Diabetic nephropathy presents an increasing trend worldwide. It has been an attractive area to find novel targets for the treatment of diabetic nephropathy. SIRT1 (Sirtuin 1), a member of deacetylation enzymes, regulates cell senescence, metabolism, and apoptosis. In last ten years, lots of studies showed that SIRT1 exerts a protective effect in the progression of the diabetic nephropathy by promoting reconstruction of energy homeostasis, modulating cell redox state, resisting cell apoptosis, inhibiting inflammation and ameliorating renal fibrosis. SIRT1 has become a potential new target for the treatment of diabetic nephropathy.
Apoptosis ; Cellular Senescence ; Diabetic Nephropathies ; pathology ; Humans ; Oxidation-Reduction ; Sirtuin 1 ; physiology

BACKGROUNDPodocyte has inflammatory role in the development of diabetic nephropathy (DN). Mycophenolate mofetil (MMF), an anti-inflammatory agent, can suppress macrophage infiltration and reduce renal injury in streptozotocin-induced diabetic rats. Angiotensin II receptor blocker (ARB), another renal protecting agent, can decrease podocyte loss in DN. In this study, we detected the expression levels of monocyte chemoattractant protein-1 (MCP-1) and nephrin to evaluate podocyte's role in inflammatory reaction in DN, observe and compare the effect of MMF alone and in combination with valsartan, on preventing podocyte loss in streptozotocin (STZ) induced diabetic rats.

METHODSDiabetic model was constructed in uninephrectomized male Wistar rats by single peritoneal injection of STZ (65 mg/kg). The successfully induced diabetic rats were randomly divided into four groups: diabetes without treatment group (DM), valsartan treated group (DMV), MMF treated group (DMM), and combined therapy group (DMVM). Normal rats of the same sibling were chosen as control (NC). At the end of the 8th week, serum biochemistry, 24-hour urinary protein (UP) and the ratio of kidney weight/body weight (RWK/B) were measured. The rats were sacrificed for the observation of renal histomorphology through light and electron microscope. Nephrin, desmin and MCP-1 levels were detected by semi-quantitative immunohistochemical assays. Real-time quantitative PCR was used to detect the mRNA levels of nephrin and MCP-1.

RESULTSCompared with group NC, serum glucose level, 24-hour UP and RWK/B in group DM were significantly higher (P < 0.01), and the nephrin mRNA level in DM group was significantly lower (P < 0.05). The nephrin mRNA expression levels in group DMV, DMM and DMVM were all higher than that of DM group (P < 0.05) and no significant differences were found among the three treatment groups (P > 0.05). Treatment with MMF, valsartan or their combination could significantly decrease the 24-hour UP and RWK/B, and suppress glomerulosclerosis and interstitial fibrotic lesions in diabetic rats. In diabetic rats, the high expressions of desmin and MCP-1 in kidney were suppressed by valsartan, MMF or their combination.

CONCLUSIONSPodocytes are involved in the inflammatory reaction of diabetic rats. MMF could suppress MCP-1 and desmin expression, enhance nephrin expression, and attenuate proteinuria in diabetic rats. The combined therapy of valsartan and MMF did not show any superiority over monotherapies on renal protection. MMF may have renoprotective effect in early stages of diabetic nephropathy through preventing podocytes loss and anti-inflammatory activity.

Animals ; Chemokine CCL2 ; analysis ; Desmin ; analysis ; Diabetic Nephropathies ; drug therapy ; pathology ; Drug Therapy, Combination ; Immunohistochemistry ; Male ; Membrane Proteins ; analysis ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Podocytes ; drug effects ; pathology ; Rats ; Rats, Wistar ; Tetrazoles ; administration & dosage ; therapeutic use ; Valine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Valsartan

Objective To study the physical-chemical parameters of antiviral drug GZ 914 and provide data for the preparation design .Methods The appearance , crystal structure and solubility of GZ 914 were investigated .An HPLC method was established to determine the content of GZ 914 in vitro before oil/water partition coefficient and solubility in different pH experiments were calculated .Results GZ914 was a straw yellow powder with a crystalline structure , low water-solubility and good lipotropy .The HPLC method had a good linear relationship within the range of 12-60 μg/ml (r=0.9998).The oil/water partition coefficient of GZ914 was 1.9.Conclusion This analytical method is accurate and reliable.The oil/water partition coefficient indicates that the drug could be formulated as an oral solid preparation.

OBJECTIVE Diabetic nephropathy (DN) has been one of the most common complications of diabetes and the leading cause of end-stage renal disease. Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities. Salvi?anolic acid A (SalA) has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy. The present study was designed to investigate the effects of SalAon glomerular endothelial dysfunctionand diabetic nephropathy. METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products (AGEs). AGEs-induced changes of RhoA/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunoflu?orescence. The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin (35 mg·kg- 1, ip). Renal function and architectonic changes were evaluated by biochemical assay and PAS staining. RESULTS SalA 3μMameliorated AGEs- induced glomerular endothelial permeability (P<0.05) and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-RhoA/ROCK pathway. SalA 1 mg · kg- 1 markedly reduced endothelium loss (P<0.01) and glomerular hyperfiltration (P<0.05) in diabetic kidney. Subsequently,SalA 1 mg·kg-1 suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen (BUN), serum creatinine (Scr) and serum n-acetyl-β-d-glucosaminidase (NAG). AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg-1. CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability, and effec?tively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway. Thus, SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.

OBJECTIVETo study the role of sirtuin 1 (SIRT1) in Fas ligand (FasL) expression regulation during vascular lesion formation and to elucidate the potential mechanisms.

METHODSSIRT1 and FasL protein levels were detected by Western blotting in either mouse arteries extract or the whole rat aortic vascular smooth muscle cell (VSMC) lysate. Smooth muscle cell (SMC)-specific human SIRT1 transgenic (Tg) C57BL/6 mice and their littermate wild-type (WT) controls underwent complete carotid artery ligation (ligation groups) or the ligation-excluded operation (sham groups). The carotid arteries were collected 1 day after operation. Reverse transcription-polymerase chain reaction was performed to detect the mRNA levels of SIRT1 and FasL. Luciferase reporter assays were performed to detect the effect of WT-SIRT1, a dominant-negative form of SIRT1 (SIRT1H363Y), and GATA-6 on the promoter activity of FasL. Flow cytometry assay was applied to measure the hypodiploid DNA content of VSMC so as to monitor cellular apoptosis.

RESULTSSIRT1 was expressed in both rat aortic VSMCs and mouse arteries. Forced SIRT1 expression increased FasL expression both in injured mouse carotid arteries 1 day after ligation (P<0.001) and VSMCs treated with serum (P<0.05 at the transcriptional level, P<0.001 at the protein level). No notable apoptosis was observed. Furthermore, transcription factor GATA-6 increased the promoter activity of FasL (P<0.001). The induction of FasL promoter activity by GATA-6 was enhanced by WT-SIRT1 (P<0.001), while SIRT1H363Y significantly relieved the enhancing effect of WT-SIRT1 on GATA-6 (P<0.001).

CONCLUSIONSOverexpression of SIRT1 up-regulates FasL expression in both flow-restricted mouse carotid arteries and serum-stimulated VSMCs. The transcription factor GATA-6 participates in the transcriptional regulation of FasL expression by SIRT1.

Animals ; Apoptosis ; Carotid Arteries ; physiology ; Fas Ligand Protein ; genetics ; GATA6 Transcription Factor ; physiology ; Male ; Muscle, Smooth, Vascular ; cytology ; metabolism ; Myocytes, Smooth Muscle ; metabolism ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Sirtuin 1 ; physiology ; Up-Regulation

OBJECTIVEHuman growth hormone (hGH) is an essential therapeutic drug for the treatment of growth hormone (GH) deficiency (GHD). However, the process of dissolving hGH of the powder form is complicated and potentially hazardous. In the present study, we evaluated the efficacy and safety of preparation in the replacement therapy for children with GH deficiency.

METHODSA 12-month randomized, open-label, multicenter trial was conducted in 31 previously untreated children with growth failure secondary to GH deficiency [20 boys and 11 girls, mean age (10.5 +/- 4.1) years]. An recombined human growth hormone (rhGH) solution (Iintropin AQ) was given via subcutaneous injection daily in every evening at a weekly dose of 0.25 mg/kg. The patients were followed up at 3, 6, 9, and 12 months of the treatment, and the course of treatment was 12 months. Body height was measured 3-monthly and height velocity (HV) and mean height standard deviation score (HT SDS) were calculated. Serum Insulin-like growth factor I (IGF-1), Insulin-like growth factor binding protein 3 (IGFBP-3), GH antibodies and safety parameters were assessed at the baseline and at 3-month intervals. Bone age (BA) was assessed at the baseline and the rate of skeletal maturation (DeltaBA/DeltaCA) was calculated after 6 and 12 months of rhGH treatment by a central bone age reader. Moreover, the safety of rhGH solution treatment was assessed.

RESULTSAfter 12 months of liquid rhGH therapy, growth parameters were significantly increased over baseline. (1) The mean (+/- SD) height increment DeltaHT (cm) was 4.0 +/- 1.3, 7.0 +/- 2.0, 10.3 +/- 2.6 and 12.9 +/- 3.3 after 3, 6, 9, and 12 months of treatment, respectively (P < 0.01), which indicated linear growth after treatment. The GV (cm/years) was 2.7 +/- 0.9 before treatment and increased to 16.0 +/- 5.1, 14.1 +/- 4.0, 13.7 +/- 3.5, and 12.9 +/- 3.3 after treatment, suggesting that catch-up growth was significant after treatment as compared to the pre-treatment status (P < 0.01). Accordingly, post-treatment catch-up growth was obvious, significant differences were observed in HT SDS, which was -4.62 +/- 1.46 at the onset of therapy and increased significantly after the treatment to -3.80 +/- 1.53, -3.28 +/- 1.60, -2.86 +/- 1.75 and -2.47 +/- 1.86, respectively (P < 0.01). The height difference between GH deficient children and unimpaired children of the same age and gender gradually decreased after treatment, which was significantly different from that seen before treatment (P < 0.01). (2) The levels of serum IGF-1 and IGFBP-3 were increased comparably for the treatment. IGF-1 level (microg/L) was 41 +/- 64 at baseline and increased to 179 +/- 155, 202 +/- 141, 156 +/- 155 and 159 +/- 167 after 3, 6, 9, 12 months of treatment. IGFBP-3 level (mg/L) was 1540 +/- 1325 at baseline, and increased to 3891 +/- 1815, 4051 +/- 1308, 3408 +/- 1435 and 3533 +/- 1413, respectively, suggesting that with the increases in height, IGF-1, and IGFBP-3 were significantly activated to relatively high levels by the medication and reached peak values between 3 and 6 months of treatment. The levels of IGF-1 and IGFBP-3 were significantly different before and after treatment (P < 0.01). The IGF-1/IGFBP-3 molar ratio significantly increased during GH therapy (0.143 +/- 0.013 pre-therapy up to 0.240 +/- 0.055 post-therapy, P < 0.01). The IGF-1/IGFBP-3 molar ratio tended to stabilize after 3-month GH therapy. (3) The bone age assessment carried out 6 and 12 months after treatment showed that the bone maturity (DeltaBA/DeltaCA) was 1.01 +/- 0.57 and 1.07 +/- 0.75, respectively, suggesting that there was no speed-up development in the bone age. No severe adverse events were observed during the trial and the most frequent accompanying event was mild hypothyroidism.

CONCLUSIONSrhGH solution (Iintropin AQ) is a safe and effective preparation in the replacement therapy for children with GH deficiency.

Child ; China ; Dwarfism, Pituitary ; blood ; drug therapy ; Female ; Growth Disorders ; blood ; drug therapy ; Human Growth Hormone ; deficiency ; therapeutic use ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; blood ; Insulin-Like Growth Factor I ; metabolism ; Male ; Prospective Studies ; Recombinant Proteins ; therapeutic use

OBJECTIVE: To study the inhibitory effect of HDAC6 on proliferation of human leukemia KG1α and to explore its mechanism by ERK signaling pathways. METHODS: .The siRNA interference technology was used to inhibit the HDAC6 gene expression; the expression of HDAC6 and prateins of ERK signal pathway was detected by Western blot; the cell proliferation ability was detected by colony forming experiment and trypan blue staining; cell cycle was detected by FCM; and the expression of Ki67 was detected by immunofluorescence. RESULTS: Western blot showed that HDAC6 expression was up-regulated in leukemia cell lines in comparison with the healthy volunteers and bone marrow stromal cells (P＜0.05). Knockdown of HDAC6 significantly inhibited the proliferation and colony formation ability of leukemia cells, promoted cell arrest at G/G phase. The Western blot and immunefluorescence showed that knockdown of HDAC6 suppressed the expression level of Ki67, CDK4, Cyclin D1 and enhanced the expression level of p16, p21, p-ERK (P＜0.05). CONCLUSION Knockdown of HDAC6 significantly inhibits the proliferation, arrest the cell cycle at G/G phase, and its mechanism probably relates with the activation of ERK signaling pathway.

Circadian rhythm disorder is a common society issue caused by jet lag,shift work,sleep disruption and changes in food consumption. Light is the major factor affecting the circadian rhythm system. Disruption of the circadian rhythm system can cause damage to the body,leading to some diseases. Maintaining a normal circadian system is of great importance for good health. Ideal therapeutic effect can not only alleviate symptoms of the diseases,but also recovery the disturbed circadian rhythm to normal. The paper summarizes the modeling methods of animal circadian rhythm disorder,diseases of circadian rhythm abnormality,regulation of circadian clock genes and medicine which are related to circadian rhythm to diseases of circadian rhythm disorder.
Animals ; Circadian Rhythm/genetics* ; Humans ; Jet Lag Syndrome/genetics* ; Sleep ; Sleep Disorders, Circadian Rhythm

Accurate classification of the acetabular injuries and appropriate treatment plan are great challenges for orthopedic surgeons because of the irregular anatomical structure of the acetabulum and aggregation of important vessels and nerves around it. Letournel-Judet classification system has been widely applied to classify acetabular fractures. However, there are several limitations, including incomplete inclusion of fracture types, difficulty in understanding and insufficient guidance for surgical treatment, etc. Serious complications such as traumatic arthritis are common due to wrong classification and diagnosis and improper selection of surgical strategy, which brings a heavy burden to the society and families. Three-column classification, based on anatomic characteristics, has advantages of containing more fracture types and being easy to understand, etc. To solve the problems existing in the diagnosis and treatment process based on Letournel-Judet classification, achieve accurate diagnosis and treatment of patients with acetabular fractures, and obtain satisfactory prognosis, the Orthopedic Trauma Emergency Center of Third Hospital of Hebei Medical University and the Trauma Orthopedic Branch of the Chinese Orthopedic Association organized experts from relevant fields to formulate the Expert consensus on the accurate diagnosis and treatment of acetabular fractures based on three-column classification ( version 2023) in terms of principles of evidence-based medicine. Based on the three-column classification, 15 recommendations were proposed, covering the diagnosis, treatment, complication prevention and management, etc, so as to provide reference for accurate diagnosis and treatment of acetabular fractures.

China prospective multicenter birth cohort (Prospective Omics Health Atlas birth cohort, POHA birth cohort) study was officially launched in 2022. This study, in collaboration with 12 participating units, aims to establish a high-quality, multidimensional cohort comprising 20 000 naturally conceived families and assisted reproductive families. The study involves long-term follow-up of parents and offspring, with corresponding biological samples collected at key time points. Through multi-omics testing and analysis, the study aims to conduct multi-omics big data research across the entire maternal and infant life cycle. The goal is to identify new biomarkers for maternal and infant diseases and provide scientific evidence for risk prediction related to maternal diseases and neonatal health.