy = (TP + TN)/(TP+FN+FP+TN)Precision = TP/(TP + FP)Recall = TP/(TP + FN)f1_score = 2 × TP/(2 × TP + FP + FN)TP: true positive, indicating that the positive class is predicted as the number of positive classes; TN: true negative, indicating that the negative class is predicted as the number of negative classes; FP: false positive, indicating that the negative class is predicted as the number of positive classes; FN: false negative, indicating that the positive class is predicted as the number of negative classes.f1_score is used to measure the merits and defects of the model; higher f1_score indicates better model performance.The importance of variables refers to the degree to which each variable in the model contributes to improving the predictive power of the whole model. Herein, we used the algorithm with the best model performance to calculate and rank the variable importance scores. In terms of importance score calculation and ranking by TabNet, the Feature Transformer layer realizes the calculation and processing of features selected by the current step. Analogous to a decision tree, for a given set of features, a decision tree constructs a combination of size relations of individual features, namely, a decision manifold. A simple neural network is used to simulate the decision manifold of the decision tree through a fully connected (FC) layer, but the FC layer constructs a set of simple linear relations and does not consider more complicated cases. TabNet performs feature calculation through a more complex Feature Transformer layer. Its decision manifold may not be similar to that of the decision tree, and it may do better than the decision tree in some Feature combinations . UnivariEventually, the confusion matrix was used to visualize the performance of the algorithm and further analyze the model performance. The confusion matrix was realized by the Matplotlib package. All experiments of machine learning and deep learning algorithms were run on Windows 10 with Intel(R) Core(TM) i5-10400F CPU @ 2.90GHz 12CPUs and 512GB memory. Data analysis was conducted using python 3.8.8 and IBM SPSS Statistics 22.We carried out six-fold cross-validation for each model with calculating the mean, standard deviation, and P-value of each indicator. As shown in A total of 149 breast cancer patients were enrolled from FUSCC in this study; the population characteristics are illustrated in After deleting variables with extremely imbalanced positive and negative sample sizes , features were selected based on 26 variables through the SFS method. RF models were established using the selected 1 to 26 variables, and the f1_score of each model was obtained  metastatic breast cancer in combination with capecitabine based on a single-arm, open-label study EGF10949), which evaluates the drug efficacy and safety 0949, whi. Our stuAs a novel deep learning technique, TabNet uses a sequential attention mechanism to choose a subset of meaningful features to process at each decision step, enabling interpretability and more efficient learning as the learning capacity used for the most salient features . AdditioAs one of the most important variables influencing lapatinib dose, protocols of combination therapy accounted for a different proportion in this study as follows: protocol_1, protocol_2, protocol_3, and protocol_4 accounted for 67.11%, 16.11%, 6.71%, and 10.07%, respectively. The combination of lapatinib + capecitabine (protocol_1) was one of the common recommended regimens for patients with HER2(+) breast cancer with prior treatment of taxanes, anthracyclines, and/or trastuzumab , 30. CliFor the physiological features, previous studies found that patients with lower weight were more likely to have higher lapatinib plasma levels (P = 0.055) . The resAccording to the confusion matrix results, the classifier correctly identified 82% of patients using the 1,250-mg lapatinib regimen and 88% of patients using the 1,000-mg lapatinib regimen, indicating a remarkable prediction performance. Nevertheless, the sample size in the training and test cohorts was small. Large samples are required to verify this result.via machine learning and deep learning methods, which could mine deep data based on real-world evidence. Through a comparison of different algorithms, TabNet was selected to establish the model based on the strength of its predictive ability. To our knowledge, few studies focused on lapatinib dose prediction previously, and this study provides a new perspective and guidance for lapatinib dose administration with a more concise and accurate model. Compared with conventional models, machine learning and deep learning models mine and use unexploited variables to cover the shortage of clinical experience from the real world. One limitation in this study was the limited sample size that affected the model to further optimize the performance. In future, more real-world evidence should be added in the model to optimize its performance, and larger prospective clinical studies will be needed to investigate the further interactions between different variables and lapatinib dose.Our study endeavored to build a dose prediction model The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee at Fudan University Shanghai Cancer Center (FUSCC) (No. 2016-106-1159-K1). The patients/participants provided their written informed consent to participate in this study.ZY and XY led the research and provided medical support. FK analyzed and interpreted the data. HYL, JZ, and ZW analyzed the data and provided technical support. HL and XH wrote the manuscript. HW and FG provided methodological guidance. QZ provided technical and medical guidance. All authors contributed to the article and approved the submitted version.FG was supported by the National Key Research and Development Program . QZ was supported by the Clinical Research Plan of SHDC [SHDC2020CR3085B].Author JZ and FG are employed by Beijing Medicinovo Technology Co. Ltd., China. Author XH is employed by Dalian Medicinovo Technology Co., Ltd., China.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The relationship between weight gain and progression of IgA nephropathy (IgAN) has been investigated by many researchers but remains controversial. The incidence of IgAN is significantly higher in Asia than in other regions. Therefore, we investigated the relationship between weight gain and primary IgAN in the Asian population.Seven databases were retrieved up to now. We stratified the included population by body mass index (BMI) and performed a meta-analysis of associated risk factors.In this study, Asian IgAN patients with different BMI were grouped together to clarify the relationship between BMI and IgAN progression in Asian populations, so as to provide more ideas and treatment means for the prevention and treatment of IgAN in the future. IgAN is a common clinical primary renal disease characterized by the deposition of IgA in the mesangial region of the glomerulus.,3 About 10% to 20% of patients will progress to end-stage renal disease (ESRD) within 10 years, so it is necessary to explore the factors associated with the progression of IgAN to prolong the survival time of patients and improve the quality of life of patients. In recent years, there have been different views on the impact of BMI on IgAN. Some authors believe that the progression of the IgAN is related to excessive BMI, and others agree that the progression of IgAN is associated with being underweight. In addition, the geographical distribution of IgAN also showed obvious differences. The incidence is high in Asia (40%–50%), moderate in Europe (20%–30%), and the lowest in Africa (<5%). Based on the high incidence of IgAN in Asia, we conducted the first systematic review and meta-evaluation of the association between BMI and IgAN progression in Asian populations to clarify the relationship between BMI and IgAN progression in Asian populations.The relationship between obesity and diseases of various systems is a hot issue worldwide, and most diseases have been confirmed linked to obesity.The classification standards for BMI are not the same, so we need to combine different BMI classifications before conducting a meta-analysis to help us analyze the correlation between different BMI levels and the progression of IgAN. Due to the differences in sample size and research methods, the results of individual studies may be inaccurate. Therefore, during the process of meta-analysis, we will standardize the results of the studies, and if necessary, we will also conduct a subgroup analysis to find out the factors that influenced the results of the article.http://links.lww.com/MD/H982. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identifier CRD42021253292.This review will follow the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA) guidelines, see S1 file, Supplemental Digital Content, We will search in Pubmed for MESH and free words for standard medicine first. We will use the following terms as search terms to conduct MESH and free word searches, respectively: Glomerulonephritides IGA, Berger’s Disease, Bergers Disease, IGA Glomerulonephritis, Nephropathy IGA, IgAN 1, Nephropathy 1 Iga, Immunoglobulin A Nephropathy, Nephropathy, Immunoglobulin A, Nephritis, IGA Type, IGA Type Nephritis, Berger Disease, IgAN, BMI, Index Body Mass, Quetelet Index, Index Quetelet, Quetelet’s Index, Quetelets Index, Body Weights, Weight Body, and Weights Body. To prevent the omission of literature that may be closely related to the study, we will review references cited in all studies selected for review, and we will select literature in English and Chinese for inclusion in the study. Two reviewers (MXL and DZ) will search papers published from the inception to now independently. We will search the following 7 electronic databases, including PubMed/MEDLINE, EMBASE, Cochrane Library, Chinese Science and Technology Journals . If 1 of the reviewers felt that the article met the inclusion criteria it will be included. In the event of disagreement on literature, a third reviewer (TYC) will decide whether the literature will be included or not. In the month of literature completion, PubMed/MEDLINE will be searched to capture all articles published after the original search date.We will include articles on the relationship between BMI and IgAN; in addition, the research needs to meet:(1) case–control, cohort, and cross-sectional studies published in English and Chinese,(2) the included studies need to be classified into at least 3 grades according to BMI classification,(3) biopsy confirmed primary IgAN,(4) the research object is Asian population.The exclusion criteria are as follows:(1) case analysis and review articles,(2) articles not grouped according to BMI classification or grouped into <3 groups,(3) patients with secondary IgAN were excluded,(4) articles that are grouped by other factors besides BMI, lack original data and duplicate data,(5) the subjects of the study are people outside Asia.The selecting process will follow the PRISMA flow diagram, see Figure  score to evaluate the quality of the cohort studies. Furthermore, the American Agency for Health Care Quality and Research (AHQR)-recommended method was used to evaluate the literature quality of cross-sectional studies. For cross-sectional studies, if the answer is “no” or “unclear,” the item will be rated “0”; if the answer is “yes,” the item will be rated “1.”Since 7 of the included studies were cohort studies and 1 was a cross-sectional study, so we will use the Newcastle-Ottawa-Scale (NOS)For all studies, we will use “☆”, “★” and “★★” to judge the overall quality of the included studies, which respectively represent 0, 1, and 2 scores. A study was scored when both raters (MXL and DZ) agreed that the individual scores were consistent. If the results of the 2 reviewers differ significantly, the 2 reviewers’ scores differ over 2 points, and a third reviewer (TYC) will conduct the study to arrive at the final opinion. Literature quality was assessed as follows: cohort studies: low quality <5, moderate quality 5–6, high quality >7; cross-sectional studies: low quality = 0–3; moderate quality = 4–7; high quality = 8–11. The quality evaluation process of the literature is presented in the included literature quality evaluation table, see Table We will extract relevant trial design data, including publication year, nationality, research type, sample size, gender, age, and outcomes as following, including 24-hour urine protein, TC, CREA, UA, eGFR, and incidence of hypertension. All the collection results were filled into the table for basic clinical indicators of the included study population and the table for basic characteristics of the included studies, see Tables  the BMI classification is mainly divided into underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obesity (30 kg/m2). Therefore, we will make a bar chart of the BMI distribution of the literature and divide the literature into different groups according to the similarity of the BMI classification method. They are as follows: the relative normal-weight group, the overweight/obese group, and the low-weight group.At present, according to the WHO BMI cutoff point,Two researchers (MXL and DZ) will assess the risk of bias for included articles independently according to the Cochrane risk of bias (ROB) tool for interventions including:(1) sequence generation,(2) allocation concealment,(3) blinding of participants and personnel,(4) blinding of outcome assessment,(5) incomplete outcome data,(6) selective reporting, and(7) other bias.The assessment will be graphed and use Review Manager 5.3 software.I2 statistic and χ2 test to evaluate the heterogeneity between studies. If the heterogeneity results showed P < .10, there was heterogeneity between the 2 groups. I2 will be used to assess the heterogeneity of the included studies. The fixed-effects model will be chosen when the heterogeneity is <50%, and the random-effects model will be used if the heterogeneity is >50%. If the number of articles is >10, publication offsets will be assessed.Odds ratios (ORs) and 95% confidence intervals analyzed dichotomous variables. The fixed-effect model was the prior model for the continuous data effect model. We will use the We will perform a meta-analysis of 6 outcomes of the relative normal-weight group, overweight/obesity group and the low-weight group and obtain the forest plot. Sensitivity analysis for each data will be conducted to evaluate the results’ robustness. If we find the direction of heterogeneity of the article has changed significantly after eliminating an article, the literature will be regarded as the source of heterogeneity. The reasons for this result will be further analyzed.,9 Many studies have shown that obesity and increased central body fat are related to diabetes, hypertension, cardiovascular and cerebrovascular diseases, sleep apnea, and many chronic diseases that seriously affect physical and mental health. Loss of weight slightly was found to improve these comorbidities in the study. Therefore, if we find that obesity is related to a certain disease, we can help treat the disease or delay the further development of the disease by weight control. BMI (kg/m2) is the main criterion for evaluating obesity. The current classification of BMI is mainly based on the standards established by WHO.,12 BMI < 18.5 kg/m2 is underweight, 25–29.9 kg/m2 is overweight, BMI > 30 kg/m2 is obese, BMI > 40 kg/m2 (or ≥ 35kg/m2 with comorbidities) is severely obese. There are significant regional differences in IgAN, so racial differences are an issue that we cannot ignore. Ethnic factors are related to ethnicity or large populations grouped according to common characteristics and customs, divided into intrinsic and extrinsic factors. Extrinsic ethnic factors include culture and environment, while intrinsic ethnic factors help define and identify subpopulations, including genetics, body composition, and other factors, therefore, whether obesity is associated with IgAN progression in Asian populations. Due to ethnic differences in various continents, WHO has also formulated different obesity definition points, including Asia. In addition to WHO, many regions and countries have developed specific BMI standards. In recent years, people have also begun to explore the relationship between obesity and IgAN. However, we found some disagreement about the relationship between BMI and IgAN. Some researchers believe that an increase in BMI is closely related to the progression of IgAN, while others believe that a low BMI is related to the progression of IgAN. Based on that, we compared the low-weight group with the normal-weight group.Obesity has been linked to many diseases.In conclusion, through this article, we hope to verify the relationship between BMI and IgAN, and provide more evidence to support for the treatment and prognosis of IgAN, so as to delay the progression of IgAN and improve the quality of survival of patients.MXL searched and selected literatures, and wrote the article. TYC and DZ searched and selected literatures, CGY controlled the quality of articles, and guided the technology. SLZ reviewed topic selection, feedback articles, and guided the technology.Conceptualization: Meixi Liu.Data curation: Meixi Liu, Chunguang Yi, Di Zou.Formal analysis: Meixi Liu, Tianying Chang, Di Zou.Funding acquisition: Shoulin Zhang.Investigation: Shoulin Zhang.Methodology: Tianying Chang, Di Zou.Project administration: Shoulin Zhang.Resources: Meixi Liu, Chunguang Yi, Tianying Chang, Di Zou.Software: Meixi Liu, Chunguang Yi, Tianying Chang.Supervision: Chunguang Yi, Shoulin Zhang.Validation: Shoulin Zhang.Visualization: Meixi Liu, Tianying Chang, Shoulin Zhang.Writing – original draft: Meixi Liu.Writing – review & editing: Meixi Liu, Chunguang Yi, Tianying Chang, Shoulin Zhang.


Neonatal herpes is a rare condition and it is normally acquired through vertical transmission in the peripartum period. Delayed diagnosis and treatment of this condition are associated with high morbidity and mortality. We present five cases of neonatal herpes in infants born to asymptomatic mothers. Three of these infants were girls, three were born preterm, three were born after prolonged rupture of membranes, three had herpes simplex virus (HSV) type 2, and one had central nervous system (CNS) involvement. In all cases, the dermatologist played a key role in establishing an early diagnosis. Given the absence of a vaccine or a cost-effective method of screening for HSV infection in asymptomatic mothers, the current management strategies focus on the prevention of maternal infection and mother-to-child transmission, as well as early diagnosis and treatment of neonatal infection. Neonatal herpes is a rare condition, and it is mostly acquired (85%) through vertical transmission in the peripartum period. The estimated annual incidence of neonatal herpes infection is between 1.6 and 8.4 per 100,000 live births ,3.HSV-1 infection may be asymptomatic in two-thirds of women, and 80% of neonates who become infected are born to mothers with no history of genital herpes . Hence, Case 12 every eight hours for six months. She had no recurrence or sequelae.The first case was a girl born at term by vacuum-assisted vaginal delivery after prelabor rupture of membranes. At five days of life, she developed grouped vesicles on an erythematous base on her forehead and scalp Figure . She wasCase 2This infant was a girl born by unassisted vaginal delivery more than 24 hours after prelabor rupture of membranes, at 32+0 weeks of a dichorionic diamniotic pregnancy. At five days of life, she developed an erosive lesion on her right cheek, followed by vesicles and ulcers on her right cheek, philtrum, and upper lip. After collecting conjunctival, rectal, buccal, and cutaneous swabs, and CSF and blood samples, we started the infant on empiric intravenous acyclovir. HSV-2 PCR testing returned positive results in all the samples except the rectal swab and the infant was diagnosed with HSV-2 infection of the central nervous system (CNS). She later developed two corneal ulcers. The eye fundus examination, physical examination, blood test, imaging tests, and electroencephalogram showed no further abnormalities. The infant received intravenous and ophthalmic acyclovir for 21 days, after which we prescribed six months of oral treatment. Owing to social problems, a microbiological analysis of the mother was not performed.Case 3This infant was the twin sister of Case 2. She had no symptoms or skin lesions; however, given her epidemiological history, we requested microbiological tests. PCR for HSV-2 was positive in plasma and on the skin surface, but not in the CSF or the other peripheral samples. The physical examination, ophthalmologic examination, blood test, and imaging tests showed no abnormalities. The infant completed 14 days of intravenous treatment and started six months of oral acyclovir.Case 4The fourth case was a boy born at 34+2 weeks by unassisted vaginal delivery, who was admitted to the neonatal ward with respiratory distress. His mother had a fever during labor. At 10 days of life, he developed grouped vesicles on an erythematous base on his upper back, right upper limb, and scalp , during the perinatal period (85%), or during the postnatal period (10%) %, during. The mosIn recent years, studies conducted in various countries have shown an increase in genital HSV-1 infection, associated with changes in sexual behaviors and viral pathogenicity ,3. In SpIn our case series, 60% of the infants were girls, 60% were premature, and 60% were born after prolonged rupture of membranes. In all cases, delivery was vaginal and the mother had no lesions or history of genital herpes. The skin lesions observed in the neonates were grouped vesicles on an erythematous base, in different locations. HSV-2 infection predominated, and one infant had CNS herpes while the others had the skin/mucosal form . As none of the mothers had a history of genital herpes, we initially considered other diagnoses . The dermatologist played a key role in the early diagnosis of HSV infection.2 every eight hours for six months. The infant must be monitored for possible recurrence, sequelae, or drug-related adverse events [Most newborns exposed to HSV do not develop a disseminated infection, which calls into question the need for acyclovir treatment, given the association of this drug with neutropenia and nephrotoxicity in neonates . Howevere events ,6,7.To date, no cost-effective method of maternal HSV screening for reducing neonatal infection has been devised ,4. In adWe presented five cases of neonatal herpes in infants born to asymptomatic mothers. Neonatal herpes is a rare condition, normally acquired through vertical transmission in the peripartum period. Most of the infected neonates are born to mothers with no history of genital herpes. Hence, early diagnosis requires a high level of suspicion, and the dermatologist can play a key role in identifying typical skin lesions. Late diagnosis and treatment of this condition are associated with high morbidity and mortality. Current management strategies focus on the prevention of maternal infection and mother-to-child transmission, as well as early diagnosis and treatment of neonatal infection.


In 190 Ukrainian patients, the integrase gene sequence was also determined. The most reported route of transmission was heterosexual contact, followed by intravenous drug use, and men having sex with men (MSM). Several pre-existing drug resistance mutations were found against non-nucleoside reverse transcriptase inhibitors (RTIs) (n = 103), protease inhibitors (n = 11), and nucleoside analogue RTIs (n = 12), mostly polymorphic mutations or revertants. In the integrase gene, four strains with accessory integrase strand transfer inhibitor mutations were identified. Sub-subtype A6 caused most of the infections  in all three countries, including in MSM. In contrast to earlier studies, no clear clusters related to the route of transmission were identified, indicating that, within the region, the exchange of viruses among the different risk groups may occur more often than earlier reported.The HIV epidemic in Eastern Europe and Russia is large and not well-controlled. To describe the more recent molecular epidemiology of HIV-1, transmitted drug resistance, and the relationship between the epidemics in this region, we sequenced the  According to the HIV/AIDS surveillance in Europe 2021 report by the European Centre for Disease Prevention and Control/WHO Regional Office for Europe [Presumably, the HIV epidemic in this region was initiated by two separate introductions of the virus in intravenous drug users (IDUs) in Ukraine in the mid-1990s . The IDUUkraine has one of the largest epidemics in Europe. Much like the situation in Russia, the epidemic was initially driven by IDUs, but more recently, sexual intercourse has become the predominant mode of transmission. Successful prevention and treatment programs were set up, leading to the stabilisation of the epidemic since 2012 .The Russian national protocol recommends initiation of antiretroviral therapy (ART) to all patients with HIV infection, as soon as possible after diagnosis, regardless of CD4 count and viral load. The preferred first regimen consists of tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and dolutegravir (DTG), or TDF, emtricitabine (FTC) + DTG, and the alternative regimens are based on abacavir (ABC), 3TC, and DTG, or TDF, 3TC, and low dose (400 mg) efavirenz (EFV). In practice, due to the low cost of EFV, this drug is most often prescribed in the first regimen and replaced with DTG in case of toxic side effects. Ukraine and Georgia have adopted the WHO consolidated guidelines on antiretroviral therapy from 2021 , recomme2, and RPV resistance-associated mutations, has been reported to be associated with an increased risk of CVF at week 48 [Differences in the clinical outcome and in the pattern of drug resistance mutations (DRMs) have been reported between HIV-1 subtypes but the impact is still under investigation. The large noninferiority studies, ATLAS, ATLAS-2M, and FLAIR ,12,13, d week 48 . In Russprotease (PR) and reverse transcriptase (RT) sequences of 812 HIV-1 genomes isolated from patients from Ukraine, Russia (Moscow and Krasnodar), and Georgia, as well as 190 HIV-1 integrase (IN) sequences from Ukraine.To gain updated insights in the molecular epidemiology and the prevalence of DRMs to NNRTIs, nucleoside/nucleotide analogue RTIs (NRTIs), protease inhibitors (PIs), and INSTIs, we analysed the We analysed 812 HIV-1 PR and RT sequences from plasma samples donated by people living with HIV (PLWH) before initiation of ART, who were recruited consecutively at HIV clinics in Moscow and Krasnodar (Russia), Kyiv (Ukraine), and Tbilisi (Georgia). HIV-positive status was determined by double repeated enzyme immunoassay and confirmed by Western blot. The demographics, clinical data, and information about the untreated status were collected by physicians from the patient’s medical charts.From Russia, 364 sequences from the Moscow region and 56 from the Krasnodar region were included. These sequences were produced in the laboratories of the Moscow regional and Gamaleya centres between 6 August 2019 and 22 July 2020. From Georgia, 201 sequences were obtained in 2013–2017 at the Infectious Diseases, AIDS, and Clinical Immunology Research Center (IDACIRC), Tbilisi. From Kyiv, Ukraine, 191 plasma samples of therapy naïve patients were obtained between 18 December 2019 and 20 October 2020. Collection was coordinated by the Public Health Centre of the Ministry of Health of Ukraine (PHC). After collection, plasma samples from Ukraine were frozen and distributed to the Karolinska Institutet, Stockholm, Sweden, the University of Siena, Siena, Italy, or the University of Cologne, Cologne, Germany, for HIV-1 RNA purification and sequence analysis. IN sequences were determined and analysed in the Ukrainian samples only, since the IN sequencing methodology was not used in routine practice at the laboratories in Russia and Georgia and it was not possible to send samples to other laboratories, except from Ukraine.Ethical approvals were obtained by the local ethical committees in Moscow , Kyiv , and Tbilisi . Written informed consent was signed by the subjects involved. Material transfer agreement was obtained for the transport and use of plasma samples from Ukraine.The pol region from plasma HIV RNA was genotyped by Sanger sequencing by the ViroSeq HIV-1 Genotyping System  as per manufacturer’s instructions or in-house methods for Ukrainian samples . Sequencintegrase sequences a subtype D sequence (D.K0345) [Phylogenetic trees were generated and visualised using a local instance of the Nextstrain workflow . The locD.K0345)  was usedPatient gender, country and region, risk group and age, and virus subtype, DRMs, and variants were assigned using the ‘augur traits’ command. Ancestral nucleotide sequences were inferred with the ‘augur ancestral’ command with the ‘--inference’ parameter set to ‘joint’. Protein sequences were translated from the nucleotide sequence with the ‘augur translate’ command using an HIV-1 subtype B sequence (Accession D86068)  annotatePreliminary determination of the HIV-1 subtypes was carried out using online reference programs: HIV-1 COMET , the HIVSamples with the assumed subtypes CRF02_AG and CRF63_02A6 were further analysed using the Recombination Identification Program (RIP) ,33, sincFor the identification and detailed analysis (determination of recombination points) of potential recombinant forms of HIV-1, we used the following tools: jumping profile Hidden Markov Model (jpHMM) ,36,37, rThe median age of the 812 HIV-1-infected patients was 40 years  case in Krasnodar; interquartile range: 33–47 years) . The perThe subtype of the 812 patients was determined based on the PR and RT sequences. For the nonrecombinant viruses, the subtype, including the sub-subtype A6, was confirmed by phylogenetic analysis using the first 919 bases from the start of the PR open reading frame (ORF) A. In linThe next most common subtype was subtype B  in the Moscow region was identified, as well as a single case of infection with subtype D in Ukraine  have been previously identified in Russia. The CRF02_AG, which originated from Cameroon and came to Russia through Uzbekistan, and the CRF63_02A6, which is the result of a recombination between the Uzbek CRF02_AG and the sub-subtype A6 . We distMoreover, 14 unique recombinant viruses (URFs) were identified , of whicThe majority of the sequences analysed (87%) was of sub-subtype A6 (earlier named FSU-A), which initially spread by IDUs, first in Ukraine and later in other parts of the former Soviet Union. Our data suggest that this subtype is now responsible for most of the infections, not only among IDUs, but also by other routes of transmission .To explore the phylogenetic relation among sub-subtype A6 viruses from the different regions, we generated a phylogenetic tree in which the HIV-1 strains were coloured by region A. ClearlThe most likely transmission routes were inferred using the Nextstrain workflow B. Brieflp < 0.001). Phylogenetic analysis did not reveal a clear clustering of the circulating viruses to reference strains of the phylogenetically distinct B strains predominant in Western Europe, Thai genotype B strains, and/or the B strain that initially spread in Ukraine (Eastern European B or B-FSU)  C. This in = 8; 1.0%) and the K103N . In addition, the V106VI  and the K103KN  were identified. V106I is an NNRTI-selected mutation that also occurs in 1% to 2% of viruses from untreated persons, and K103N is a nonpolymorphic mutation selected in patients receiving nevirapine (NVP) and/or EFV [The study participants were included in the study before receiving any ART. The sequences were analysed using the Stanford University HIV Drug Resistance Database to identify pre-existing pDRMs . By far,d/or EFV .In total, eight different single NRTI mutations were observed  each in an individual patient. These mutations, when occurring in combinations, are mostly associated with reduced susceptibility to zidovudine (AZT), didanosine (ddI), and stavudine (d4T). Single mutations can reflect the process of reversion of resistant viruses to the wild phenotype. In addition, three phylogenetically unrelated viruses  with muln = 2), as well as the nonpolymorphic N88NS mutation, which is selected by NFV, ATV, and IDV (n = 1), were found. A D30N patient also had several NRTI  and NNRTI  DRMs.Several PI mutations were observed. The most common was at position M46 . These mutations are associated with reduced susceptibility to atazanavir (ATV), fosamprenavir (FPV), indinavir (IDV), lopinavir/ritonavir (LPV), and nelfinavir (NFV). Moreover, the nonpolymorphic D30N mutation, which is selected by NFV (n = 190). The sequences clustered well by the subtypes previously determined based on the PR and RT genes  infected with sub-subtype A6, a prevalence which is somewhat lower than previously obtained data for sub-subtype A6 (48–54%) . This man = 42; 5.2%). In addition, the E138EA  were identified. The E138A can be weakly selected by etravirine and RPV. We found it in 5.8% of the patients with an association with sub-subtype A6, which is in line with earlier report in sub-subtype A6, where the frequency was 4–8% depending on the region [protease ORF, the L33F (0.7%) polymorphism was found, which is similar to the frequency observed in other subtypes.The most common mutation was the E138A  of the cases in this region are still caused by the sub-subtype A6, which initiated the epidemic amongst IDUs in Ukraine in the mid-1990s, and later in other parts of the former Soviet Union. However, it should be noted that a change in the sub-subtype A6 distribution seems to have occurred during these years, since A6 is now dominating also among MSM. In addition, almost all URFs consisted of A6 and B sequences. Together with our finding that the two variants of subtype B were no longer concentrated in different transmission groups, the data suggest an increased spread and intermingling of virus strains between the groups.The most self-reported route of infection in our study was heterosexual contact (61%), followed by IDU 26%) and MSM (11%). These numbers are comparable to those gathered by the Russian agency Rospotrebnadzor, which estimated in 2020 that of the total number of PLWH in Russia , 64.9% were infected by heterosexual contact, 31.1% by IDU, and 2.8% by MSM [6% and MSIn our study, the most likely transmission routes were inferred from the phylogenetic analysis. Although this method is not as accurate as classic epidemiological investigation and is biased by sample size and differences in the observed periods, our conclusions are in line with historical observations. In line with earlier studies, our molecular epidemiology analysis gives support for the view that the A6 epidemic started in Ukraine and spread further in Eastern Europe ,4,5,6. TThe next most common subtype was subtype B (59/812 sequences). In the past, the archetypical IDU-B virus for Eastern Europe dominated in Ukraine, and the Western European B-variant in Russia. In contrast to earlier observations in the region, B-strains from Ukraine and Russia could not be distinguished by phylogeny in our study . The anaIn total, 40 recombinant viruses were identified, mostly the previously described CRF02_AG and CRF63_02A6, but also 14 URFs, which almost all (12/14) were between recombinants between A6 and B. The URFs appeared not to be spreading through the population, as only one new URF was found in two different patients from Ukraine. However, the number of involved subtypes, sub-subtypes, and CRFs recombining to create the URFs found in the present study are also in line with the spread of HIV-1 strains among individuals outside closed social networks.The HIV sequences presented in this study were obtained at diagnosis, before the initiation of ART. Several pre-existing DRMs were identified, most frequently (12.7%) NNRTI DRMs. However, the most common was E138A (5.2%), a polymorphic mutation common in sub-subtype A6, which seems not to affect the response to RPV. Interestingly, some of these mutations were probably in the process of reverting. This indicate that there was a selection pressure to revert making it less likely that the mutations occurred spontaneously. This may be due to either unreported earlier treatment with NNRTIs or transmitted virus with these mutations. Although less common, pre-existing DRMs against NRTIs and PIs were also found. These numbers are higher than those found in Russia between 1998 and 2017 (5.3%) . At that2, and RPV resistance-associated mutations has been reported to be associated with an increased risk of treatment failure [A high prevalence of the L74I mutation 93%) was found in the IN gene of Ukrainian A6 strains, consistent with earlier data ,44. A on failure ,9,10,11.3% was foOne of the limitations of this study is that the data came from four different sources with different sampling techniques and different data collection methods for self-reported transmission, as well as at five different laboratories. However, the study was performed within a larger collaborative study, the CARE study, in which we aimed at the harmonization of the approaches. MSM are often stigmatized and, as a consequence, they might have been underreported in our study, and thereby the distribution of subtypes across the different transmission categories may have not been fully correct. The patients were recruited during a similar time period in Ukraine, Moscow, and Krasnodar, but at earlier time points in Tbilisi. This is likely to have contributed to the fact that the Georgian strains were rooted at different locations in the phylogenetic tree, indicating introduction on multiple occasions at different timepoints since the start of the epidemic.In conclusion, our data suggest that the HIV-1 epidemic in Eastern Europe is still driven by regional variants, mainly the sub-subtype A6. However, the change in sub-subtype A6 distribution with increased prevalence among MSM, together with the evolution from the archetypical B strains, as well as a significant number of CRFs and URFs, mainly A6/B, suggest an increased spread of the virus and intermingling between the risk groups. The prevalence of pretreatment HIV-1 DRMs was relatively low (12.7%), and at least some of these mutations seem to be natural polymorphisms rather than transmitted drug resistance. However, the numbers are higher than those previously reported, indicating that there is still an important need to monitor transmission of DRMs before initiation of ART, and thus continuous surveillance is warranted.


P. lactiflora Pall. is a plant origin traditional medicine that has been widely used for the treatment of various diseases for more than a millennium in China, Japan and Korean. Paeoniflorin is a bioactive monomer extracted from P. lactiflora Pall. with anti-atherosclerosis effects. In this article, we comprehensively reviewed the potential therapeutic effects and molecular mechanism whereby paeoniflorin protects against atherosclerosis from the unique angle of inflammation and immune-related pathway dysfunction in vascular endothelial cells, smooth muscle cells, monocytes, macrophages, platelets and mast cells. Paeoniflorin, with multiple protective effects in atherosclerosis, has the potential to be used as a promising therapeutic agent for the treatment of atherosclerosis and its complications. We conclude with a detailed discussion of the challenges and future perspective of paeoniflorin in translational cardiovascular medicine.Epidemiological studies have shown that the incidence, prevalence and mortality of atherosclerotic cardiovascular disease (ASCVD) are increasing globally. Atherosclerosis is characterized as a chronic inflammatory disease which involves inflammation and immune dysfunction.  For example, inflammation of endothelial cells and macrophages, T-cell infiltration within atherosclerotic plaques, activation of Th17 cells, etc. . The curP. lactiflora is receiving increasing attention in the research and development of natural drugs. In China and North Asia, P. lactiflora is considered as one of the most well-known flowering plants and was cultivated as an ornamental plant throughout the Xia, Shang and Zhou dynasties  and red peony (Paeonia lactiflora), and the medicinal part is the dried root (23H28O11). In the following section, we will discuss in detail the pharmacological effects and mechanism of action of paeoniflorin in preventing atherosclerosis, focusing on inflammation and immunity-related effects and mechanisms.The discovery of new drugs from natural products has become a new approach to discovering the treatment of CVD including atherosclerosis. Some extracts or single units of natural drugs have shown enormous potential for the therapy of atherosclerosis, such as paeonol . As an oynasties . Its rooynasties .Paeonia ied root . As a Chied root . The mos22.1Paeonia has 52 species, mainly located in temperate regions of Europe, Asia, and North America . China is an important region for the origin, evolution, progression and diversification of the genus. The genus Paeonia is further classified into three sections, namely the Sect. Moutan, the Sect. Onaepia and the Sect. Paeonia. The Sect. Moutan is the most protologous taxon in the genus, with 11 species, all of them are shrubs or subshrubs, and native to China. There are two species of the Sect. Onaepia, both are herbaceous perennials and distributed only in western North America. The Sect. Paeonia is a relatively young and evolved taxon in the genus, and also the largest section, with about 22 species, all of which are herbaceous perennials .The genus Paeonia suffruticosa Andr. of the Sect. Moutan , Paeonia lactiflora Pall. of the Sect. Paeonia (distributed in Eurasia and northwestern Africa), and Paeonia veitchii Lynch. (In the western Sichuan and Qinghai-Tibet Plateau of China). In the Chinese Pharmacopoeia, Paeonia lactiflora Pall. or noted as P. lactiflora Pall.  is further subdivided into Paeoniae Radix Alba.  (Paeonia veitchii Lynch. (PVL) is classified as red peony (23H28O11), a water-soluble triterpene glycoside, is the major bioactive ingredient of PLP : e peony)  and Paeoed peony  in the Ced peony . Specified peony . In traded peony . Paeonift of PLP . The cheThe relevant quality test standards for paeoniflorin are detailed in the Chinese Pharmacopoeia , while paeoniflorin is approved as the only test index for quality control of PRA and PRR. The Chinese Pharmacopoeia provides for content determination according to high-performance liquid chromatography (HPLC) , in which the content of paeoniflorin in PRA shall not be less than 1.2% and the content of paeoniflorin in PRR shall not be less than 1.5%.2.223H28O11, Molecular Weight: 480.5, Density: 1.6 ± 0.1 g/cm3, Boiling Point: 683.3 ± 55.0°C at 760 mmHg, Flash point: 235.9 ± 25.0°C, Vapor pressure: 0.0 ± 2.2 mmHg at 25°C, Refractive index: 1.683, Polar Surface Area (PSA): 164.Paeoniflorin, oxy-9,10- dioxatetracyclodecan-2-yl]methyl benzoate, PubChem CID No. 442534, Molecular Formula: CThe solubility and oil-water partition coefficient of paeoniflorin in phosphate buffer solution with various pH values had certain effects on the solubility and oil-water partition coefficient, and the trends of solubility and oil-water partition coefficient were almost the same. In the range of pH 2.0-5.0, the solubility and oil-water partition coefficient of paeoniflorin increased with the rise of pH, and in the range of pH 5.0-6.8, the solubility and oil-water partition coefficient decreased with the increase of pH. The solubility and oil-water partition coefficient values of paeoniflorin were greatest in phosphate buffer solution at pH 5.0. Some data  showed t2.3Pharmacokinetic studies are an essential and crucial part for realizing the transition from laboratory to clinical application. In addition to helping to evaluate the efficacy and potential toxic actions of a medication, it also allows the exploration of interactions between different components. pharmacokinetic studies of paeoniflorin were first reported in 1985 . In the After absorption by enema in rats, paeoniflorin was quickly and extensively distributed in heart, liver, spleen, lung, kidney, brain, stomach and intestine, mainly in stomach (33.66 mg/ml), followed by intestine (19.57 mg/ml) and heart (11.70 mg/ml). The concentration of paeoniflorin in all tissues except liver and stomach peaked at 10 min, after which the levels of paeoniflorin decreased with time . In addiPaeoniflorin is mainly metabolized in the intestine, where intestinal bacteria first convert paeoniflorin to paeonolactone glucoside, which is then further metabolized through several pathways such as deglucose, de benzoyl, and quaternary ring cleavage rearrangement. These pathways gradually convert paeoniflorin into metabolites with smaller relative molecular mass and greater hydrophobicity for better absorption by the intestine . The maiin vivo and in vitro models. We will first present the effects and mechanisms of paeoniflorin on animal models of atherosclerosis and related vascular diseases, and later on the effects and molecular mechanisms of paeoniflorin on important cell types associated with the development and progression of atherosclerosis.In the process of drug metabolism described above, the paeoniflorin, as the main bioactive ingredient originating from PLP, may have potent efficacy against atherosclerosis and shows potential and far-reaching medicinal value. In the following sections, we will elaborate protective effects of paeoniflorin against atherosclerosis in both 33.1Dyslipidemia is one of the common clinical conditions in the progress of atherosclerosis, and high levels of triglycerides (TG) and total cholesterol (TC) are thought to play a very critical function in the progression of the disease . Hyperli-/- mice and examined the effects of paeoniflorin on plasma levels of TC, TG, free cholesterol (FC) and superoxide dismutase (SOD) in mice. Their results showed that paeoniflorin could dose-dependently elevate serum SOD activity, and significantly reduce TC, TG, and FC in serum. Xu et al.  and abnormal platelet aggregation and activation . Paeonif4.1The vascular endothelium is tightly connected to each other and performs various topological configurations in three dimensions, forming the inner wall of arteries, veins and capillaries and shaping itself into the largest distributive organ in the human body . It has Many external risk factors (such as hyperlipidemia and low/oscillatory shear stress in blood flow) can cause damage to endothelial cells, making their function impaired. During this process, secretion of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as a range of other adhesion molecules and/or interleukins, is significantly increased. In parallel, blood monocytes are recruited to the damaged endothelial surface and further differentiate into macrophages. These cells further secrete monocyte chemoattractant protein-1 (MCP-1), which attracts more monocytes and leads to the production of foam cells. The above process is accompanied by the release of inflammatory factors, which in turn leads to a prolonged local inflammatory response in the vasculature, exacerbating the initiation and development of atherosclerosis .Our literature review found that paeoniflorin can exert protective effects on endothelial cells through a variety of mechanisms, thereby exerting effects on atherosclerosis. These mechanisms targeting endothelial cells mainly include suppression of cellular damage, inhibition of oxidative stress, prevention of overproduction of inflammatory factors, improvement of cell adhesion function, regulation of cellular autophagy, and apoptosis Figure 54.1.1Endothelial cell dysfunction is a predominant characteristic of the initial progression of atherosclerosis . Under hIt has been reported in the literature that when endothelial cells are subjected to certain adverse stimuli, their actin may be disrupted, which in turn leads to an increase in permeability . There a4.1.2When the body is under oxidative stress, excess of free radicals and intracellular reactive oxygen species (ROS) are released, which can further lead to endothelial dysfunction . The mecAt the same time, the release of ROS further exacerbates the oxidation of LDL, leading to the formation of oxidized LDL, all of which can further damage the vascular endothelium. Both lactate dehydrogenase (LDH) and malondialdehyde (MDA) are the most widely used biomarkers when assessing oxidative stress damage as described above . To counIt is well known that the core processes of cellular energy metabolism are regulated by mitochondria, which are the most important place for most ATP production in the body . Increasvia a Bcl2-dependent mechanism , Toll-like receptor (TLR)-2 and TLR-4 . The combination of HMGB1 with its particular receptor leads to the activation of nuclear factor-κB (NF-κB), which further upregulates the expression and release of inflammatory factors (Lysophosphatidylcholine (LPC) is the major biologically active component of oxidized LDL and is an essential contributor to atherosclerotic activity . High mo factors , thereby factors  showed tIn numerous studies over the past decade, TAK1 has been clearly demonstrated to play a key role in a range of physiological and biochemical processes  . Yu et a4.1.4Cell adhesion molecules (CAMs) are membrane receptor glycoproteins whose main function is to achieve cell adhesion on the endothelial surface . CAMs arChemokines are a category of minor cytokines or proteins responsible for leukocyte recruitment, adhesion, and activation. They are classified into the CC, CXC, CX3C, and XC subfamilies . Among cChen et al.  found th4.1.52-induced hypoxia-inducible factor 1α (HIF-1α) accumulation and downregulated p53 and BNIP3 expression in endothelial cells, reducing apoptosis and improving endothelial cell viability in a dose-dependent manner. Because HIF-1α, the active subunit of HIF-1, can inhibit apoptosis by activating a variety of anti-apoptotic genes, it is associated with the development of human atherosclerosis  is one of the critical mechanisms leading to endothelial cell dysfunction . Endothe4.2In the pathological development of atherosclerosis, abnormal proliferation, migration and phenotypic conversion of vascular smooth muscle cells (VSMC) are prominent manifestations of VSMC dysfunction and are closely associated with the formation of neointima and the development of atherosclerosis . An incr4.2.1The follow-up activity after endothelial cell injury is abnormal VSMC proliferation and migration . Along wvia A2BAR has been proven to inhibit SMC proliferation . In addition, Wang et al.  and healing macrophages (M2) . Interfe4.4.2Closely linked to the aforementioned polarization of macrophages, polarized macrophages promote the secretion of various inflammatory factors, thereby exacerbating the response in the process of atherosclerosis . Cao et 4.4.3The regulation of macrophage survival and fate by paeoniflorin mainly covers three aspects: proliferation, apoptosis, and pyroptosis. Macrophage apoptosis is a non-negligible feature of atherosclerotic plaque progression, especially in early stages of the lesion, and macrophage apoptosis greatly inhibits the progression of atherosclerotic plaque . It has Pyroptosis is an inflammatory form of programmed cell death activated by the caspase family  and accompanied by cell swelling, osmotic lysis, and activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory vesicles . Excessi4.4.4Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, peripheral artery disease, cerebrovascular disease and aortic atherosclerosis. In each vascular bed, migration and aggregation of macrophages help to maintain the inflammatory local reaction, spread plaque development and facilities thrombosis . Zhang eFoam cell formation and accumulation are important markers of early atherosclerotic lesions, and previous studies have shown that their formation within the intima is mainly due to impaired cholesterol efflux or excessive uptake of ox-LDL by macrophages . The con4.4.52+ influx and triggering subsequent inhibition of NF-κB and P38MAPK activation. Kim et al. , platelets are activated, trigger a coagulation cascade effect that leads to the formation of arterial thrombi. These thrombi may lead to vascular obstruction and eventually to life-threatening acute coronary events . In contNgo et al.  showed tin vivo, demonstrating a good antithrombotic effect. This conclusion was also confirmed by Fang et al. based on Swiss mice  has been gradually acknowledged. Mast cells interact with the surrounding microenvironment, and release a series of bioactive mediators to specifically recognize and respond to various stimuli . Recentlin vitro DNP-BSA-induced mast cell degranulation, and inhibited IgE-mediated histamine release and calcium inward flow. Paeoniflorin also downregulates the phosphorylation levels of key kinases such as ERK1/2, P38 and Phospholipase C (PLC), and reduces IgE-mediated release 5-hydroxytryptamine , MCP-1, IL-8, and TNF-α, suppressed the local inflammatory response. Meanwhile, they found through molecular docking experiments that paeoniflorin may be a potential FcRI ligand.IgE (FcRI) on the surface of mast cells can cross-link with high-affinity receptors for immunoglobulin E (IgE) to secrete granules that are filled with inflammatory mediators and can induce a variety of biological activities . A study2+ concentration in mast cells, while paeoniflorin can regulate local inflammation through MAPK and PI3K/Akt pathways to regulate local inflammation. In addition, paeoniflorin can regulate mast cell proliferation and apoptosis by modulating NF-κB activity. Thus, the stabilizing effect of paeoniflorin on mast cells appears to be a promising new mechanism for the inhibition of atherosclerosis  and increase levels of “Positive cholesterol” (such as HDL), thereby regulating lipid metabolism and playing a critical role in inhibiting the development and progression of atherosclerosis  cannot be clearly explained yet. For some cellular effects, current studies have only observed macroscopic results, e.g., cell migration, aggregation, foaming, etc., and the molecular mechanisms and gene targets behind them have not been studied in depth. Previous studies have found that some of the pharmacological effects of paeoniflorin are achieved possibly through: (1) regulation of the inflammatory response of immune cells through the balance of Th17 and Treg; (2) acts on HLA-DR and CD80 to regulate antigen presentation in the innate immunity function; (3) activating the LXR pathway, which regulates cholesterol metabolism and thus exerting anti-atherosclerotic effects; (4) regulates the inflammatory response of relevant cells and maintains cellular homeostasis through NF-kB, JNK, and ERK signaling pathways; (5) regulation of cell recruitment and adhesion by acting on ICAM-1 and VCAM-1 targets; (6) modulating the survival and fate of atherosclerosis-associated cells by acting on Bcl-2 and Bax targets; (7) regulation of relevant cellular phenotypic changes through STAT and TLR targets; (8) plays an important role against cellular oxidative stress through NO and SOD.5.2The wide variety of actions of paeoniflorin fully demonstrates that it can play an essential role in the prevention and treatment of atherosclerosis and has a large potential for clinical applications. Drug similarity is a very important aspect in translational medicine, and we examined the drug similarity of paeoniflorin through the SwissADME website  and LipiThe oral bioavailability ensures the effective drug concentration achieved physiologically . As we pin vivo to exert pharmacological effects. Compared to paeoniflorin, the pharmacokinetics of CP-25 (in rats) reflects higher lipid solubility, resulting in superior absorption and distribution, while it has lower clearance and can stay in the body for longer periods of time, thus obtaining higher bioavailability  is a new ester derivative of paeoniflorin developed by Wei et al. . It is mlability . The devlability  and carrlability  also gre5.3-/- and LDLR-/- mice, that are currently the most mainstream animal models of atherosclerosis. However, there is a lack of validated studies in other large animal models, such as rabbit, quail, canines, porcine and monkeys.Our review found that the protective effect of paeoniflorin against atherosclerosis has only been studied in rodents (mainly mice and rats). There are very few studies based on APOEHowever, until now, we still lack clinical data on paeoniflorin in CVD patients. Therefore, there is an urgent need for a multicenter, large-scale randomized design, placebo-controlled and blinded design clinical trial to evaluate the efficacy and safety of paeoniflorin based on a clinical perspective.5.4Two risk factors, hypertension and diabetes, have been relatively well studied. Relevant studies in epidemiology have shown that modifiable risk factors such as smoking, unhealthy diet, obesity and lack of physical activity, as well as underlying genetic factors, contribute to atherosclerosis . NumerouIn recent decades, the research of botanical drugs has made many remarkable achievements. The bioactive ingredients of some traditional herbal medicines have been developed into new drugs for clinical applications. Through literature review, we found that paeoniflorin can exert anti-atherosclerotic effects through multiple pathways and mechanisms, as well as possible synergistic therapeutic effects for some accompanying other chronic conditions , all of which highlight the advantages of paeoniflorin as a potential cardiovascular drug for further clinical development.Conceptualization: WY, SX, HY. Write: WY. Revise: WY, SX, II, XH, HY. All authors contributed to the article and approved the submitted version.


A long-term complication of obesity is the development of type 2 diabetes (T2D). Patients with T2D have been described as having epigenetic modifications. Epigenetics is the post-transcriptional modification of DNA or associated factors containing genetic information. These environmentally-influenced modifications, maintained during cell division, cause stable changes in gene expression. Epigenetic modifications of T2D are DNA methylation, acetylation, ubiquitylation, SUMOylation, and phosphorylation at the lysine residue at the amino terminus of histones, affecting DNA, histones, and non-coding RNA. DNA methylation has been shown in pancreatic islets, adipose tissue, skeletal muscle, and the liver. Furthermore, epigenetic changes have been observed in chronic complications of T2D, such as diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. Recently, a new drug has been developed which acts on bromodomains and extraterminal (BET) domain proteins, which operate like epigenetic readers and communicate with chromatin to make DNA accessible for transcription by inhibiting them. This drug  is being studied to prevent major adverse cardiovascular events in people with T2D, low HDL cholesterol, chronic kidney failure, and recent coronary events. This review aims to describe the relationship between obesity, long-term complications such as T2D, and epigenetic modifications and their possible treatments. The current view of epigenetics considers DNA modifications or associated factors with information content other than the DNA sequence itself. These modifications are maintained during cell division, influenced by the environment, and cause stable changes in gene expression. Hence, the epigenetic definition is now contemplated more dynamically than when Conrad Waddington first described it as the science that analyzes the link between genes and the events that give birth to the phenotype . AcknowlThe first hypothesis suggesting the role of epigenetics in the development of metabolic diseases described how early life events affect health outcomes in adulthood. However, this field of knowledge has reached enormous relevance with new laboratory technologies, especially with regard to epigenetic marks . The sigGenetic and external factors are then involved in many diseases, and, in some cases, environmental changes result in adaptive epigenetic changes. These changes are heritable and can be altered in response to developmental signals or environmental exposures associated with adverse health conditions, although it is challenging to establish a causal role ,13. SomeIn the same way, there is evidence that alterations in DNA methylation can contribute to the increased prevalence of obesity and both type 1 (T1D) and T2D . VisceraPatients with obesity have been shown to have epigenetic alterations associated with CpG methylation and the expression pattern of miRNAs at all stages of adipocyte differentiation, affecting their lipid metabolism and insulin sensitivity in adipose tissue and causing β-cell dysfunction ,24. ThesVariabilities in DNA methylation at the HIF3A locus have been reported in the blood cells and adipose tissue of people with obesity . ReprogrAs described above, histone modifications are another epigenetic process linked to obesity. Among the histones related to TNF-α and IL6 is H3K4, and these proinflammatory cytokines are involved in insulin signaling . miRNAs The permanence of genetic and environmental factors, such as a high-fat diet, a sedentary lifestyle, or toxic agent exposure, leads to chronic metabolic inflammation, which can cause hyperglycemia, IR, β-cell dysfunction, and as a consequence, T2D ,31. ObesSeveral genes are involved in the presence of T2D and are associated with obesity, as shown by the GWAS studies  . Among tThe incidence of T2D in the world is proliferating, with it becoming a public health problem that represents enormous costs for individuals who suffer from it and society ,38. The Previously it was mentioned that the main mechanisms involved in the epigenetic modification of T2D are histone modifications, DNA methylation/demethylation within CpG islands, and non-coding RNA . A vitalDNA methylation also causes alterations in pancreatic islets, adipose tissue, skeletal muscle, and the liver . DNA metIn 2013, a complete genome sequencing identified 25,820 differentially methylated regions (DMRs) covering the promoters of PDX1, TCF7L2, and adenylate cyclase 5 (ADCY5) . In 2014Acetylation and methylation at the amino-terminal lysine residue is the primary mechanism of epigenetic modification of histones in muscle, the clinical result of which leads to IR being expressed in two ways: in peripheral use  and hepatic noninhibition of gluconeogenesis; there is hepatic resistance to inhibit this last process . The conThe stability of gene expression occurs due to the balance between the histone acetylation and deacetylation processes without affecting DNA sequencing ,49. HistAnother mechanism that regulates gene expression at both the transcriptional and post-transcriptional levels is ncRNA . miRNAs The importance of intensive glucose control in diabetic patients is challenging. Complications in this pathology involve microangiopathic, macroangiopathic, musculoskeletal, neurological, and other events . In thisA multicenter clinical trial enrolled 500 participants with a mean age of 26.4 +/− 2.8 years and a diagnosis of youth-onset T2D 13.3 +/− 1.8 years ago. This observational follow-up study (performed from 2011 to 2020) was conducted in two phases; at the end of the second phase of follow-up, the trial pointed out that the risk of micro- and macrovascular complications increased over time and that the risk factors for the development of such complications were hyperglycemia, minority race, hypertension, and dyslipidemia .In 499 participants in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study using blood DNA, the association between methylation of DNA in CpG and HbAb1 was demonstrated. These results suggested that DNA methylation in CpG may play an essential role in hyperglycemia and complications caused by metabolic memory (it negatively increases long-term complications if there was a previous period of hyperglycemia) . In anotMicroangiopathies result from the thickening of the basement membrane and glycosylation of structures resulting from T2D. Diabetic nephropathies (DNe) are associated with glomerulosclerosis, caused by an inflammatory process secondary to hyperglycemia. In addition, it is characterized by the presence of albuminuria and a decrease in the glomerular filtration rate generated by apoptosis and functional loss or alteration of podocytes, endothelial cells, and mesangial cells ,60.DNA methylation in cytosine in the CpG island is present in renal damage in diabetic patients. This methylation process is mediated by DNMT1 and DNMT3a/3b . In an eHistone modification is another process that plays an essential role in the epigenetics of DNe and metabolic memory. These processes are mediated by hyperglycemia and in response to the presence of transforming growth factor-beta (TGF-β), triggering active methylation of histones such as H3K4, H3K27, and H3K9 ,64.2 = 0.902; p < 0.0001), miRNA124 with synaptopodin, uNAG, UACR, and eGFR , and miRNA21 with podocalyxin, uNAG, UACR, and eGFR  [Multiple miRNAs regulate the characteristics of DNe. In a study carried out on 68 patients with T2D and 11 healthy subjects, whose objective was to establish a relationship between podocyte damage and proximal tubule dysfunction, it was shown that there is an association between podocyte damage and impaired proximal tubule function and excreted miRNA. Among the multiple regression models that showed correlation were miRNA192 with synaptopodin, uNAG, and eGFR (R 0.0001) . Togethe 0.0001) . A cross 0.0001) .Another factor related to the severity and presence of DNe is S-adenosylhomocysteine (SAH), a product of DNA methylation and histone modification . AlthougDiabetic retinopathy (DR) is another microvascular alteration in patients with T2D, whose hyperglycemic state causes progressive and irreversible blindness, even in normoglycemic diabetic states . In addiThree situations may occur: (a) retinal neovascularization with vitreous hemorrhage and retinal detachment, called proliferative DR; (b) a process without neovascularization called non-proliferative DR with the formation of microaneurysms and subtle dilation of retinal vessels, generally in the early stages; and (c) neurodegeneration that causes neuroapoptosis, resulting in the death of retinal ganglion cells, glial alteration, and abnormalities in the retinal pigment layer .Recent research on the molecular mechanisms of epigenetics has revealed that oxidative stress is the promoter of these alterations in photoreceptor cells since they are rich in easily oxidized polyunsaturated fatty acids. Therefore, the epigenetic changes caused by hyperglycemia lead to an excessive accumulation of cytosolic reactive oxygen species (ROS)  due to tp < 0.01 [Five established pathways produce metabolic abnormalities due to oxidative damage: the increased flow of the polyol pathway  and the hexosamine pathway, hyperactivation of protein kinase C isoforms and angiotensin II, and the concentration of advanced glycation end products (AGEs) ,74. In ap < 0.01 .p = <0.05, establishing DR in the short term [DR patients may have hyperlipidemia associated with hyperglycemia that further increases Rac1–Nox2–ROS activation, causing progressive mitochondrial damage with the loss of capillary cells , cell aport term .Diabetic neuropathy is a very complex complication of T2D that can appear as diabetic peripheral neuropathy (DPN), diabetic autonomic neuropathy, or uremic neuropathy ,79,80. Dp = 0.041) [miRNAs also play a role in the pathogenesis of diabetic neuropathy as there are genes that are expressed in the brain and peripheral neuronal tissue . In 2017= 0.041) . Subsequ= 0.041) . On the = 0.041) . Another= 0.041) .p = <0.0005), two of which (MTHFSD and LMAN2L) were partially non-coding. In addition, the TUBA4B gene was overexpressed in the DPN samples; however, this study has inconsistent results [LncRNA has been considered the epigenetic mechanism that mediates this damage . In 2018 results , and, li results .Epigenetic factors and signal transduction pathways contribute significantly to DM; they affect gene expression and phenotypes associated with DNe. Life-threatening complications, including DNe and significant cardiovascular problems, denote the need for a more molecular mechanism to clarify better therapies for DM . FurtherRecently, data proposed a detailed mechanism related to modifying gene expression to manipulate the etiology of T2D and its complications. One of the essential issues of diabetic stimuli triggers some epigenetic modifications to be the basis of metabolic memory ,91,92. NHyperglycemia and its related complications are the main objectives for conventional management, including diet, insulin, and/or anti-diabetic drugs. Their correct management favors patients; however, these traditional medications have substantial side effects, such as lactic acidosis, severe hypoglycemia, cardiovascular problems, and urinary tract infections . AlthougEpigenetic modulators are a brand-new drug therapy that modifies gene transcription ; BET domThe leading causes of CKD are T2D and hypertension, accounting for more than 50% of the cases . DM and The placebo’s main results summarized that patients with CKD presented with acute coronary syndrome and myocardial infarction; the proportion without ST elevation was more significant in the placebo group. The main laboratory findings for apabetalone treatment were a decrease in serum alkaline phosphatase compared to the placebo group, especially in participants with CKD, and a modest increase in HDL cholesterol . ParticiApabetalone was related to a declining hazard for MACE and fewer hospitalizations for heart failure . ApabetaVarious epigenetic factors are involved in developing T2D, such as DNA methylation, which causes alterations in pancreatic islets, adipose tissue, skeletal muscle, and the liver. Many genes are implicated in deregulating insulin secretion in pancreatic β cells and inducing proinflammatory signals. Other epigenetic alterations in visceral adipose tissues and the liver favor IR. At the same time, acetylation and methylation of histones in muscle are expressed in two ways: in the peripheral insulin use and the hepatic noninhibition of gluconeogenesis, and, consequently, there is an increase in fasting blood glucose that causes greater stimulation of the islet.Epigenetic modifications can also decrease the glucose transporter’s expression and alter glucose’s movement into the cell. Histone acetylation and deacetylation processes can also induce pancreatic β cell death or inactivation of transporters at the muscle level, causing hyperinsulinemia and hyperglycemia.Currently, miRNAs act on the target cells responsible for hepatic glycogen metabolism and insulin secretion, causing destruction and apoptosis of β cells and IR in the peripheral organs. Therefore, the two general epigenetic modifications and ncRNA stated in this review have been described at different levels of glucose metabolism and IR, and so in T2D.Some studies have found that epigenetic modifications in DM and microvascular complications that affect small blood vessels are also related. DNA methylation and histone modifications are processes of enormous significance in the epigenetics of DNe and metabolic memory. These processes are mediated by hyperglycemia. Multiple miRNAs and LncRNA regulate the characteristics of DNe, especially related to podocyte and proximal tubule injury. Research in animals has shown that SAH, a product of DNA methylation and histone modification, is related to the presence and severity of DNe. LncRNAs regulate vascular changes in DNE. On the other hand, DPN has been linked to miRNAs and LncRNA. These two epigenetic factors have been considered the mediating epigenetic mechanisms responsible for this complication of T2D.Research in therapeutic advances in this area has been published with drugs that alter those mechanisms. In particular, in CVD and T2D, BET protein inhibitors are being studied in clinical trials due to their property to modify the disease-driven cellular response in people with the probability of CVD and CKD. The BD2-selective BET inhibitor apabetalone has been used in trials as a therapy for epigenetic changes, and it has shown that it might decrease cardiovascular risk in individuals with CKD, T2D, and recent acute coronary syndrome and also might modulate the pathways associated with inflammation, vascular calcification, and thrombosis, but the mechanism underlying this benefit is still unclear. Although the reported evidence between the association of complications related to obesity and diabetes and epigenetic modifications is unclear as to whether they are a cause or a consequence, it would seem that treatment with drugs that modulate said modifications could be a promising therapy. The results are inconsistent with subgroups of patients and post-hoc results, but much still needs to be explored in the future.