Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.
Dipeptidyl-Peptidase IV Inhibitors ; chemical synthesis ; chemistry ; Drug Design ; Drug Discovery ; methods ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; Linagliptin ; chemical synthesis ; chemistry ; Molecular Structure ; Piperidines ; chemical synthesis ; chemistry ; Structure-Activity Relationship ; Uracil ; analogs & derivatives ; chemical synthesis ; chemistry

Objective To investigate the effects of AGEs-RAGE on the apoptosis of GLUTag cells and explore the possiblc mechanism.Methods GLUTag cells treated with 0、100、200、300μg/ml of AGEs for 24h were examined for gene and protein expression of RAGE using RT-PCR and western blotting,respectively.GLUTag cells were randomly divided into four groups:control,200μg/ml AGEs,AGEs+siRNA-RAGE and AGEs+apocynin.The protein expression of p22phox、p47phox 、Bcl-2、Bax in the cells were detected with western blotting.The reactive oxygen species (ROS) levels were examined using 2'7'-dichlorodihydroflur-rescein diacetate (DCFH-DA) and the apoptosis of L cells were tested by AnnexinV-FITC/PI.Results AGEs increased thc cxpression of RAGE in a dose dependent manner.Treatment with AGEs induced a significant increase in the expression of p22phox,p47phoxand the activity of ROS,caused up-regulation of Bax and down-regulation of Bcl-2,which enhanced the apoptosis of GLUTag cells.Apocynin,the inhibitor of NADPH oxidase,prevented those responses and the effects caused by AGEs were abolished by inhibition of RAGE activity with siRNA.Conclusion AGEs positively regulate the exprcssion of NADPH oxidase-derived ROS and its down-steam signaling pathway p53/Bax by targeting RAGE,leading to the apoptosis of GLUTag cells.

Objective To study the influence of periacetabular muscle contraction on acetabular] fractures.Methods Twenty intact adult cadaveric pelvis(40 hip joints)treated antiseptically with bilat- eral 1/2 femoral shafts were selected and divided randomly into two groups(20 hip joints in each group). Then,the specimens were trimmed to fit the RMT-150B rock mechanics measuring system and the special in- creasing pressure system.After pressure of 3 500 N was pressed to the control group and pressure of 4500 N to the experimental group,acetabular fracture model was made by beatening with special striking machine,when striking force was recorded.Results We made forty aeetabular fracture models from 40 cadaveric hips. Pearson correlation coefficient of pressing force and striking force was -0.923(P＜0.01).The striking force of the control group and the experimental group was 445-550 N and 290-400 N,respectively(t= 14.727,P＜0.01).Conclusion The increase of contraction force of the periaeetabular muscles can decrease aeetabular stress and strain,influence the result of violent injury and play a vital role in inducing acetabular fractures.

Systems-based integrated course is the core and hot spot in current advanced medical education reform.An integrated organ-system oriented curriculum system of endocrinology and metabolism was applied in eight year clinical medicine and five year excellent doctor education.The teaching contents of endocrinology and metabolism from traditional Basic Medicine,Internal Medicine and Surgery were integrated and optimized to compile the integrated syllabus and teaching cases.Curriculum integration oriented PBL teaching and comprehensive morphology experimental teaching were implemented into the integrated endocrinology and metabolism system curriculum.This endocrinology and metabolism course integration based on organ-system based learning is conducive to establishing the organic connection between Basic Medicine and Clinical Medicine,and cultivating high-quality medical talents.

Objective:To establish a rat model of diabetic microangiopathopathy and simulate the biochemical and pathological changes of diabetic retinal and renal microangiopathopathy.Methods:Forty healthy male Sprague-Dawley rats were randomly divided into blank group and model group (10 and 30 rats, respectively). After the rats in blank group and model group were fed ordinary diet and high-fat and high-sugar diet for 5 weeks, respectively, the rats in model group were injected with 1% streptozotocin (STZ) through the abdominal cavity at the dose of 35 mg/kg to establish a type 2 diabetes model. After modeling, the rats were continuously fed until the 10th week (4 weeks after modeling), the general conditions of the rats were observed, and samples were collected for follow-up experiments. Serum creatinine (CREA), triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), microalbuminuria, urinary creatinine (UCr) and urine sugar were detected. Calculate the kidney index and microalbumin/urinary creatinine ratio (UACR). Optical coherence tomography angiography (OCTA) was used to observe the vascular changes and non-perfusion area of retinal superficial capillary plexus. The morphological and structural changes of kidney and retina were observed by hematoxylin-eosin and periodate Scheff staining. The expression of nerve fibers and nucleus of Müller cells in rat retina was observed by immunofluorescence staining. Ultrastructural results of retina were observed by transmission electron microscope. Independent sample t test was used for comparison between groups. Results:Four weeks after modeling, compared with blank group, the body weight of rats in model group was significantly decreased, and random glucose was significantly increased, with statistical significance ( t=5.755, -51.291; P<0.05). Renal index, urinary glucose and UACR were significantly increased, while UCr was significantly decreased, with statistical significance ( t=10.878, 137.273, 3.482,-6.110; P<0.05). CREA decreased, TG, TC, HDL-C, LDL-C increased, and the differences were statistically significant ( t=-28.012, 33.018, 118.018, 13.585, 16.480; P<0.05). OCTA examination showed that there was no perfusion area of shallow retinal capillaries. The optical microscope showed that the inner boundary membrane of retina in model group was swollen and thickened, the surface was uneven, the inner and outer nuclear layer cells were disordered and the density decreased. Glomerular congestion was accompanied by cortical tubular epithelial swelling, widening of the mesangial area, and thickening of the basement membrane. The results of immunostaining showed that the inner and outer plexiform layers of the retina showed lamellar strong green fluorescence expression, and the inner and outer nuclear layers showed scattered dot green fluorescence expression. Transmission electron microscopy showed that the basal membrane of retinal microvessels in model group was slightly thickened, vascular endothelial cells edema, endothelial nucleus and perinucleus contraction, nuclear membrane contraction, mild mitochondrial swelling, vacuolation. Conclusion:High-glucose and high-fat feeding plus a single intraperitoneal injection of STZ 35 mg/kg can successfully establish a microangiopathic model of type 2 diabetes.

Adolescent ; Adult ; Brain Neoplasms ; diagnosis ; metabolism ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Magnetic Resonance Imaging ; Male ; Meningeal Neoplasms ; diagnosis ; metabolism ; pathology ; surgery ; Meningioma ; diagnosis ; metabolism ; pathology ; surgery ; Middle Aged ; Mucin-1 ; metabolism ; Neoplasm Recurrence, Local ; Reoperation ; Retrospective Studies ; Tomography, X-Ray Computed ; Vimentin ; metabolism ; Young Adult

Serum cortisol and plasma ACTH were determined in 10 patients with severe sepsis and 12 with septic shock on day 1,3,5 after diagnosis were made,and the data were compared with 12 control patients. To evaluate the hypothalamic-pituitary-adrenal(HPA)axis function in patients with severe sepsis and septic shock,1?g ACTH stimulation test was applied after hormone concentrations were obtained on day 1.Compared with the control patients,ACTH level was significantly higher in patients with severe sepsis and lower in septic shock(P

Opioid medications have been used for pain management, but there are negative side effects, including a potential delay in recovery and increased risk of permanent disability. In this paper, analgesic targets including N-methyl-D-aspartate receptors, cannabinoid receptors, prostaglandin E2 receptor 4 receptors, matrix metalloproteinase receptors, and some new targets for blocking pain signaling pathways associated with these receptors are reviewed. In addition, some novel agonists, antagonists, and leading compounds with agonistic (antagonistic) activities interacting with the target are also described. These novel compounds usually have better analgesic activity and lower side effects than traditional opioids. They are expected to be developed into new analgesics and benefit clin?ical patients who need pain treatment.

OBJECTIVETo evaluate the status of complementary feeding frequency (CFF) for infants and young children in southwestern China.

METHODSA total of 3644 infants and young children aged 6 - 24 months from urban and rural areas of Chengdu, Kunming and Guiyang were selected by stratified random cluster sampling from March to June in 2011. Data of CFF in the recent one month were collected through the questionnaires, and assessed quantitatively by a new comprehensive evaluation system. Level and distribution characteristics of CFF for infants and young children among different month groups in urban and rural areas were analyzed.

RESULTSAverage CFF score was 8.1 ± 3.1, and the score for all was 54.1% of total score (15 points). The average score of urban and rural groups was 8.9 ± 3.0 (59.3% of total score) and 7.4 ± 3.0 (49.1% of total score) respectively (t = 15.60, P < 0.05). Ratio of ≥ 80.0% of total CFF score was 12.2% (443/3644) for all. The rate of urban and rural group was 18.0% (324/1796) and 6.4% (119/1848) respectively (χ(2) = 136.64, P < 0.05). Average CFF score in 6 - 8, 9 - 11 and 12 - 24 months groups was 7.0 ± 2.9 (46.4% of total score), 8.1 ± 3.0 (54.1% of total score) and 9.0 ± 3.0 (60.1% of total score) respectively (F = 148.27, P < 0.05). The CFF score increased with months growing.

CONCLUSIONStatus of CFF for infants and young children in southwestern China is generally inadequate, with differences between urban and rural groups. This problem is more serious in early month infants and rural areas and should be emphasized and improved.

China ; Cross-Sectional Studies ; Humans ; Infant ; Infant Food ; statistics & numerical data ; Infant Nutritional Physiological Phenomena ; Nutrition Surveys ; Rural Population ; Surveys and Questionnaires ; Urban Population

Objective: To assess the efficacy and safety of ultrasound (US)-guided radiofrequency ablation (RFA) in patients with primary hyperparathyroidism (PHPT). Materials and Methods: This prospective study enrolled 39 participants (14 male, 25 female; mean age, 59.5 ± 15.3 [range, 18–87] years) between September 1, 2018, and January 31, 2021. All participants had parathyroid lesions causing PHPT, proven biochemically and through imaging. The imaging features of the PHPT nodules, including the shape, margin, size, composition, and location, were evaluated before treatment. Serum intact parathyroid hormone, calcium, and phosphorus levels; parathyroid nodule volume; and PHPT-related symptoms were recorded before and after treatment. We calculated the technical success, biochemical cure, and clinical cure rates for these patients. Complications were evaluated during and after the ablation. Results: Complete ablation was achieved in 38 of the 39 nodules in the 39 enrolled participants. All the patients were treated in one session. The technical success rate was 97.4% (38/39). The mean follow-up duration was 13.2 ± 4.6 (range, 6.0–24.9) months. At 6 and 12 months post-RFA, the biochemical cure rates were 82.1% (32/39) and 84.4% (27/32), respectively, and the clinical cure rates were 100% (39/39) and 96.9% (31/32), respectively. Only 2.6% (1/39) of the patients had recurrent PHPT. At 1, 3, 6, and 12 months after technically successful RFA, 44.7% (17/38), 34.3% (12/35), 15.8% (6/38), and 12.5% (4/32) of participants, respectively, had elevated eucalcemic parathyroid hormone levels. Recurrent laryngeal nerve paralysis occurred in 5.1% (2/39) of the patients, who recovered spontaneously within 1–3 months. Conclusion US-guided RFA was effective and safe for PHPT patients. RFA may be an alternative treatment tool for patients who cannot tolerate or refuse to undergo surgery.