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Eye deformity, a noteworthy embryopathy, is intricately linked with maternal diabetes, frequently resulting in embryonic malformation or even death. In this investigation, a hyperglycemic chick embryo model was established to delve into the protective potential of tamarind shell extract (TSE) on eye development. Chick embryos were administered with TSE (at dosages of 1, 2, and 4 µg/egg) through air sac injection on embryo development day 0 (EDD0) and later exposed to D-glucose (0.4 mmol/egg) on EDD1. To validate our findings, we replicated hyperglycemic environment using D-glucose in ARPE-19 cell model. Our research unveiled that TSE proficiently counters O-GlcNAcylation of proteins in the presence of D-glucose, thereby reinstating levels of key proteins involved in eye development, including Pax6, Daam1, mTOR, and Cdc42. Furthermore, TSE was pinpointed to curtail the D-glucose concentration within the embryo eye, considerably decreasing the accumulation of reactive oxygen species and malondialdehyde accumulation in both the ARPE-19 cells and chick embryos. Beyond its fundamental role in boosting the cellular antioxidative activity, the improved expression of apoptosis-related proteins like Caspase-3, BAX, BCL-2 and other like PI3K and AKT were observed. This suggests a probable activation of the PI3K-AKT-mTOR pathway on ARPE-19 cells by TSE, thereby downregulating apoptotic proteins in ARPE-19 cells during oxidative stress. TSE may become a potent natural countermeasure against D-glucose-induced eye malformation.

Testosterone (T), an environmental androgen, significantly disrupts endocrine systems in wildlife and ecosystems. Despite growing concern over its high levels in aquatic environments, the reproductive toxicity of testosterone and its mechanisms are not well understood. In this study, we investigated the reproductive toxicity and mechanisms of testosterone using Caenorhabditis elegans (C. elegans) and assessed its ecological toxicity through the benchmark dose (BMD) method. Our results indicate that T concentrations exceeding 0.01 μg/L significantly reduce the brood size, decrease germ cell counts, and prolong the generation time in C. elegans as T concentrations increase. Furthermore, to elucidate the specific mechanisms, we analyzed the expression of nhr-69, mpk-1, and other genes involved in sex determination. These findings suggest that the nhr-69-mediated reproductive toxicity of T primarily affects sperm formation and the offspring number by influencing its downstream targets, mpk-1 and fog-1/3, which are critical in the germ cell sex-determining pathway. Additionally, this study determined that the 10% lower boundary of the baseline dose (BMDL10) is 1.160 ng/L, offering a more protective reference dose for the ecological risk assessment of T. The present study suggests that nhr-69 mediates the reproductive toxicity of T by influencing mpk-1 and fog-1/3, critical genes at the end of the germ cell sex-determining pathway, thereby providing a basis for establishing reproductive toxicity thresholds for T.

Approximately 31% of patients with 22q11.2 deletion syndrome (22q11.2DS) have genitourinary system disorders and 6% of them have undescended testes. Haploinsufficiency of genes on chromosome 22q11.2 might contribute to the risk of 22q11.2DS. In this study, we used mice with single-allele deletion in mitochondrial ribosomal protein L40 (Mrpl40+/−) as models to investigate the function of Mrpl40 in testes and spermatozoa development. The penetrance of cryptorchidism in Mrpl40+/− mice was found to be higher than that in wild-type (WT) counterparts. Although the weight of testes was not significantly different between the WT and Mrpl40+/− mice, the structure of seminiferous tubules and mitochondrial morphology was altered in the Mrpl40+/− mice. Moreover, the concentration and motility of spermatozoa were significantly decreased in the Mrpl40+/− mice. In addition, data-independent acquisition mass spectrometry indicated that the expression of genes associated with male infertility was altered in Mrpl40+/− testes. Our study demonstrated the important role of Mrpl40 in testicular structure and spermatozoa motility and count. These findings suggest that Mrpl40 is potentially a novel therapeutic target for cryptorchidism and decreased motility and count of spermatozoa.

Alcohol liver disease (ALD) is one of the leading outcomes of acute and chronic liver injury. Accumulative evidence has confirmed that oxidative stress is involved in the development of ALD. In this study, we used chick embryos to establish ALD model to study the hepatoprotective effects of tamarind shell exttract (TSE). Chick embryos received 25% ethanol (75 μL) and TSE (250, 500, 750 μg/egg/75 μL) from embryonic development day (EDD) 5.5. Both ethanol and TSE were administrated every two days until EDD15. Ethanol-exposed zebrafish and HepG2 cell model were also employed. The results suggested that TSE effectively reversed the pathological changes, liver dysfunction and ethanol-metabolic enzyme disorder in ethanol-treated chick embryo liver, zebrafish and HepG2 cells. TSE suppressed the excessive reactive oxygen species (ROS) in zebrafish and HepG2 cells, as well as rebuilt the irrupted mitochondrial membrane potential. Meanwhile, the declined antioxidative activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), together with the content of total glutathione (T-GSH) were recovered by TSE. Moreover, TSE upregulated nuclear factor erythroid 2—related factor 2 (NRF2) and heme oxyense-1 (HO-1) expression in protein and mRNA level. All the phenomena suggested that TSE attenuated ALD through activating NRF2 to repress the oxidative stress induced by ethanol.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous and widespread human pathogen, which gives rise to a range of diseases, including cold sores, corneal blindness, and encephalitis. Currently, the use of nucleoside analogs, such as acyclovir and penciclovir, in treating HSV-1 infection often presents limitation due to their side effects and low efficacy for drug-resistance strains. Therefore, new anti-herpetic drugs and strategies should be urgently developed. Here, we reported that baicalein, a naturally derived compound widely used in Asian countries, strongly inhibited HSV-1 replication in several models. Baicalein was effective against the replication of both HSV-1/F and HSV-1/Blue (an acyclovir-resistant strain) in vitro. In the ocular inoculation mice model, baicalein markedly reduced in vivo HSV-1/F replication, receded inflammatory storm and attenuated histological changes in the cornea. Consistently, baicalein was found to reduce the mortality of mice, viral loads both in nose and trigeminal ganglia in HSV-1 intranasal infection model. Moreover, an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication. Further investigations unraveled that dual mechanisms, inactivating viral particles and inhibiting IκB kinase beta (IKK-β) phosphorylation, were involved in the anti-HSV-1 effect of baicalein. Collectively, our findings identified baicalein as a promising therapy candidate against the infection of HSV-1, especially acyclovir-resistant strain.

Previous studies have indicated that α1D/1A antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α1D- and α1A- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR in vitro. However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. In vivo, HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). In vitro, HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.

Abstract.: Carnosine is a natural dipeptide that has shown multiple benefits in the treatment of various diseases. This study investigated the ameliorative effects of carnosine on glucose metabolism in restraint-stressed mice. Our results showed that restraint stress could significantly influence glucose metabolism, as reflected by lowered glucose tolerance, hepatic and muscle glycogen content, and increased plasma corticosterone concentration in mice. Oral administration of carnosine (150 and 300 mg/kg) not only reverted stress-induced decline in glucose tolerance and glycogen content in liver and muscle, but also reduced plasma corticosterone level. Carnosine has also significantly suppressed mRNA expression of glucose-6-phosphatase, while elevating glycogen synthase 2, glucokinase and glucose transporter 2 expressions in the liver. The obtained results demonstrated the harmful effects induced by restraint stress, while proving that carnosine could ameliorate stress-induced glucose metabolism disturbance. It is presumable that carnosine exerts its anti-stress effects by indirectly affecting the histaminergic neuron system, modulating the stress-activated hypothalamic–pituitary–adrenal axis and improving glucose metabolism through regulation of the enzymes in the glucose metabolic pathways. Keywords:: carnosine, restraint stress, glucose metabolism disorder, corticosterone, gene expression

Carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, has been characterized as a putative neurotransmitter and serves as a reservoir for brain histamine, which could act on histaminergic neurons system to relieve stress-induced damages. However, understanding of the role of carnosine in stress-evoked immunocompromise is limited. In this study, results showed that when mice were subjected to restraint stress, spleen index and the number of spleen lymphocytes including Natural Killer (NK) cells were obviously decreased. Results also demonstrated that restraint stress decreased the cytotoxic activity of NK cells per spleen (LU(10)/spleen) while the activity of a single NK cell (LU(10)/10(6) cells) was not changed. However, oral administration of carnosine (150 and 300 mg/kg) increased spleen index and number of spleen lymphocytes (including NK cells), and elevated the cytotoxic activity of NK cells per spleen in restraint-stressed mice. These results indicated that carnosine ameliorated stress-evoked immunocompromise through spleen lymphocyte number maintenance. Carnosine was further found to reduce stress-induced elevation of plasma corticosterone level. On the other hand, results showed that carnosine and RU486 (a glucocorticoids receptor antagonist) treatment prevented the reduction in mitochondrion membrane potential and the release of mitochondrial cytochrome c into cytoplasm, increased Bcl-2/Bax mRNA ratio, as well as decreased terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in spleen lymphocytes of stressed mice. The results above suggested that the maintenance of spleen lymphocyte number by carnosine was related with the inhibition of lymphocytes apoptosis caused by glucocorticoids overflow. The stimulation of lymphocyte proliferation by carnosine also contributed to the maintenance of spleen lymphocyte number in stressed mice. In view of the elevated histamine level, the anti-stress effects of carnosine on restraint-evoked immunocompromise might be via carnosine-histamine metabolic pathway. Taken together, carnosine maintained spleen lymphocyte number by inhibiting lymphocyte apoptosis and stimulating lymphocyte proliferation, thus prevented immunocompromise in restraint-stressed mice.

Sweet potato has played an important role in human diets for centuries. Sweet potato is an excellent source of nutrients and natural health-promoting chemicals such as carotenoids, vitamin C, and polyphenols. In this article, we selected forty-eight sweet potato cultivars to evaluate the contents of proximate compositions, phytochemicals, and total antioxidative capacity (TAC). In addition, the sensory taste test was conducted as well. The concentrations of chemical constituents varied significantly among the 48 cultivars. The starch content ranged from 10.58% to 28.08%. The protein concentration was between 2.00% and 12.16%. A noticeable variability was found in vitamin C (8.17–66.09 mg·100 g−1), total polyphenols (0.32–13.82 µg·g−1), and carotenoids (0.22–559.70 µg·g−1). 3,5-dicaffeoylquinic acid was the dominant phenolic acid derivative in all varieties, followed by chlorogenic acid. The content ranges of 3,5-dicaffeoylquinic acid and chlorogenic acid were 0.41–92.18 µg·100 g−1 and 1.59–63.98 µg·100 g−1, respectively. Remarkable DPPH (0.19–0.59 µg·g−1) and ABTS+ (0.19–1.42 µg·g−1) antioxidant activities were also observed in these sweet potatoes. TAC was related to vitamin C, carotenoids, total polyphenols, and caffeic acid derivatives. The purple flesh cultivars, especially Mianzishu-9, Jiheishu-1, and Qianshu-18-5-1, rich in protein, starch, and antioxidants, had immense potential to improve malnutrition and hidden hunger. The dark orange flesh cultivars Hongxiangjiao and Ziyunhongxinshu performed best in sensory taste evaluation, but the nutrients and antioxidant effects were ordinary. These cultivars were suitable for enriching the human food systems. [ABSTRACT FROM AUTHOR]

We study the well-posedness of a hyperbolic quasi-linear version of hydrostatic Navier--Stokes system in I x TT and prove the global well-posedness of the system with initial data which are small and analytic in both variables. We also prove the convergence of such analytic solutions to that of the classical hydrostatic Navier--Stokes system when the delay time converges to zero. Furthermore, we obtain a local well-posedness result in Gevrey class 2 when the initial datum is a small perturbation of some convex function. [ABSTRACT FROM AUTHOR]

We establish the well-posedness of the MHD boundary layer system in Gevrey function space without any structural assumption. Compared to the classical Prandtl equation, the loss of tangential derivative comes from both the velocity and magnetic fields that are coupled with each other. By observing a new type of cancellation mechanism in the system for overcoming the loss derivative degeneracy, we show that the MHD boundary layer system is well-posed with Gevrey index up to 3/2 in both two- and three-dimensional spaces. [ABSTRACT FROM AUTHOR]

We study the well-posedness of the Prandtl system without monotonicity and analyticity assumption. Precisely, for any index σ ∈ [3/2, 2], we obtain the local in time well-posedness in the space of Gevrey class Gσ in the tangential variable and Sobolev class in the normal variable so that the monotonicity condition on the tangential velocity is not needed to overcome the loss of tangential derivative. This answers an open question raised by D. Gérard-Varet and N. Masmoudi [Ann. Sci. École Norm. Sup. (4) 48 (2015), 1273-1325], who solved the case σ = 7/4. [ABSTRACT FROM AUTHOR]

It is well known that the Prandtl boundary layer equation is unstable for general initial data, and is well-posed in Sobolev space for monotonic initial data. Recently, under the Oleinik's monotonicity assumption for the initial datum, R. Alexandre, Y. Wang, C.-J. Xu, and T. Yang [J. Amer. Math. Soc., 28 (2015) pp. 745{784] recovered the local well-posedness of the Cauchy problem in Sobolev space by virtue of an energy method (see also N. Masmoudi and T. K. Wong [Comm. Pure Appl. Math., 68 (2015), pp. 1683{1741.]). In this work, we study the Gevrey smoothing effects of the local solution obtained in R. Alexandre, Y. Wang, C.-J. Xu, and T. Yang [J. Amer. Math. Soc., 28 (2015) pp. 745{784]. We prove that the Sobolev's class solution belongs to some Gevrey class with respect to tangential variables at any positive time. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) has been suggested to increase the risk of cancers. The aim of this study was to investigate the risk of common cancers in Chinese patients with T2DM.Methods: A population-based retrospective cohort study including 36,379 T2DM patients was conducted in Minhang District of Shanghai, China, during 2004 to 2010. All T2DM patients were enrolled from the standardized management system based on local electronic information system. Newly-diagnosed cancer cases were identified by record-linkage with the Shanghai Cancer Registry. Standardized incidence ratios (SIR) and 95% confidence interval (CI) were used to estimate the risk of cancers among T2DM patients.Results: Overall crude incidence rate (CIR) of cancers was 955.21 per 105 person-years in men and 829.57 per 105 person-years in women. Increased risk of cancer was found in both gender, with an SIR being 1.28 (95% CI = 1.17-1.38) in men and 1.44 (95% CI =1.32-1.55) in women. Increased risk of colon (SIR = 1.97; 95% CI = 1.49 to 2.46), rectum (1.72; 1.23 to 2.21), prostate (2.87; 2.19 to 3.56), and bladder cancers (1.98, 1.28 to 2.68) were observed in men and elevated risk of colon (1.67; 1.25 to 2.08), breast (1.66; 1.38 to 1.95), and corpus uteri cancers (2.87; 2.03 to 3.71) were observed in women.Conclusions: Our results indicate that Chinese patients with T2DM may have an increased risk of some cancers, and the increase may vary by sub-sites of cancers. [ABSTRACT FROM AUTHOR]