Polymeric nanoparticles (PNPs) for oral delivery of insulin.

Successful oral insulin administration can considerably enhance the quality of life (QOL) of diabetes patients who must frequently take insulin injections. Oral insulin administration, on the other hand, is seriously hampered by gastrointestinal enzymes, wide pH range, mucus and mucosal layers, which limit insulin oral bioavailability to ≤ 2%. Therefore, a large number of technological solutions have been proposed to increase the oral bioavailability of insulin, in which polymeric nanoparticles (PNPs) are highly promising for oral insulin delivery. The recently published research articles chosen for this review are based on applications of PNPs with strong future potential in oral insulin delivery, and do not cover all related work. In this review, we will summarize the controlled release mechanisms of oral insulin delivery, latest oral insulin delivery applications of PNPs nanocarrier, challenges and prospect. This review will serve as a guide to the future investigators who wish to engineer and study PNPs as oral insulin delivery systems.

Generation of Chemical Space of Compounds for Prostate Cancer Treatment: Biological Activity Prediction, Clustering, and Visualization of Chemical Space.

Designing molecules for pharmaceutical purposes has been a significant focus for several decades. The pursuit of novel drugs is an arduous and financially demanding undertaking. Nevertheless, the integration of computer-assisted frameworks presents a swift avenue for designing and screening drug-like compounds. Within the context of this research, we introduce a comprehensive approach for the design and screening of compounds tailored to the treatment of prostate cancer. To forecast the biological activity of these compounds, we employed machine learning (ML) models. Additionally, an automated process involving the deconstruction and reconstruction of molecular building blocks leads to the generation of novel compounds. Subsequently, the ML models were utilized to predict the biological activity of the designed compounds, and the t-SNE method was employed to visualize the chemical space covered by the novel compounds. A meticulous selection process identified the most promising compounds, and their potential for synthesis was assessed, offering valuable guidance to experimental chemists in their investigative endeavors. Furthermore, fingerprint and heatmap analysis were conducted to evaluate the chemical similarity among the selected compounds. This multifaceted approach, encompassing predictive modeling, compound generation, visualization, and similarity assessment, underscores our commitment to refining the process of identifying potential candidates for further exploration in prostate cancer treatment.

Oxidative Stress and Dopaminergic Metabolism: A Major PD Pathogenic Mechanism and Basis of Potential Antioxidant Therapies

Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS produced during the metabolism of dopamine is immediately neutralized by the endogenous antioxidant defense system (EADS) under physiological conditions. Aging decreases the vigilance of EADS and makes the dopaminergic neurons more vulnerable to oxidative stress. As a result, ROS left over by EADS oxidize the dopamine-derived catechols and produces a number of reactive dopamine quinones, which are precursors to endogenous neurotoxins. In addition, ROS causes lipid peroxidation, uncoupling of the electron transport chain, and DNA damage, which lead to mitochondrial dysfunction, lysosomal dysfunction, and synaptic dysfunction. The mutations in genes such as DNAJC6, SYNJ1, SH3GL2, LRRK2, PRKN, and VPS35 caused by ROS have been associated with synaptic dysfunction and the pathogenesis of Parkinson's disease (PD). The available drugs that are used against PD can only delay the progression of the disease, but they produce various side effects. Through their antioxidant activity, flavonoids can substantiate the EADS of dopaminergic neurons and disrupt the vicious cycle incepted by oxidative stress. In this review, we show how the oxidative metabolism of dopamine generates ROS and dopamine-quinones, which then exert unrestrained OS, causing mutations in several genes involved in the proper functioning of mitochondrion, synapse, and lysosome. Besides, we also present some examples of approved drugs used for the treatment of PD, therapies in the clinical trial phase, and an update on the flavonoids that have been tested to boost the EADS of dopaminergic neurons.

Comparative impact of streptozotocin on altering normal glucose homeostasis in diabetic rats compared to normoglycemic rats.

Diabetes mellitus is a syndrome and an endocrine disorder, primarily considered as a loss of glucose homeostasis because of the insulin action and/or secretion or both. Currently there are more than 150 million people in the world affected by diabetes mellitus with a higher share of Asian and European countries. The current study aimed to investigate the comparative altering properties of streptozotocin (STZ), based on up-turn and down-turn configuration of biochemical, toxicological and hematological parameters in comparison with normoglycemic male albino rats. This comparative study was conducted among normoglycemic and STZ based induced-type 2 diabetic male albino rats groups. The male albino rats were intra-peritoneally injected with STZ with the dose rate of 65 mg/kg body weight for one time to developed type 2 diabetic model. Biochemical (blood glucose, uric acid, urea and creatinine), toxicological (AST, ALT and ALP) and hematological parameters (red and white blood cells) and their functional indices were evaluated in type 2 diabetic induced group along with normoglycemic rats. The STZ based induced- type 2 diabetic rats showed statistically significance (p < 0.001) higher level in the blood glucose, alongwith the change in the levels of biochemical parameters including urea, uric acid, and creatinine. Toxicological parameters comprising AST, ALT and ALP were also shown significance (p < 0.001) as sufficient after experimental evaluation of biologically important parameter in STZ based induced-type 2 diabetic rats. Likewise, the red blood cells, white blood cells and their efficient components were exposed significantly insufficient after the injecting of STZ to induce the rats as type 2 diabetic. The results of the current study indicates the comparatively higher levels of variation among biochemical, toxicological and hematological parameters in STZ based Induced-type 2 diabetic model as compared to normoglycemic group.

Dehydroepiandrosterone Sulfate (DHEAS) Levels in Polycystic Ovarian Syndrome (PCOS).

OBJECTIVE: To compare DHEAS levels among subjects with and without PCOS, evaluating differences between lean-PCOS or obese-PCOS phenotype for insulin resistance, anthropometric indices, glycemic and lipid parameters. STUDY DESIGN: Descriptive study. Study Place and Duration of Study: PNS Hafeez Naval Hospital, Islamabad, Pakistan, from January 2018 to August 2019. METHODOLOGY: Three hundred and twenty-eight subjects were included in the study for evaluation. PCOS was defined as per Rotterdam criteria, while insulin resistance, anthropometric measurements, various hormonal and biochemical analyses were carried out as per standard protocols. Hirsutism was calculated as per modified Ferrimen Gallwey score and free androgen index (FAI) was calculated using formula as: FAI = [(Total testosterone/Sex hormone binding globulin (SHBG)] x100. These subjects underwent clinical biochemical evaluation and were segregated into 2 groups: lean-PCOS and obese-PCOS.   Results: DHEAS levels were higher in subjects with PCOS [(171.50) (111.75-244.25) ug/dl], n=164] than in subjects without PCOS [(130.50) (78.95-189.75) ug/dl, n=164, p<0.001]. Area under curve (AUC) in diagnosing PCOS was highest for modified FG score [0.802, p<0.001], followed by FAI [0.785, p<0.001]. Total testosterone [0.743, p<0.001] and DHEAS [0.637, p<0.001]. DHEAS levels were found to be inversely related to age, anthropometric indices, glycemia, dyslipidemia, nephropathy and reproductive hormones. The DHEAS in lean-PCOS was higher than obese female subjects with or without PCOS. CONCLUSION: DHEAS levels were high in lean-PCOS in comparison to obese-PCOS and non-PCOS females. However, receiver operating curve (ROC) analysis showed DHEAS as a weaker marker for diagnosing PCOS than FAI and modified FG score. Key Words: DHEAS, Polycystic ovarian syndrome (PCOS), Homeostasis model assessment for insulin resistance (HOMAIR), Rotterdam criteria, Free androgen index.

Biosynthesis of Polyhydroxyalkanoates (PHAs) by the Valorization of Biomass and Synthetic Waste.

Synthetic pollutants are a looming threat to the entire ecosystem, including wildlife, the environment, and human health. Polyhydroxyalkanoates (PHAs) are natural biodegradable microbial polymers with a promising potential to replace synthetic plastics. This research is focused on devising a sustainable approach to produce PHAs by a new microbial strain using untreated synthetic plastics and lignocellulosic biomass. For experiments, 47 soil samples and 18 effluent samples were collected from various areas of Punjab, Pakistan. The samples were primarily screened for PHA detection on agar medium containing Nile blue A stain. The PHA positive bacterial isolates showed prominent orange-yellow fluorescence on irradiation with UV light. They were further screened for PHA estimation by submerged fermentation in the culture broth. Bacterial isolate 16a produced maximum PHA and was identified by 16S rRNA sequencing. It was identified as Stenotrophomonas maltophilia HA-16 (MN240936), reported first time for PHA production. Basic fermentation parameters, such as incubation time, temperature, and pH were optimized for PHA production. Wood chips, cardboard cutouts, plastic bottle cutouts, shredded polystyrene cups, and plastic bags were optimized as alternative sustainable carbon sources for the production of PHAs. A vital finding of this study was the yield obtained by using plastic bags, i.e., 68.24 ± 0.27%. The effective use of plastic and lignocellulosic waste in the cultivation medium for the microbial production of PHA by a novel bacterial strain is discussed in the current study.

Role of HbA1c in diagnosis of gestational diabetes mellitus.

OBJECTIVE: To evaluate glycated haemoglobin as a biomarker for diagnosing gestational diabetes mellitus while keeping the oral glucose tolerance test as the gold standard. METHODS: The cross-sectional study was conducted from Januray, 2016, to January, 2018, at PNS Hafeez Hospital, Islamabad, Pakistan and comprised of pregnant subjects who were first subjected to 2-hour oral glucose tolerance test along with the first evaluation of glycated haemoglobin. Clinical evaluation, including history and measurements of anthropometric indices and blood pressure, were also done. On the basis of the results, the subjects were grouped as those having gestational diabetes mellitus (group A) and those without it (group B). Data was analysed using SPSS 15. RESULTS: Of the 280 subjects, gestational diabetes mellitus was found in 50(17.85%). Differences in glycated haemoglobin between the groups was significant (p<0.002). Glycated haemoglobin test provided sensitivity of 70% and specificity of 84.78%. CONCLUSIONS: With due adjustments, glycated haemoglobin testing can help in reducing the frequency of oral glucose tolerance test.

A review on structure, extraction, and biological activities of polysaccharides isolated from Cyclocarya paliurus (Batalin) Iljinskaja.

Cyclocarya paliurus is essential and only living specie of the genus Cyclocarya Iljinskaja. The leaves of this plant have been extensively used as food in the form of tea and green vegetable. Many compounds have been isolated from this plant, and their useful aspects explored, including the polysaccharides. Studies conducted on leaves show that different methods of extraction have been used, as well as a combination of different techniques that have been applied to isolate polysaccharides from the leaves. Their structure has been elucidated because the activity of polysaccharides mainly depends upon their composition. It has been reported that different activities exhibited by the isolated crude, purified as well as modified polysaccharides include, anticancer, anti-inflammatory, antioxidant, antimicrobial, anti-hyperlipidemic and anti-diabetic activities. In some studies, a comparison of crude extract, as well as purified polysaccharide, has been performed. In this review, we have summarized all the available literature available on the methods of extraction, structure, and biological activities of polysaccharides from the leaves of C. paliurus and indicated the potential research areas that should be focused on future studies. We believe that this review will provide an up to date knowledge regarding polysaccharides of C. paliurus for the researchers.

Synergistic Neuroprotective Effect of Endogenously-Produced Hydroxytyrosol and Synaptic Vesicle Proteins on Pheochromocytoma Cell Line Against Salsolinol.

Oxidative stress triggers a lethal cascade, leading to Parkinson's disease by causing degeneration of dopaminergic neurons. In this study, eight antioxidants were screened for their neuroprotective effect on PC12 cells (pheochromocytoma cell line) under oxidative stress induced by salsolinol (OSibS). Hydroxytyrosol was found to be the strongest neuroprotective agent; it improved viability of PC12 cells by up to 81.69% under OSibS. Afterward, two synaptic vesicle proteins, synapsin-1 and septin-5, were screened for their neuroprotective role; the overexpression of synapsin-1 and the downregulation of septin-5 separately improved the viability of PC12 cells by up to 71.17% and 67.00%, respectively, compared to PC12 cells only treated with salsolinol (PoTwS) under OSibS. Subsequently, the PC12+syn++sep- cell line was constructed and pretreated with 100 µM hydroxytyrosol, which improved its cell viability by up to 99.03% and led to 14.71- and 6.37-fold reductions in the levels of MDA and H2O2, respectively, and 6.8-, 12.97-, 10.57-, and 7.57-fold increases in the activity of catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase, respectively, compared to PoTwS under OSibS. Finally, alcohol dehydrogenase-6 from Saccharomyces cerevisiae was expressed in PC12+syn++sep- cells to convert 3,4-dihydroxyphenylacetaldehyde (an endogenous neurotoxin) into hydroxytyrosol. The PC12+syn++sep-+ADH6+ cell line also led to 22.38- and 12.33-fold decreases in the production of MDA and H2O2, respectively, and 7.15-, 13.93-, 12.08-, and 8.11-fold improvements in the activity of catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase, respectively, compared to PoTwS under OSibS. Herein, we report the endogenous production of a powerful antioxidant, hydroxytyrosol, from 3,4-dihydroxyphenylacetaldehyde, and evaluate its synergistic neuroprotective effect, along with synapsin-1 and septin-5, on PC12 cells under OSibS.

Self-Redirection of Metabolic Flux Toward Squalene and Ethanol Pathways by Engineered Yeast.

We have previously reported that squalene overproducing yeast self-downregulate the expression of the ethanol pathway (non-essential pathway) to divert the metabolic flux to the squalene pathway. In this study, the effect of co-production of squalene and ethanol on other non-essential pathways (fusel alcohol pathway, FA) of Saccharomyces cerevisiae was evaluated. However, before that, 13 constitutive promoters, like IRA1p, PET9p, RHO1p, CMD1p, ATP16p, USA3p, RER2p, COQ1p, RIM1p, GRS1p, MAK5p, and BRN1p, were engineered using transcription factor bindings sites from strong promoters HHF2p (-300 to -669 bp) and TEF1p (-300 to -579 bp), and employed to co-overexpress squalene and ethanol pathways in S. cerevisiae. The FSE strain overexpressing the key genes of the squalene pathway accumulated 56.20 mg/L squalene, a 16.43-fold higher than wild type strain (WS). The biogenesis of lipid droplets was stimulated by overexpressing DGA1 and produced 106 mg/L squalene in the FSE strain. AFT1p and CTR1p repressible promoters were also characterized and employed to downregulate the expression of ERG1, which also enhanced the production of squalene in FSE strain up to 42.85- (148.67 mg/L) and 73.49-fold (255.11 mg/L) respectively. The FSE strain was further engineered by overexpressing the key genes of the ethanol pathway and produced 40.2 mg/mL ethanol in the FSE1 strain, 3.23-fold higher than the WS strain. The FSE1 strain also self-downregulated the expression of the FA pathway up to 73.9%, perhaps by downregulating the expression of GCN4 by 2.24-fold. We demonstrate the successful tuning of the strength of yeast promoters and highest coproduction of squalene and ethanol in yeast, and present GCN4 as a novel metabolic regulator that can be manipulated to divert the metabolic flux from the non-essential pathway to engineered pathways.

The Effect of Gamma-Ray-Induced Central Nervous System Injury on Peripheral Immune Response: An In Vitro and In Vivo Study.

Radiotherapy to treat brain tumors can potentially harm the central nervous system (CNS). The radiation stimulates a series of immune responses in both the CNS as well as peripheral immune system. To date, studies have mostly focused on the changes occurring in the immune response within the CNS. In this study, we investigated the effect of γ-ray-induced CNS injury on the peripheral immune response using a cell co-culture model and a whole-brain irradiation (WBI) rat model. Nerve cells (SH-SY5Y and U87 MG cells) were γ-ray irradiated, then culture media of the irradiated cells (conditioned media) was used to culture immune cells (THP-1 cells or Jurkat cells). Analyses were performed based on the response of immune cells in conditioned media. Sprague-Dawley rats received WBI at different doses, and were fed for one week to one month postirradiation. Spleen and peripheral blood were then isolated and analyzed. We observed that the number of monocytes in peripheral blood, and the level of NK cells and NKT cells in spleen increased after CNS injury. However, the level of T cells in spleen did not change and the level of B cells in the spleen decreased after γ-ray-induced CNS injury. These findings indicate that CNS injury caused by ionizing radiation induces a series of changes in the peripheral immune system.

A secret that underlies Parkinson's disease: The damaging cycle.

Parkinson's disease (PD) is a movement disorder, and its common characteristics include the loss of dopaminergic neurons and the accumulation of a special type of cytoplasmic inclusions called Lewy bodies in the substantia nigra pars compacta, which are more prevalent in the elderly. However, the pathophysiology of PD is still elusive. In this review, we summarized five common factors involved in PD, namely, (i) oxidative stress, (ii) mitochondrial dysfunction, (iii) inflammation, (iv) abnormal α-synuclein, and (v) endogenous neurotoxins, and proposed a hypothesis involving a damaging cycle. Oxidative stress-triggered aldehydes react with biogenic amines to produce endogenous neurotoxins. They cause mitochondrial dysfunction and the formation of inflammasomes, which induce the activation of neuroglial cells and the infiltration of T lymphocytes. The synergistic effect of these processes fosters chronic inflammation and α-synuclein aggregation and further exacerbates the impact of oxidative stress to establish a damaging cycle that eventually results in the degeneration of dopaminergic neurons. This damaging cycle provides an explanation of progressive neuronal death during the pathogenesis of PD and provides new potential targets beneficial for developing new drugs and approaches for clinical neuroprotection.

Glucose Tolerance versus HbA1c Results as Depictive of Gestational Diabetes Mellitus.

OBJECTIVE: To evaluate glucose tolerance patterns in pregnant ladies undergoing 2-hour oral glucose tolerance test (OGTT) for comparing fasting, 1-hour, 2-hour post-glucose load results, HbA1c, sum of all glucose readings with and without gestational diabetes mellitus (GDM) using International Association of the Diabetes and Pregnancy Study Group (IADPSG) diagnostic criteria. STUDY DESIGN: Cross-sectional analysis. PLACE AND DURATION OF STUDY: PNS Hafeez, Naval Hospital, Islamabad, from January 2016 to July 2017. METHODOLOGY: For 280 evaluated subjects reporting in mid-pregnancy for OGTT, results were segregated into four groups based upon comparison of 2-hour glucose result with 1-hour glucose. Group-1 2-hour results drop being >2.0 mmol/L than1-hour results, group-2 with 2-hour result between <2.0 to >0.5 mmol/L than peak at 1-hour, and group-3 with either 2-hour glucose drop being <0.5mmol/L or >1-hour results. Further, the ROC curve analysis was performed to compare the AUC for fasting plasma glucose, 1-hour post OGTT result, 2-hour post-OGTT result, factor additive of all OGTT readings and HbA1c. RESULTS: There was a progressive rise in HbA1c from group-1 to group-3 (p<0.001). Area under curve (AUC) for various diagnostic parameters for diagnosing GDM for additive value of all glucose results was 0.962 (95% CI: 0.935-0.988), 0.881 (95% CI: 0.818-0944) for plasma glucose at 2-hour, for plasma glucose at 1-hour 0.898 (95% CI: 0.0.842-0.954), 0.831 (95% CI: 0.0.762-0.901) for fasting plasma glucose and 0.668 (95% CI: 0.0.578-0.759) for HbA1c (p<0.001). CONCLUSION: Pregnant ladies demonstrating poor tolerance to glucose at 2-hour were observed to have higher HbA1c levels.

Green tea (Camellia sinensis) and l-theanine: Medicinal values and beneficial applications in humans-A comprehensive review.

Green tea (Camellia sinensis) is a famous herb, and its extract has been extensively used in traditional Chinese medicinal system. In this context, several studies have revealed its health benefits and medicinal potentialities for several ailments. With ever increasing scientific knowledge, search for safer, potential and novel type of health-related supplements quest, scientists are re-directing their research interests to explore natural resources i.e. medicinal herbs/plant derived compounds. Green tea consumption has gained a special attention and popularity in the modern era of changing lifestyle. The present review is aimed to extend the current knowledge by highlighting the importance and beneficial applications of green tea in humans for safeguarding various health issues. Herein, we have extensively reviewed, analyzed, and compiled salient information on green tea from the authentic published literature available in PubMed and other scientific databases. Scientific literature evidenced that owing to the bioactive constituents including caffeine, l-theanine, polyphenols/flavonoids and other potent molecules, green tea has many pharmacological and physiological functions. It possesses multi-beneficial applications in treating various disorders of humans. This review also provides in-depth insights on the medicinal values of green tea which will be useful for researchers, medical professionals, veterinarians, nutritionists, pharmacists and pharmaceutical industry. Future research emphasis and promotional avenues are needed to explore its potential therapeutic applications for designing appropriate pharmaceuticals, complementary medicines, and effective drugs as well as popularize and propagate its multidimensional health benefits.