The phenylborate-ester-cross-linked hydrogel microneedle patch (MNP) was promising in the diabetic field for the glucose-responsive insulin-delivering property and simple fabrication process. However, the unfit design of the charging microneedle network limited the improvement of blood-glucose regulating performances. In this work, insulin-loaded phenylborate-ester-cross-linked MNPs, with the polyzwitterion property, were constructed based on the modified ε-polylysine and poly(vinyl alcohol). The relationship between the charging nature of the MNP network and insulin release was verified by regulating the content of postprotonated positively charged amino groups. The elaborately designed MNP possessed improved glucose-responsive insulin-delivering performance. The in vivo study revealed the satisfactory results on blood-glucose regulation by the optimized MNP under the mimic three-meal-per-day mode. Moreover, the insulin bioactivity in the MNP could be maintained for 2 weeks under 25 °C. In summary, this work developed an effective strategy to improve the glucose-responsive phenylborate-ester-cross-linked MNP and enhance its potential for clinical transformation.

Severely diabetic patients need insulin input to maintain the body's glycemic balance. However, traditional injection methods are often associated with poor adherence and an increased risk of hypoglycemia. Microneedle technology offers a promising solution by minimizing pain and trauma during insulin administration. Nonetheless, achieving prolonged glycemic control by microneedle with high insulin loading remains a significant challenge. Herein, we introduce an innovative microneedle patch that draws inspiration from the elegant light-induced blooming of water lily petals. The patch features a glucose-responsive hydrogel network crafted from two modified polysaccharide polymers, which enables the delivery of long-acting insulin without depending on glucose oxidase. By incorporating phenylboronic acid-modified sodium alginate, quaternary ammonium chitosan, and polyvinyl alcohol into a hydrogel matrix, we have created a microneedle system that harbors dynamic borate ester linkages and electrostatic attractions, resulting in heightened sensitivity to blood glucose levels. The electrostatic interaction acts as a relatively stable crosslinking point, balancing the dynamic reproducibility response based on the borate ester bond. This self-adaptive hydrogel can regulate insulin-controlled release by responding to changes in glucose concentration. Herein, we achieved massive insulin loading (20 IU) with long lasting glycaemic control (48 h) in a single treatment of diabetic SD rats.

It was greatly significant, but difficult, to develop stimulus-responsive polymeric nanoparticles with efficient protein-loading and protein-delivering properties. Crucial obstacles were the ambiguous protein/nanoparticle-interacting mechanisms and the corresponding inefficient trial-and-error strategies, which brought large quantities of experiments in design and optimization. In this work, a molecular docking-guided universal "segment-functional group-polymer" process was proposed to simplify the previous laborious experimental step. The insulin-delivering glucose-responsive polymeric nanoparticles for diabetic treatments were taken as the examples. The molecular docking study obtained insights from the insulin/segment interactions. It was then experimentally confirmed in six functional groups for insulin-loading performances of their corresponding polymers. The optimization formulation was further proved effective in blood-glucose stabilization on the diabetic rats under the "three-meal-per-day" mode. It was believed that the molecular docking-guided designing process was promising in the protein-delivering field.

Foggy surfaces can damage the optical performance of devices and even cause adverse consequences like safety concerns in some cases. Various antifogging coatings have been proposed to relieve this trouble. Nevertheless, most coatings suffer from temporary fog-repellency features due to hygroscopic swelling behavior and detachable interface. Herein, we reported an antifogging coating with persistent fogging prevention via the introduction of the amphiphilic polymer and interfacial layer. With the aid of benzophenone (BP) groups, both bulk crosslinking and interfacial bonding were achieved to prevent relatively macroscopic motions of coating from the substrate under extreme conditions. In virtue of the minor swelling and interfacial adhesion, the coating could preserve the fog-free behavior after 50-cycle antifogging tests and even aging for 90 days under harsh conditions. Notably, both in vitro (pig larynx) and vivo (living rabbit) outcomes indicated excellent fog-repellency of the polymer-coated endoscope.

To simplify the preparation process of a glucose-responsive microneedle patch, a cross-linking-density changeable microneedle patch was designed. The microneedle patch was made up of a hydrogel formed by phenylboronic acid-grafted polyallylamine and poly(vinyl alcohol) (PVA). The gel was cross-linked by boronate ester bonds between phenylboronic acid groups and PVA. It still had fluidity and could be filled into a mold to prepare microneedle patches. Moreover, insulin could be directly loaded into the microneedle patch by mixing with the gel. The boronate ester bond would be broken in the presence of glucose, resulting in a decrease in the cross-linking density. Therefore, the gel could achieve a greater swelling degree and insulin could be released faster. In addition, PVA chains were crystallized by repeatedly freezing and thawing to improve the mechanical strength of the microneedle patch. In terms of glucose-dependent insulin release, the gel showed good glucose-responsive insulin-release ability. Through additional ion cross-linking, the microneedle patch could also control the insulin release according to glucose concentration. In the hypoglycemic experiment of diabetic rats, the microneedle patch effectively pierced the skin and slowly released insulin.

Background This systematic review aimed to investigate whether diabetes mellitus is a risk factor for low bone density, as this might be important and necessary for doctors specialized in treating patients with low bone density. Methods PubMed, Embase, CINAHL, and SciELO were searched for cohort, case-control, and cross-sectional studies that investigated the effects of diabetes mellitus on bone mineral density till January 2020. Data screening and extraction are done independently, whereas the methodological quality of the studies was assessed according to the Newcastle-Ottawa Scale (NOS). Results A total of 14 studies that met the eligibility criteria including 24,340 participants were enrolled. The overall quality of the studies had a scale of over 6 points. The overall odds ratio (OR) regarding the risk of diabetes mellitus in low bone density patients was 1.20 [95% confidence interval (CI)0.80–1.79, P = 0.30], and type 2 diabetes mellitus (T2DM) (OR = 0.69 [0.11, 4.55], P = 0.70). Subgroup analysis revealed that whether females or males, developed or developing countries, T2DM, studies after 2015, and quality over 7 points (all P values > 0.05) showed no significant differences with the risk of low bone density, except type 1 diabetes mellitus (T1DM) (OR = 3.83 [1.64, 8.96], P = 0.002), and studies before 2015 (OR = 1.76 [1.06, 2.92], P = 0.03), and quality below 7 points (OR = 2.27 [1.50, 3.43], P = 0.0001). Funnel plot showed no significant asymmetry. Conclusions These findings revealed no relationship between T2DM and low bone density, and also, the evidence between T1DM and low bone density is inadequate, requiring further analysis of well-designed cohort studies.

Microneedles with self-regulated drug releasing behaviors are desirable and promising to improve the treatment quality of diabetics. Here, we fabricate a phenylboronic acid-based hydrogel microneedle patch (MNP) with glucose responsiveness and excellent biocompatibility for drug delivery at 37 degrees C. In this hydrogel-based MNP, the glucose-responsive properties are realized by introducing reversible phenylborate ester crosslinking points based on phenylboronic acid units and diol-containing units. The reversible crosslinking points also improve the mechanical strength for skin insertion. This novel phenylboronic acid-based hydrogel MNP lays the foundation for fabrication of a sensitive, safe and stable transdermal drug delivery system.

Different hydrogels of poly(acrylamide-co-3-acrylamido phenylboronic acid-co-chitosan grafted maleic acid) (P(AM-co-AAPBA-co-CSMA)s) were synthesized using poly(ethylene glycol) diacrylate (PEGDA) as a crosslinker to serve for glucose sensing and insulin delivery. The structure and morphology of the hydrogels, named as CSPBA were studied by FTIR and SEM, while the mechanical properties were tested using dynamic mechanical analysis (DMA) and universal testing machine. The prepared hydrogels shrinked at low glucose concentration due to the 2:1 boronate-glucose binding, and swelled at high glucose concentration because of 1:1 boronate-glucose complexation. Both binding mechanisms are useful for glucose sensing and insulin delivery. The integration of CSMA into hydrogels network not only enhanced the response to glucose at physiological pH, but also improved the mechanical properties and increased the encapsulation efficiency of the prepared hydrogels. These CSPBA may find potential as implantable hydrogels in applications were continuous glucose monitoring and controlled release is beneficial.

Purpose: To determine the anti-diabetic effect of a monoamine oxidase inhibitor (tranylcypromine) in sulphonyl urea-refractory rats with poorly-controlled blood glucose levels. Methods: Alloxan-induced diabetic Wistar rats were assigned to two groups (30 rats/group). One group received glibenclamide at a dose of 0.6 mg/kg, while the other group was given monoamine oxidase inhibitor (tranylcypromine) at a dose of 5 mg/day. The two groups were treated for 2 weeks. Blood samples were collected at baseline (before treatment) and at the end of treatment for determination of plasma glucose (fasting and fed), hemoglobin A1c, lipid profiles (serum total cholesterol, very-low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and triglycerides); oxidative stress parameters (anti-oxidant enzymes), insulin levels, and some hepatic enzymes of glucose metabolism. Results: Monoamine oxidase inhibitor treatment resulted in significant decrease in the levels of blood glucose, HbA1c, and lipid levels from baseline, relative to glibenclamide (p < 0.05). Greater improvements in oxidative stress biomarkers (glutathione and superoxide dismutase), insulin levels and hepatic enzymes of glucose metabolism were observed in monoamine oxidase inhibitor group than in glibenclamide group (p < 0.05). Oxidative stress was significantly inhibited by monoamine oxidase inhibitor via increases in glutathione (GSH) level and superoxide dismutase (SOD) activity, when compared to glibenclamide (p < 0.05). Conclusion: These results suggest that monoamine oxidase inhibitor may be a better treatment option for diabetes than glibenclamide.

Hyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen-secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range. A 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin α, melan A, β-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided. Pure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.

Background Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children, but this disease is significantly rarer in patients who are older than 15 years. In this disease, any organ can be involved. The skeleton, skin and lung are commonly affected, and isolated hypothalamic-pituitary (HP) involvement is relatively rare. Here we report a 17-year-old adolescent with isolated HP-LCH of enlarged pituitary stalk presented with central diabetes insipidus (CDI). Case presentation A 17-year-old male adolescent with polydipsia and polyuria accompanied with elevated serum sodium level and low urine osmolality for 3 weeks was referred to our hospital. After admission, hormonal evaluation showed that his growth hormone (GH) was slightly elevated, and serum osmolality and glucose were normal. The fluid deprivation-vasopressin test demonstrated CDI. Imaging examination showed an obvious thickening of the pituitary stalk. Lymphocytic hypophysitis, sarcoidosis and granulation tissue lesions were suspected. After oral 1-deamino-8-Darginine vasopressin (DDAVP) and prednisone were administered for 2 months, symptoms were relieved, and he discontinued taking the drugs by himself. On reexamination, imaging revealed changes in the size and shape of the pituitary stalk, with thickened nodules. Then, a diagnostic biopsy of the pituitary stalk lesion was performed. Immunohistochemistry confirmed the definitive diagnosis of LCH. The clinical symptoms subsided with oral hormone replacements. Conclusion CDI is a rare symptom in children and adolescents. Most of the causes are idiopathic, while others are caused by central nervous system (CNS) disorders. Meanwhile, lymphocytic hypophysitis, germinoma, LCH and other CNS disorders can all present as thickening of the pituitary stalk, diffuse enlargement of the pituitary gland, and weakening of high signal intensity in the neurohypophysis on magnetic resonance imaging (MRI). The differential diagnosis among these diseases depends on immunohistochemistry evidence.

人类基因组计划发现编码蛋白的基因占很少一部分,而非编码RNA有强大的功能,其中长度>200 bp的即长链非编码RNA(lncRNA),参与调节细胞的增殖、分化和凋亡等各种生命活动.T2DM患者存在胰岛素分泌不足及外周组织IR,现发现在胰腺、肝脏、脂肪和骨骼肌组织中表达异常的lncRNA参与调节胰岛素的分泌和外周组织的糖代谢.本文主要从细胞和动物模型层面综述相关lncRNA的调节机制,探讨其在糖尿病发生发展中的作用,为糖尿病的治疗提供新靶点.

Postmenopausal osteoporosis (PMO) is the most common type of primary osteoporosis (OP), a systemic skeletal disease. Although many factors have been revealed to contribute to the occurrence of PMO, specific biomarkers for the early diagnosis and therapy of PMO are not available. In the present study, a weighted gene co‑expression network analysis (WGCNA) was performed to screen gene modules associated with menopausal status. The turquoise module was verified as the clinically significant module, and 12 genes (NUP133, PSMD12, PPWD1, RBM8A, CRNKL1, PPP2R5C, RBM22, PIK3CB, SKIV2L2, PAPOLA, SRSF1 and COPS2) were identified as 'real' hub genes in both the protein‑protein interaction (PPI) network and co‑expression network. Furthermore, gene expression analysis by microarray in blood monocytes from pre‑ and post‑menopausal women revealed an increase in the expression of these hub genes in postmenopausal women. However, only the expression of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) was correlated with bone mineral density (BMD) in postmenopausal women. In the validation set, a similar expression pattern of PPWD1 was revealed. Functional enrichment analysis revealed that the fatty acid metabolism pathway was significantly abundant in the samples that exhibited a higher expression of PPWD1. Collectively, PPWD1 is indicated as a potential diagnostic biomarker for the occurrence of PMO.

急性痛风是一种常见的自身炎症性关节炎,由滑膜关节软组织内单钠尿酸盐(monosodium urate,MSU)晶体沉积引起,尿酸盐通过半胱天冬酶(caspase)激活单核巨噬细胞分泌白细胞介素-1β(interleukin-1β,IL-1β),从而介导痛风性炎症反应.由于痛风常见的一些合并症,目前首选治疗药物的使用受到许多限制.2016年更新的欧洲风湿病防治联合会(European League Against Rheumatism,EULAR)指南建议对急性痛风频繁发作以及难以使用常规疗法治疗的患者使用IL-1受体拮抗剂(interleukin-1 receptor antagonist,IL-1 Ra).阿那白滞素(anakinra)是一种重组非糖基化的人IL-1 Ra,目前已被美国食品药品管理局(FDA)批准上市,并用于治疗类风湿关节炎等疾病多年,相比于其他IL-1 Ra,anakinra的性价比更高.近年来anakinra治疗急性痛风的研究日益增多,研究结果支持其在治疗急性痛风发作中的有效性.本文就其对急性痛风的作用与治疗研究作一综述.

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo. We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.

骨质疏松是一种随着年龄增长或病态而骨质不断流失、骨微结构不断恶化且易致骨折的全身代谢性疾病.随着人口的老龄化,全世界的发病率都在持续上升,这严重的影响了老年人群的健康和生活质量.白藜芦醇具有雌激素样作用且在骨骼中具有多向靶点,能促进骨髓间充质干细胞成骨分化、增加成骨细胞增殖生长及抑制破骨细胞,白藜芦醇治疗骨质疏松的研究日益增多并有一定的进展.本文将对近年来白藜芦醇防治骨质疏松症的研究进展作一综述.

RATIONALE:The incidence of severe hyperandrogenism associated with masculinity in women is very low. While rare and difficult to diagnose, androgen secreting tumors should be suspected in women with hyperandrogenism and hirsutism, especially in the postmenopausal population. Herein we present one case of ovarian Leydig cell tumor (LCT) with markedly elevated serum testosterone levels and frank hirsutism.PATIENT CONCERNS:A 60-year-old woman, presented with increased hair growth and androgenic alopecia and the hormonal laboratory examination showed that she had elevated serum testosterone level and normal dehydroepiandrosterone sulfate (DHEAS), androstenedione, 17- hydroxyprogesterone, cortisol and thyroid stimulating hormone (TSH).DIAGNOSES:The diagnosis of possible testosterone secreting tumor was performed when pelvic computed tomography (CT) and magnetic resonance image (MRI) showed a right adnexal mass of 15mm×16mm indicative of sex cord- stromal tumors.INTERVENTIONS:The patient received laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy.OUTCOMES:After operation, testosterone got back to the normal level and clinical symptoms subsided.LESSONS:It is common that postmenopausal androgen excess is a state of relative or absolute androgen excess originating from the adrenal gland and/or ovaries. In either case, doctors need to assess such patients and exclude relatively rare potential causes of tumors. Any woman who has hirsutism or frank evidence of markedly increased testosterone should exclude this kind of possibility of androgen producing tumors. It is possible to determine the origin of androgen hypersecretion with the severity of symptoms, the extent of androgen excess, and the relevant imaging studies. Since LCT are rare ovarian sex-cord stromal tumors, it can be beneficial for diagnosis with careful research of patient history of the defeminization followed by virilization, and a CT and MRI image.

Microneedle technology relates to pharmacy, polymer chemistry and micromachining. Microneedle can effectively deliver insulin into systemic circulation across the skin. This process does not affect the activity of insulin. Compared to subcutaneous injection, microneedles cause less pain for their special structure. This review thoroughly discusses the preparation technologies of the microneedles-based insulin delivery system including solid, hollow, dissolving, phase transition, glucose-responsive microneedle patches. In the meantime, the properties, challenges and clinical/commercial status of the microneedles-based insulin delivery system are also discussed in this review.

Microneedle technology relates to pharmacy, polymer chemistry and micromachining. Microneedle can effectively deliver insulin into systemic circulation across the skin. This process does not affect the activity of insulin. Compared to subcutaneous injection, microneedles cause less pain for their special structure. This review thoroughly discusses the preparation technologies of the microneedles-based insulin delivery system including solid, hollow, dissolving, phase transition, glucose-responsive microneedle patches. In the meantime, the properties, challenges and clinical/commercial status of the microneedles-based insulin delivery system are also discussed in this review.

As a dipeptidyl peptidase-4 (DPP-4) inhibitor used in diabetes mellitus (DM) therapy, saxagliptin (Saxa) has been reported an additional protective benefit of diabetic nephropathy (DN), which might be independent of its glucose-lowering effect. However, the mechanism is not fully understood. In this study, STZ-induced DM rat model received a placebo or Saxa (10mg or 20mg/kg, 8-10 rats in each group). Blood glucose, serum lipid, creatinine, blood urea nitrogen, as well as urine protein and albumin concentration, were examined. Gene expression and protein level of advanced glycation end products (AGEs) and their receptor (RAGE) were also tested. Moreover, markers for oxidative stress and antioxidant ability were determined. The results showed moderate albuminuria in diabetic rats was attenuated after Saxa treatment, consistent with morphological improvement supported by histological analysis. Both AGEs and RAGE levels were elevated in DM group but reduced after Saxa administration. Furthermore, the level of malondialdehyde (MAD), Caspase 3, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in kidney were much lower in Saxa group compared with DM group, indicating the oxidation and apoptosis in DM were ameliorated by Saxa. On the other hand, markers of antioxidation such as total antioxidation capability (TAOC), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD), had a relevant increase, suggesting enhanced antioxidation in the kidney. In conclusion, these findings show that Saxa possesses anti-oxidative activity to ameliorate diabetic renal damage, which is related to the regulation of the AGEs-RAGE axis.