PEI functionalized cell membrane for tumor targeted and glutathione responsive gene delivery.

Polyethylenimine (PEI) is a broadly exploited cationic polymer due to its remarkable gene-loading capacity. However, the high cytotoxicity caused by its high surface charge density has been reported in many cell lines, limiting its application significantly. In this study, two different molecular weights of PEI (PEI10k and PEI25k) were crosslinked with red blood cell membranes (RBCm) via disulfide bonds to form PEI derivatives (RMPs) with lower charge density. Furthermore, the targeting molecule folic acid (FA) molecules were further grafted onto the polymers to obtain FA-modified PEI-RBCm copolymers (FA-RMP25k) with tumor cell targeting and glutathione response. In vitro experiments showed that the FA-RMP25k/DNA complex had satisfactory uptake efficiency in both HeLa and 293T cells, and did not cause significant cytotoxicity. Furthermore, the uptake and transfection efficiency of the FA-RMP25k/DNA complex was significantly higher than that of the PEI25k/DNA complex, indicating that FA grafting can increase transfection efficiency by 15 %. These results suggest that FA-RMP25k may be a promising non-viral gene vector with potential applications in gene therapy.

Combination of metformin with liraglutide in treating HAIR-AN syndrome in children: A case report and literature review. / 二甲双胍联合利拉鲁肽治疗儿童HAIR-AN综合征1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome is a special and rare subtype of polycystic ovarian syndrome. It can lead to hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) accompanied by acne, hirutism, irregular menstruation, and other androgen excess symptoms. A case of pediatric HAIR-AN syndrome with severe AN was admitted to the Department of Endocrinology, China-Japan Friendship Hospital. The patient's clinical manifestations, laboratory data, imaging features, and gene sequencing were analyzed, and the patient was diagnosed with pediatric HAIR-AN syndrome. Obesity, IR, hyperglycemia, menstrual disorder, and AN were significantly improved after treating with metformin and liraglutide. HAIR-AN syndrome occurs in various forms. When the patient appears unexplained acanthosis nigricans and menstrual disorders, the disease should be considered possible. Early diagnosis and symptomatic supportive treatment can improve the quality of life.

Preparation of PEI-modified nanoparticles by dopamine self-polymerization for efficient DNA delivery.

Achieving efficient and safe gene delivery is of great significance to promote the development of gene therapy. In this work, a polydopamine (PDA) layer was coated on the surface of Fe3 O4 nanoparticles (NPs) by dopamine (DA) self-polymerization, and then magnetic Fe3 O4 NPs were prepared by the Michael addition between amino groups in polyethyleneimine (PEI) and PDA. The prepared Fe3 O4 NPs (named Fe3 O4 @PDA@PEI) were characterized by Fourier transform infrared (FTIR), atomic force microscopy (AFM), and scanning electron microscopy (SEM). As an efficient and safe gene carrier, the potential of Fe3 O4 @PDA@PEI was evaluated by agarose gel electrophoresis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, fluorescence microscopy, and flow cytometry. The results show that the Fe3 O4 @PDA@PEI NPs are stable hydrophilic NPs with a particle size of 50-150 nm. It can efficiently condense DNA at low N/P ratios and protect it from nuclease degradation. In addition, the Fe3 O4 @PDA@PEI NPs have higher safety than PEI. Further, the Fe3 O4 @PDA@PEI/DNA polyplexes could be effectively absorbed by cells and successfully transfected and exhibit higher cellular uptake and gene transfection efficiency than PEI/DNA polyplexes. The findings indicate that the Fe3 O4 @PDA@PEI NPs have the potential to be developed into a novel gene vector.

Development and assessment of diabetic nephropathy prediction model using hub genes identified by weighted correlation network analysis.

Diabetic nephropathy (DN) is one microvascular complication of diabetes. About 30% of diabetic patients can develop DN, which is closely related to the high incidence and mortality of heart diseases, and then develop end-stage renal diseases. Therefore, early detection and screening of high-risk patients with DN is important. Herein, we explored the differences of serum transcriptomics between DN and non-DN in type II diabetes mellitus (T2DM) patients. We obtained 110 target genes using weighted correlation network analysis. Gene Ontology enrichment analysis indicates these target genes are mainly related to membrane adhesion, alpha-amino acid biosynthesis, metabolism, and binding, terminus, inhibitory synapse, clathrinid-sculpted vesicle, kinase activity, hormone binding, receptor activity, and transporter activity. Kyoto Encyclopedia of Genes and Genomes analysis indicates the process of DN in diabetic patients can involve synaptic vesicle cycle, cysteine and methionine metabolism, N-Glycan biosynthesis, osteoclast differentiation, and cAMP signaling pathway. Next, we detected the expression levels of hub genes in a retrospective cohort. Then, we developed a risk score tool included in the prediction model for early DN in T2DM patients. The prediction model was well applied into clinical practice, as confirmed by internal validation and several other methods. A novel DN risk model with relatively high prediction accuracy was established based on clinical characteristics and hub genes of serum detection. The estimated risk score can help clinicians develop individualized intervention programs for DN in T2DM. External validation data are required before individualized intervention measures.

Flavonoid-containing supplements for preventing acute respiratory tract infections: A systematic review and meta-analysis of 20 randomized controlled trials.

BACKGROUND: This systematic review and meta-analysis was conducted to investigate the efficacy and safety of flavonoid-containing supplements in preventing acute respiratory tract infection (ARTI). METHODS: Randomized controlled trials (RCTs) investigating the effects of flavonoid-containing supplements on ARTI prevention in the aspects of ARTI incidence, mean ARTI sick days, symptoms, bio-immune markers, and adverse effects were searched in 5 databases. Data were searched from inception to November 26, 2021. Stata 16.0 was used to perform the meta-analysis. RESULTS: Twenty RCTs (n = 4521) were included in this systematic review and meta-analysis. Pooled results showed that in the flavonoid-containing supplement group, the ARTI incidence and mean ARTI sick days were significantly decreased compared to those in the control group (RR = 0.81, 95% CI: 0.74-0.89, p < 0.001; WMD = -0.56, 95% CI: -1.04 to -0.08, p = 0.021; respectively). In 8 RCTs, flavonoids were singly used for interventions, ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.85, 95% CI: 0.72-1.00, p = 0.047). In ten RCTs, flavonoid-containing mixtures were applied for interventions, and ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.79, 95% CI: 0.71-0.89, p < 0.001). Furthermore, the ARTI incidence and mean ARTI sick days were significantly decreased in the experimental group compared to those in the control group in the flavan-3-ols subgroup (RR = 0.79, 95% CI: 0.67-0.92, p = 0.002; WMD = -2.75, 95% CI: -4.30 to -1.21, p < 0.001; respectively) and the multiple subclasses subgroup (RR = 0.75, 95% CI: 0.63-0.88, p = 0.001; WMD = -0.56, 95% CI: -1.11 to -0.01, p = 0.046; respectively). However, the bio-immune markers including interleukin-6, hypersensitive-c-reactive-protein, tumor necrosis factor-α, and interferon-γ did not differ between the flavonoid group and the control group. Moreover, in the flavonoid-containing supplement group, the incidence of adverse reactions did not increase compared to that in the control group (RR = 1.16, 95% CI: 0.78-1.73, p = 0.469). CONCLUSIONS: This systematic review and meta-analysis showed that flavonoid-containing supplements were efficacious and safe in preventing ARTIs. The most important limitations result from the small number of trials, poor quality of some included RCTs, differences in the composition and types of interventions, principal subclasses of flavonoids, methods of administration, and methodology. Moreover, only a few RCTs conducted independent verification of the flavonoid supplements used in the trial in terms of purity and potency, which may lead to a potential source of bias. Thus, larger and better-designed studies are needed to further verify this conclusion.

Flavonoids for Treating Viral Acute Respiratory Tract Infections: A Systematic Review and Meta-Analysis of 30 Randomized Controlled Trials.

BACKGROUND: This meta-analysis aimed to investigate the efficacy and safety of flavonoids in treating viral acute respiratory tract infections (ARTIs). METHODS: Randomized controlled trials (RCTs) were entered into meta-analyses performed separately for each indication. Efficacy analyses were based on changes in disease-specific symptom scores. Safety was analyzed based on the pooled data from all eligible trials, by comparing the incidence of adverse events between flavonoids and the control. RESULTS: In this study, thirty RCTs (n = 5,166) were included. In common cold, results showed that the flavonoids group decreased total cold intensity score (CIS), the sum of sum of symptom intensity differences (SSID) of CIS, and duration of inability to work vs. the control group. In influenza, the flavonoids group improved the visual analog scores for symptoms. In COVID-19, the flavonoids group decreased the time taken for alleviation of symptoms, time taken for SARS-CoV-2 RT-PCR clearance, the RT-PCR positive subjects at day 7, time to achievement of the normal status of symptoms, patients needed oxygen, patients hospitalized and requiring mechanical ventilation, patients in ICU, days of hospitalization, and mortality vs. the control group. In acute non-streptococcal tonsillopharyngitis, the flavonoids group decreased the tonsillitis severity score (TSS) on day 7. In acute rhinosinusitis, the flavonoids group decreased the sinusitis severity score (SSS) on day 7, days off work, and duration of illness. In acute bronchitis, the flavonoids group decreased the bronchitis severity score (BSS) on day 7, days off work, and duration of illness. In bronchial pneumonia, the flavonoids group decreased the time to symptoms disappearance, the level of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). In upper respiratory tract infections, the flavonoids group decreased total CIS on day 7 and increased the improvement rate of symptoms. Furthermore, the results of the incidence of adverse reactions did not differ between the flavonoids and the control group. CONCLUSION: Results from this systematic review and meta-analysis suggested that flavonoids were efficacious and safe in treating viral ARTIs including the common cold, influenza, COVID-19, acute non-streptococcal tonsillopharyngitis, acute rhinosinusitis, acute bronchitis, bronchial pneumonia, and upper respiratory tract infections. However, uncertainty remains because there were few RCTs per type of ARTI and many of the RCTs were small and of low quality with a substantial risk of bias. Given the limitations, we suggest that the conclusions need to be confirmed on a larger scale with more detailed instructions in future studies.Systematic Review Registration: inplasy.com/inplasy-2021-8-0107/, identifier: INPLASY20218010.

[Effectiveness analysis of lateral condyle sliding osteotomy in total knee arthroplasty for the treatment of lateral femoral bowing deformity].

OBJECTIVE: To investigate the effectiveness of lateral condyle sliding osteotomy (LCSO) in total knee arthroplasty (TKA) for the treatment of lateral femoral bowing deformity. METHODS: The clinical data of 17 patients with lateral femoral bowing deformity treated by LCSO during TKA between July 2018 and July 2020 was retrospectively analysed. There were 3 males and 14 females, with an average of 63.2 years (range, 58-68 years). The etiology of lateral femoral bowing deformity included 12 cases of femoral developmental deformity and 5 cases of femoral fracture malunion. Kellgren-Lawrence classification of knee osteoarthritis was 4 cases of grade Ⅲ and 13 cases of grade Ⅳ. The preoperative hip-knee shaft was 9.5°-12.5° (mean, 10.94°). The disease duration was 3-25 years (mean, 15.1 years). The mechanical lateral distal femur angle (mLDFA), hip-knee-ankle angle (HKA), and mechanical axis deviation (MAD) of the distal femur were measured before operation and at last follow-up to evaluate the correction of extra-articular deformities in the joints and the recovery of mechanical force lines of the lower extremities. The knee society score (KSS) knee score and function score, visual analogue scale (VAS) score, knee joint range of motion (ROM) were used to evaluate effectiveness. The knee varus/valgus stress test and osteotomy healing by X-ray films were performed to evaluate the joint stability and the safety of LCSO. RESULTS: All incisions of the patients healed by first intention after operation, and there was no early postoperative complication such as infection of the incision and deep vein thrombosis of the lower extremities. All 17 patients were followed up 12-36 months, with an average of 23.9 months. The osteotomy slices all achieved bony healing, and the healing time was 2-5 months, with an average of 3.1 months. After operation, the knee varus/valgus stress tests were negative, and there was no relaxation and rupture of the lateral collateral ligament, instability of the knee joint, loosening, revision and infection of the prosthesis occurred. At last follow-up, mLDFA, HKA, MAD, knee ROM, VAS score, KSS knee score and function score significantly improved when compared with preoperative ones ( P<0.05). CONCLUSION: LCSO is effective and safe in TKA with lateral femoral bowing deformity. Extra-articular deformities are corrected intra-articularly. The mechanical force line and joint balance of the lower extremities can be restored simultaneously in an operation.

Immune-Related Multiple-Organs Injuries Following ICI Treatment With Tislelizumab in an Advanced Non-Small Cell Lung Cancer Patient: A Case Report.

Immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors (ICIs) can affect almost any organ systems. Multiple-organs irAEs are a rare occurrence which makes its management and treatment very challenging. This is a case report of a 71-year-old man with advanced non-small cell lung cancer (NSCLC) who developed multiple-organs irAEs (lung, muscle, myocardium, liver, and pituitary) after a single cycle (21 days) of the BGB-A317 (Tislelizumab). After more than two months of immunosuppression treatment with glucocorticoids, the tumor and inflammatory lesions in the lung were reduced. The levels of serum creatase, cardiac troponin T (TNT), and hepatic transaminase were also reduced. Four months after the termination of ICI therapy, the lung tumor reappeared in the previous site. This rare case report supplies several experiences in the management of multiple-organs irAEs, including full-scale monitoring of immunological indicators, early differential diagnosis, and prompt glucocorticoid therapy. This patient was not a candidate for the ICI re-challenge therapy due to the number and seriousness of irAEs. Multiple-organs irAEs add complexity to the management, and additional research is needed to develop optimal therapeutic guidelines.

Effect of Extracellular Matrix Coating on Cancer Cell Membrane-Encapsulated Polyethyleneimine/DNA Complexes for Efficient and Targeted DNA Delivery In Vitro.

Polyethyleneimine (PEI) has a good spongy proton effect and is an excellent nonviral gene vector, but its high charge density leads to the instability and toxicity of PEI/DNA complexes. Cell membrane (CM) capsules provide a universal and natural solution for this problem. Here, CM-coated PEI/DNA capsules (CPDcs) were prepared through extrusion, and the extracellular matrix was coated on CPDcs (ECM-CPDcs) for improved targeting. The results showed that compared with PEI/DNA complexes, CPDcs had core-shell structures (PEI/DNA complexes were coated by a 6-10 nm layer), lower cytotoxicity, and obvious homologous targeting. The internalization and transfection efficiency of 293T-CM-coated PEI70k/DNA capsules (293T-CP70Dcs) were 91.8 and 74.5%, respectively, which were higher than those of PEI70k/DNA complexes. Then, the internalization and transfection efficiency of 293T-CP70Dcs were further improved by ECM coating, which were 94.7 and 78.9%, respectively. Then, the internalization and transfection efficiency of 293T-CP70Dcs were further improved by ECM coating, which were 94.7 and 78.9%, respectively. Moreover, the homologous targeting of various CPDcs was improved by ECM coating, and other CPDcs also showed similar effects as 293T-CP70Dcs after ECM coating. These findings suggest that tumor-targeted CPDcs may have considerable advantages in gene delivery.

Effects of Pulse Parameters on Weld Microstructure and Mechanical Properties of Extra Pulse Current Aided Laser Welded 2219 Aluminum Alloy Joints.

In order to expand the application range of laser welding and improve weld quality, an extra pulse current was used to aid laser-welded 2219 aluminum alloy, and the effects of pulse current parameters on the weld microstructure and mechanical properties were investigated. The effect mechanisms of the pulse current interactions with the weld pool were evaluated. The results indicated that the coarse dendritic structure in the weld zone changed to a fine equiaxed structure using an extra pulse current, and the pulse parameters, including medium peak current, relatively high pulse frequency, and low pulse duty ratio benefited to improving the weld structure. The effect mechanisms of the pulse current were mainly ascribed to the magnetic pinch effect, thermal effect, and electromigration effect caused by the pulse current. The effect of the pulse parameters on the mechanical properties of welded joints were consistent with that of the weld microstructure. The tensile strength and elongation of the optimal pulse current-aided laser-welded joint increased by 16.4% and 105%, respectively, compared with autogenous laser welding.

Sex-Specific Prevalence of Diabetes and Cardiovascular Risk Factors in the Middle-Aged Population of China: A Subgroup Analysis of the 2007-2008 China National Diabetes and Metabolic Disorders Study.

The sex difference in the prevalence rates of diabetes and cardiovascular diseases (CVDs) among the middle-aged population in China remain largely unknown. Therefore, we analyzed differences in the prevalence of diabetes, self-reported CVDs, and some CVD risk factors among men and women in the middle-aged population (30-49 years) and in individuals aged 50 years and older using data from the China National Diabetes and Metabolic Disorders Study of 2007-2008. Middle-aged men appeared to have significantly a higher prevalence of diabetes and self-reported CVDs than middle-aged women (8.07% vs 5.06% for diabetes, P < 0.001; 0.64% vs 0.22% for CVDs, P < 0.001). Men also showed higher rates of central obesity, hypertension, and dyslipidemia than women (all P < 0.01). Compared with women, men were more likely to drink alcohol and smoke cigarettes but less likely to be under diet control. The sex-specific differences in prediabetes, CVD, and CVD risk factors between men and women were diminished or even reversed in the population aged 50 years and older. No sex-specific differences were found in the prevalences of a family history of diabetes, coronary heart disease, and hypertension (P > 0.05) in middle-aged population. Specific strategies to reduce modifiable risk factors for the prevention and control of diabetes and CVD may be warranted in this population.

Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China National Diabetes and Metabolic Disorders Study.

AIMS: Cardiovascular disease (CVD) is now the most prevalent and debilitating disease affecting the Chinese population. The goal of the present manuscript was to analyse cardiovascular risk factors and the prevalence of non-fatal CVDs from data gathered from the 2007-2008 China National Diabetes and Metabolic Disorders Study. METHODS AND RESULTS: A nationally representative sample of 46 239 adults, 20 years of age or older, was randomly recruited using a multistage stratified design method. Lifestyle factors, diagnosis of CVD, stroke, diabetes, and family history of each subject were collected, and an oral glucose tolerance test or a standard meal test was performed. Various non-fatal CVDs were reported by the subjects. SUDAAN software was used to perform all weighted statistical analyses, with P < 0.05 considered statistically significant. The prevalence of coronary heart disease, stroke, and CVDs was 0.74, 1.07, and 1.78% in males; and 0.51, 0.60, and 1.10% in females, respectively. The presence of CVDs increased with age in both males and females. The prevalence of being overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia was 36.67, 30.09, 67.43, and 26.69% in males; and 29.77, 24.79, 63.98, and 23.62% in females, respectively. In the total sample of 46 239 patients, the prevalence of one subject having 1, 2, 3, or ≥4 of the 5 defined risk factors (i.e. smoking, overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia) was 31.17, 27.38, 17.76, and 10.19%, respectively. Following adjustment for gender and age, the odds ratio of CVDs for those who had 1, 2, 3, or ≥4 risk factors was 2.36, 4.24, 4.88, and 7.22, respectively, when compared with patients with no risk factors. CONCLUSION: Morbidity attributed to the five defined cardiovascular risk factors was high in the Chinese population, with multiple risk factors present in the same individual. Therefore, reasonable prevention strategies should be designed to attenuate the rapid rise in cardiovascular morbidity.

[Clinical application of acupuncture for treatment of heroin withdrawal syndrome].

OBJECTIVE: To make technical standard of acupuncture manipulation for acupuncture treatment of heroin withdrawal syndrome. METHODS: Two hundred and twenty cases of heroin withdrawal syndrome were randomly divided into an acupuncture group of 111 cases and a control group of 109 cases. They were respectively treated with acupuncture and oral administration of lofexidine hydrochloride, and their therapeutic effects were observed. RESULTS: The heroin dependence (acute stage) were effectively withdrawn in the two groups. The treatment group in change of total scores for withdrawal symptoms before and after treatment, the total scores for withdrawal symptoms at the 4th and 5th days, treatment of insomnia and the score for self-Hamilton Anxiety Scale and the score after at the 4th day was superior to the control group (P < 0.05, P < 0.01, P < 0.001). CONCLUSION: Acupuncture has a satisfactory, rapid, safe and reliable clinical therapeutic effect.