Rosa canina extract relieves methylation alterations of pancreatic genes in STZ-induced diabetic rats : Gene methylation in diabetic rats treated with an extract.

BACKGROUND: Diabetes is a chronic metabolic disease that affects many parts of the body. Considering diabetes as a beta cells' defect and loss, the focus is on finding mechanisms and compounds involved in stimulating the function and regeneration of pancreatic ß-cells. DNA methylation as an epigenetic mechanism plays a pivotal role in the ß-cells' function and development. Considering the regenerative and anti-diabetic effects of Rosa canina extract, this study aimed to assess the methylation levels of Pdx-1, Pax-4, and Ins-1 genes in diabetic rats treated with Rosa Canina extract. METHODS AND RESULTS: Streptozotocin-induced diabetic rats were used to evaluate the frequency of Pdx-1, Pax-4, and Ins-1 gene methylation. Treatment groups were exposed to Rosa canina as spray-dried and decoction extracts. Following blood glucose measurement, pancreatic DNA was extracted and bisulfited. Genes' methylation was measured using MSP-PCR and qRT-PCR techniques. Oral administration of Rosa canina extracts significantly reduced blood sugar levels in diabetic rats compared to the control group. The methylation levels of the Pdx-1, Pax-4, and Ins-1 genes promoter in streptozotocin-induced diabetic rats increased compared to the control rats while, the treatment of diabetic rats with Rosa canina extracts, spray-dried samples especially, led to a decreased methylation in these genes. CONCLUSION: The results of this study showed that Rosa canina extract as a spray-dried sample could be effective in treating diabetes by regulating the methylation of genes including Pdx-1, Pax-4, and Ins-1 involved in the activity and regeneration of pancreatic islet cells.

In vitro investigation of wound healing performance of PVA/chitosan/silk electrospun mat loaded with deferoxamine and ciprofloxacin.

Electrospinning is an advanced method used for developing wound dressings. Biopolymer-based electrospun mats have been extensively studied in tissue engineering due to their similarity to the extracellular matrix. In this study, electrospun poly(vinyl alcohol)/chitosan/silk fibroin (PChS) mat demonstrated improved mechanical properties, including tensile strength, strain at break, and Young's modulus, compared to electrospun poly(vinyl alcohol) and poly(vinyl alcohol)/chitosan mats. Similarly, the swelling capability, thermal stability, and hydrophilicity were higher in the PChS mat compared to the other ones. Hence, the PChS mat was selected for further investigation. Ciprofloxacin (CIP) was added to the PChS electrospinning solution at 5 % and 10 % concentration, and deferoxamine (DFO) was immobilized on CIP-loaded mats at 1 and 2 g/L concentration using a polydopamine linker. Evaluating mats with the dimensions of 1 × 1 cm2 showed that those containing 5 % and 10 % CIP exhibited bactericidal activity against Escherichia coli and Staphylococcus aureus. Moreover, Human dermal fibroblast cells were compatible with the fabricated mats, as confirmed by the MTT assay. Finally, drug-loaded mats had a positive effect on wound healing in a scratch test, and mats with 10 % CIP and 2 g/L DFO showed the highest effect on promoting wound healing, indicating potential for use as a wound dressing.

Codelivery of resveratrol melatonin utilizing pH responsive sericin based nanocarriers inhibits the proliferation of breast cancer cell line at the different pH.

Protein-based nanocarriers have demonstrated good potential for cancer drug delivery. Silk sericin nano-particle is arguably one of the best in this field. In this study, we developed a surface charge reversal sericin-based nanocarrier to co-deliver resveratrol and melatonin (MR-SNC) to MCF-7 breast cancer cells as combination therapy. MR-SNC was fabricated with various sericin concentrations via flash-nanoprecipitation as a simple and reproducible method without complicated equipment. The nanoparticles were subsequently characterized for their size, charge, morphology and shape by dynamic light scattering (DLS) and scanning electron microscope (SEM). Nanocarriers chemical and conformational analysis were done by fourier transform infrared spectroscopy (FT-IR) and circular dichroism (CD) respectively. In vitro drug release was determined at different pH values (7.45, 6.5 and 6). The cellular uptake and cytotoxicity were studies using breast cancer MCF-7 cells. MR-SNC fabricated with the lowest sericin concentration (0.1%), showed a desirable 127 nm size, with a net negative charge at physiological pH. Sericin structure was preserved entirely in the form of nano-particles. Among the three pH values we applied, the maximum in vitro drug release was at pH 6, 6.5, and 7.4, respectively. This pH dependency showed the charge reversal property of our smart nanocarrier via changing the surface charge from negative to positive in mildly acidic pH, destructing the electrostatic interactions between sericin surface amino acids. Cell viability studies demonstrated the significant toxicity of MR-SNC in MCF-7 cells at all pH values after 48 h, suggesting a synergistic effect of combination therapy with the two antioxidants. The efficient cellular uptake of MR-SNC, DNA fragmentation and chromatin condensation was found at pH 6. Nutshell, our result indicated proficient release of the entrapped drug combination from MR-SNC in an acidic environment leading to cell apoptosis. This work introduces a smart pH-responsive nano-platform for anti-breast cancer drug delivery.

The anti-cancer effect of resveratrol nano-encapsulated supplements against breast cancer via the regulation of oxidative stress.

AIM: Several shreds of evidence have supported the growth-inhibitory effect of resveratrol in breast cancer. Owing to the low efficiency, we aimed to fabricate an ACN nanoparticle containing resveratrol to target the proliferation of breast cancer cells. METHODS: Resveratrol encapsulation was characterized using spectrophotometry, FTIR, and SEM. The cytotoxicity and antioxidant activities of compounds were evaluated by MTT, NO, FRAP, and qRT-PCR assays on MCF7 and SKBr3 cells. RESULTS: Our result found that the encapsulation efficiency was 87%, the particle size was 200 ± 15 nm, and the zeta potential was 31 ± 0.4 mV. The prepared RES + ACN had controlled in vitro release. RES + ACN nanoparticle showed a significantly increased cytotoxicity in both cell lines. The reduced level of NO and enhance antioxidative content in both cells, especially the MCF7, were in line with increased expression of Nrf2 and SOD as well as more apoptotic effect. CONCLUSION: Decreased growth and increased expression of Nrf2 in MCF7 compared to SKBr3 cells proved that the upregulation of Nrf2 by nanoresveratrol is likely contributed to its relationship with ER/PR signaling factors, albeit its precise mechanism is needed to be more elucidated.

Gentamycin Rationally Repositioned to Inhibit miR-34a Ameliorates Oxidative Injury to PC12 Cells.

Ischemic stroke accompanies oxidative stress and cell death in the cerebral tissue. The microRNA miR-34a plays a pivotal role in this molecular pathology. This study presents the rational repositioning of aminoglycosidic antibiotics as miR-34a antagonists in order to assess their efficiency in protecting the PC12 stroke model cells from oxidative stress occurring under cerebral ischemic conditions. A library of 29 amino-sugar compounds were screened against anticipated structural models of miR-34a through molecular docking. MiR-ligand interactions were mechanistically studied by molecular dynamics simulations and free-energy calculations. Cultured PC12 cells were treated by H2O2 alone or in combination with gentamycin and neomycin as selected drugs. Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) and annexin V-FITC/propidium iodate (PI) double staining assays, respectively. The expression levels of key factors involved in cell proliferation, oxidative stress, and apoptosis in treated PC12 cells were measured through a quantitative real-time polymerase chain reaction and flow cytometric annexin V-FITC/PI double staining assays. A stable and energetically favorable binding was observed for miR-34a with gentamycin and neomycin. Gentamycin pretreatments followed by H2O2 oxidative injury led to increased cell viability and protected PC12 cells against H2O2-induced apoptotic events. This study will help in further understanding how the suppression of miR-34a in neural tissue affects the cell viability upon stroke.

Anti-diabetic Effects of Macronutrients via Modulation of Angiogenesis: A Comprehensive Review on Carbohydrates and Proteins.

BACKGROUND: Diabetes is a major global health concern, manifesting the symptoms of chronic hyperglycemia. Either insufficient or excessive angiogenesis is generally involved in the pathogenesis of diabetes and its complications. OBJECTIVE: Given that macronutrients are important dietary players in global health issues, we aimed to review the role of macronutrients, including carbohydrates and proteins, to manage diabetes via angiogenesis modulation. METHODS: Sixteen studies regarding the effects of macronutrients, including carbohydrates and proteins derived from plants, fungus, bacteria, and their derivatives, on angiogenesis in diabetes were included in our study. RESULTS: Reviewing these studies suggests that carbohydrates, including low molecular weight fucoidan (LMWF), Astragalus polysaccharide (APS), and Ganoderma lucidum polysaccharide (Gl-PS), as well as oligopeptides, like sea cucumber-isolated small molecule oligopeptides (SCCOPs), can induce angiogenesis in the process of wound healing. Considering retinopathy, carbohydrates, including Diphlorethohydroxycarmalol (DPHC), Lyciumbarbarum (LBP), Sulfated K5 Escherichia coli polysaccharide (K5-N, OS (H)), and carnosine suppressed retinal angiogenesis. Furthermore, rice bran protein (RBP) ameliorated angiogenesis in diabetic nephropathy. Carbohydrates, including DPHC, Anoectochilus roxburghii polysaccharide (ARP), and LMWF, showed beneficial effects on endothelial cell dysfunction. CONCLUSION: In conclusion, data suggest that a number of macronutrients, including proteins and carbohydrates, could have protective effects against complications of diabetes via modulation of angiogenesis.

Endoplasmic reticulum as a therapeutic target in type 2 diabetes: Role of phytochemicals.

Type 2 diabetes mellitus (T2DM) is a metabolic disorders characterized by insulin resistance and ß-cell dysfunction with an increasing worldwide incidence. Several studies have revealed that long-term glucotoxicity results in ß-cell failure and death through induction of endoplasmic reticulum (ER) stress. Owing to the chronic progression of T2DM and the low effectiveness of antidiabetic drugs in long-term use, medicinal plants and their secondary metabolites seem to be the promising alternatives. Here we have provided a comprehensive review regarding the role of phytochemicals to alleviate ER stress in T2DM. Ginsenoside compound K, baicalein, quercetin, isopulegol, kaempferol, liquiritigenin, aspalathin, and tyrosol have demonstrated remarkable improvement of T2DM via modulation of ER stress. Arctigenin and total glycosides of peony have been shown to be effective in the treatment of diabetic retinopathy through modulation of ER stress. The effectiveness of grape seed proanthocyanidins and wolfberry is also shown in the relief of diabetic neuropathy and retinopathy. Resveratrol is involved in the prevention of atherosclerosis via ER stress modulation. Taken together, the data described herein revealed the capability of herbal constituents to prevent different complications of T2DM via a decrease in ER stress which open new doors to the treatment of diabetes.

Notch signaling-induced cyclin d1 in diabetes ameliorating effects of the isolated polysaccharide from Rosa canina: In vitro and in vivo studies.

Notch signaling has a role in the expansion of the pancreas and the pathogenesis of diabetes. Modulation of Notch signaling by natural products seems to pave the way for treating diabetes. This research aimed to scrutinize the involvement of the Notch cascade in the diabetes-ameliorating effects of an isolated polysaccharide from Rosa canina. The isolated polysaccharide was characterized using Fourier transform infrared, nuclear magnetic resonance, high-performance gel-permeation chromatography, and liquid chromatography with tandem mass spectrometry techniques. Rat pancreatic ß cells and STZ-induced diabetic rats were treated with the isolated polysaccharide. MTT assay, cell cycle analysis, quantative realtime-polymerase chain reaction, immunohistochemistry, and immunoblotting were used to reveal the growth and the expression levels of Notch1, DLL4, Jagged-1, hes1, Ins-1, Pdx-1, and cyclin d1 in treated and untreated pancreatic cells and tissues. The ameliorating effect of the polysaccharide in STZ-treated cells was accomplished by upregulation of cyclin d1 and hes1 as well as cell cycle progression. Notch inhibition by LY-411575 was associated with the downregulation of cyclin d1 which upregulates with polysaccharide treatment. The significant expression of cyclin d1 (90%) and nuclear expression of hes1 in the pancreas of the polysaccharide group were accompanied by improvement of hyperglycemia and associated biochemical factors as well as regeneration of islet cells as compared to untreated diabetic rats. Based on these findings, upregulation of Notch signaling-induced cyclin d1 could be proposed as the underlying diabetes-reducing effects of the isolated polysaccharide derivative implying that cyclin d1 actuation through activation of the Notch-DLL4 circuit may play the causal role in the treatment of diabetes.

Neuroprotective effect of naringenin-loaded solid lipid nanoparticles against streptozocin-induced neurotoxicity through autophagy blockage.

Autophagy is a pivotal contributing factor to modulate the progression of neurodegenerative diseases. Although naringenin (Nar) has shown beneficial effects against neurodegenerative diseases, its poor solubility and bioavailability have limited its application. The present research aimed to design a nanostructured formulation of Nar to achieve an enhanced therapeutic effect. Herein, Nar-loaded solid lipid nanoparticles (Nar-SLNs) were prepared and characterized. Then, PC12 cells were exposed to streptozocin (STZ) and/or Nar and Nar-SLNs in vitro to clarify the protective effect of Nar and its nanoformulation against STZ-stimulated neurotoxicity. The empty SLNs and Nar-SLNs indicated a narrow polydispersity index value with a negative zeta potential. As determined by the scanning electron microscopy images, the nanoparticles had a spherical shape and were less than 20 nm in size. FTIR results demonstrated the interaction between Nar and SLNs and supported the presence of Nar in the nanoparticle. The nanoformulation revealed an initial burst release followed by a sustained release manner. Treatment of PC12 cells with STZ resulted in mitochondrial dysfunction and increased autophagic markers, including LC3-II, Beclin1, Akt, ATG genes, and accumulation of miR-21 and miR-22. Both Nar and Nar-SLNs pre-treatment improved cell survival and augmented mitochondrial membrane potential, accompanied by reduced autophagic markers expression. However, Nar-SLNs were more effective than free Nar. As a result, our findings suggested that SLNs effectively enhance the neuroprotective effect of Nar, and Nar-SLNs may be a promising candidate to suppress or prevent STZ-elicited neurotoxicity. PRACTICAL APPLICATIONS: According to the beneficial effect of Nar in the management of neurodegenerative diseases, we evaluated the protective effect of Nar and Nar-SLNs against STZ-stimulated neurotoxicity and analyzed the role of autophagy in STZ-stimulated neurotoxicity. Our results proposed that Nar-SLNs could be a promising option for neurological disorders prevention through autophagy suppression.

New Insights into the Biosensing of Parkinson's Disease Biomarkers: A Concise Review.

BACKGROUND: Parkinson's disease (PD) is a long-term, degenerative, and neurological disease in which a person loses control of certain body functions. The formulation of novel effective therapeutics for PD as a neurodegenerative disease requires accurate and efficient diagnosis at the early stages. OBJECTIVE: Analyzing data gathered by measurable signals converted from biological reactions allows for qualitative and quantitative evaluations. Among various approaches reported so far, biosensors are powerful analytical tools that have been used in detecting the biomarkers of PD. METHODS: Biosensor's biological recognition components include antibodies, receptors, microorganisms, nucleic acids, enzymes, cells and tissues, and biomimetic structures. This review introduces electrochemical, optical, and optochemical detection of PD biomarkers based on recent advances in nanotechnology and material science, which resulted in the development of high-performance biosensors in this field. RESULTS: PD biomarkers such as α-synuclein protein, dopamine (DA), urate, ascorbic acid, miRNAs, and their biological roles are summarized. Additionally, the advantages and disadvantages of the usual standard methods are reviewed. We compared electrochemical, optical, and optochemical biosensors' properties and novel strategies for higher sensitivity and selectivity. CONCLUSION: The development of novel biosensors is required for the early diagnosis of PD as sensitive, rapid, reliable, and cost-effective systems.

Immunoengineering Biomaterials in Cell-Based Therapy for Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by low insulin production and chronic hyperglycemia due to destruction of pancreatic ß-cells. Cell transplantation is an attractive alternative approach compared to insulin injection. However, cell therapy has been limited by major challenges, including life-long requirement for immunosuppressive drugs to prevent host immune responses. Encapsulation of the transplanted cells can solve the problem of immune rejection, by providing a physical barrier between the transplanted cells and the recipient's immune cells. Despite current disputes in cell encapsulation approaches, thanks to recent advances in the fields of biomaterials and transplantation immunology, extensive effort has been dedicated to immunoengineering strategies, in combination with encapsulation technologies, to overcome the problem of host's immune responses. This review summarizes the most commonly used encapsulation and immunoengineering strategies combined with cell therapy, which have been applied as a novel approach to improve cell replacement therapies for management of T1D. Recent advances in the fields of biomaterial design, nanotechnology, as well as deeper knowledge about immune modulation had significantly improved cell encapsulation strategies. However, further progress requires combined application of novel immunoengineering approaches and islet/ß-cell transplantation. Impact statement Cell encapsulation shows promising potential in preventing host's immune responses and rejection of islets or ß-cells by providing a selectively permeable barrier between the host and the transplanted cells. Innovative materials, conformal nanocoatings, and immunomodulation have provided promising approaches in the field of encapsulation technology. Novel nanocarriers have been synthesized to release and deliver immunosuppressive agents to islets/ß-cells within the capsules in a controlled manner. The immunoengineering approach (immunosuppressive and immunomodulatory agents) could overcome the challenges of cell replacement therapy in type 1 diabetes.

Anti-Diabetic Effects of Isolated Lipids from Natural Sources through Modulation of Angiogenesis.

BACKGROUND: Aberrant angiogenesis plays a fateful role in the development of diabetes and diabetic complications. Lipids, as a diverse group of biomacromolecules, are able to relieve diabetes through the modulation of angiogenesis. OBJECTIVES: Owing to the present remarkable anti-diabetic effects with no or few side effects of lipids, the aim of this study was to assess the state-of-the-art research on anti-diabetic effects of lipids via the modulation of angiogenesis. METHODS: To study the effects of lipids in diabetes via modulation of angiogenesis, we have searched the electronic databases including Scopus, PubMed, and Cochrane. RESULTS: The promising anti-diabetic effects of lipids were reported in several studies. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil (FO) were reported to significantly induce neovasculogenesis in high glucose (HG)-mediated endothelial progenitor cells (EPCs) with neovasculogenesis dysfunction in type 2 diabetic mice. Linoleic acid, mono-epoxy-tocotrienol- α (MeT3α), and ginsenoside Rg1 facilitate wound closure and vessel formation. N-Palmitoylethanolamine (PEA), α-linolenic acid (ALA), omega-3 (ω3) lipids from flaxseed (FS) oil, ω-3 polyunsaturated fatty acids (PUFA), lipoic acid, taurine, and zeaxanthin (Zx) are effective in diabetic retinopathy via suppression of angiogenesis. Lysophosphatidic acid, alkyl-glycerophosphate, crocin, arjunolic acid, α-lipoic acid, and FS oil are involved in the management of diabetes and its cardiac complications. Furthermore, in two clinical trials, R-(+)-lipoic acid (RLA) in combination with hyperbaric oxygenation therapy (HBOT) for treatment of chronic wound healing in DM patients, as well as supplementation with DHA plus antioxidants along with intravitreal ranibizumab were investigated for its effects on diabetic macular edema. CONCLUSION: Proof-of-concept studies presented here seem to well shed light on the anti-diabetic effects of lipids via modulation of angiogenesis.

Modulation of Notch signaling and angiogenesis via an isolated polysaccharide from Momordica charantia in diabetic rats.

Given the impact of notch signaling in the modulation of metabolic diseases and normal tissue homeostasis, this study aimed to evaluate whether notch signaling has a role in anti-diabetic and islet regenerative effects of the isolated polysaccharide from Momordica charantia in diabetic rats. The polysaccharide was isolated from M. charantia (MCP) and was characterized by using FTIR and LC-MS/MS. The diabetic model was established by intraperitoneal administration of streptozotocin in male Wistar rats and grouped into control, diabetic, metformin (500 mg kg-1  day-1 ), and treatment (10 mg kg-1  day-1 ) groups. The levels of Hes1, Notch 1, DLL4, Jagged1, Pdx1, CD34, CD31, and VEGF were analyzed by using immunohistochemistry and real-time PCR. Structural analyses have revealed the polysaccharide structure of the isolated fraction. High blood glucose was normalized by MCP treatment in diabetic rats. MCP scaled up the mRNA levels of Ins1, jagged1, Pdx1, and Hes1 while it scaled down the levels of Notch1, Dll4, and the ratio of Bax/Bcl2 in diabetic rats. Furthermore, the immunohistochemistry staining levels of hes1, cyclin d1, and VEGF proteins were increased in the pancreas of MCP-treated diabetic rats compared to the diabetic group. These findings provide insights into the anti-diabetic potential of MCP through modulation of islets' regeneration and suggest that modulation of notch and angiogenesis pathways may play a pivotal role in the restoration of the islets to relieve diabetes. PRACTICAL APPLICATIONS: Polysaccharides extracted from Momordica charantia could normalize the level of blood glucose in STZ-induced type 2 diabetic rats through modulation of notch and angiogenesis singling pathways. Given that this effect was associated with the increased expression of Pdx-1 and Insulin in the pancreas, the isolated polysaccharide is expected to be introduced as a convenient medicine in the treatment of diabetes through modulation of ß-cell regeneration.

Purification and Characterization of an Extracellular Alkaline Solvent-stable Metalloprotease Secreted from Newly Isolated Bacillus sp. DEM05: Optimization of Protease Production.

BACKGROUND: Proteases play an important role in food, leather, detergent, and medical technologies. OBJECTIVES: In the current study, an alkaliphilic solvent-stable thermotolerant metalloprotease was isolated from Bacillus sp. DEM05. MATERIAL AND METHODS: For culture optimization, carbon, and nitrogen sources as well as incubation temperature, pH, and time were examined. RESULTS: Herein the highest outcome for bacterial growth and protease production was obtained after 72 h incubation (pH 7) at 37 °C. DEM05 protease was successfully purified and the specific activity of the protease was 1075 U.mg-1. The purity of the enzyme was verified by SDS-PAGE electrophoresis as a single band of 30 kDa. The optimal activity of the enzyme was at pH 10 and 50 °C. H2O2, SDS, Triton X-100, Zn2+, Co2+, and Cu2+ could increase the protease activity. EDTA inhibited the protease activity, revealed that it can be classified as a metalloprotease. The enzyme was compatible with the water-miscible and water-immiscible organic solvents and proteolyzed several substrates, implying the wide substrate specificity. CONCLUSIONS: The results brought convincing evidence that DEM05 protease could be recruited as a novel prevailing protease that can be earmarked on industrial and medical technologies.

Antidiabetic potential of the isolated fractions from the plants of Rosaceae family in streptozotocin-induced diabetic rats.

BACKGROUND AND PURPOSE: Diabetes is a group of multifactorial disorders characterized by chronic-elevated blood glucose levels (hyperglycemia). Natural remedies are used as alternative medications to treat diabetes. Here, we tested the protective effect of the plant extracts of the Rosaceae family on improving insulin secretion and repairing the pancreatic beta cells in diabetic rats. EXPERIMENTAL APPROACH: The oligosaccharide fraction was isolated from the Rosaceae family of herbs. LC-MS/MS was applied to characterize the isolated fractions. The male Wistar rats were randomly divided into six groups, 10 each, including the control group with no intervention, diabetic rats without treatment, diabetic rats that received the extract of Malus domestica (apple), Cydonia oblonga (quince), Prunus persica (nectarine), and Prunus persica (peach), separately. Rats were monitored for the weight, fasting plasma glucose, and insulin levels. The effect of extracts in streptozotocin (STZ)-induced diabetic rats on the pancreatic islets was evaluated by morphometric analysis. FINDINGS/RESULTS: LC-MS/MS results indicated a similar mass spectrum of isolated fractions from nectarine and peach with Rosa canina. Oral administration of nectarine and peach extracts to STZ-induced diabetic rats showed restoration of blood glucose levels to normal levels with a concomitant increase in insulin levels. Morphometric analysis of pancreatic sections revealed the increase in number, diameter, volume, and area of the pancreatic islets in the diabetic rats treated with extracts compared to the untreated diabetic rats. CONCLUSION AND IMPLICATIONS: Nectarine and peach extracts' anti-diabetic properties improved insulin secretion and pancreatic beta-cell function and subsequently led to restoring pancreatic islet mass in STZ-induced diabetic rats.

Targeting Common Signaling Pathways for the Treatment of Stroke and Alzheimer's: a Comprehensive Review.

Neurodegenerative diseases such as stroke and Alzheimer's disease (AD) are two inter-related disorders that affect the neurons in the brain and central nervous system. Alzheimer's is a disease by undefined origin and causes. Stroke and its most common type, ischemic stroke (IS), occurs due to the blockade of cerebral blood vessels. As an important feature, both of disorders are associated with irreversible damages to the brain and nervous system. In this regard, finding common signaling pathways and the same molecular origin between these two diseases may be a promising way for their solution. On the basis of literature appraisal, the most common signaling cascades implicated in the pathogenesis of AD and stroke including notch, autophagy, inflammatory, and insulin signaling pathways were reviewed. Furthermore, current therapeutic strategies including natural and synthetic pharmaceuticals aiming modulation of respective signaling factors were scrutinized to ameliorate neural deficits in AD and stroke. Taken together, digging deeper in the common connections and signal targeting can be greatly helpful in understanding and unified treating of these disorders.

Co-encapsulation of tertinoin and resveratrol by solid lipid nanocarrier (SLN) improves mice in vitro matured oocyte/ morula-compact stage embryo development.

As a promising strategy in overcoming drug resistance, the nano drug co-delivery system (NDCDS) can transport two or more drugs into the cell. In this study, we sought to compare the dual and single drug-delivery system, to deliver the optimal dose of Resveratrol (RES) and Tretinoin (TTN) into the in vitro matured oocyte and morula-compact stage embryonic cells. The formation of single (RES/TTN) and dual-drug (RES + TTN)-SLN were confirmed by Uv-vis spectrophotometery, dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) technologies. In two experiments, the oocytes/presumptive zygotes were cultured under various concentrations of the single (RES/TTN) and dual-drug (RES + TTN)-SLN. In vitro toxicity studies, including nuclear staining (Aceto-orcein and Hoechst 33342), H2DCFDA fluorescent staining, chemiluminescence assay, and quantitative reverse transcription-PCR (qRT-PCR) techniques, indicated an excellent oocyte/embryo internalization of RES and TTN. Moreover, when oocytes/embryos were treated with the lowest concentration of RES + TTN-SLN, antioxidants-related genes were upregulated, apoptotic-related genes were downregulated, and intra/extracellular ROS production was reduced. In vitro cytotoxicity studies also demonstrated that single/dual-encapsulation of RES or TTN were safe even at the highest concentration (10 and 5 µM) compared to the control group. To sum it up, both delivery systems of RES and TTN by SLN (dual or single encapsulation) can deliver the optimal dose of RES and TTN into the oocyte/embryo. Where the dual-delivery of RES and TTN even at the lowest concentration (0.25 µM + 0.1 µm) showed a synergistic anti-oxidative effect in oocyte/embryo with a better inhibition of intra/extra-cellular ROS production by an enhanced/controlled intracellular penetration.

Rapid and sensitive UHPLC-DAD method for simultaneous determination of sofosbuvir and ledipasvir in human serum.

Today, the direct-acting antiviral agents (DAAs) such as sofosbuvir (SOF) and ledipasvir (LED) are widely used to treat the hepatitis virus infection. The aim of this study was to develop a rapid, simple and valid method for simultaneous determination of SOF and LED in human plasma for bioavailability and pharmacokinetic studies. Chromatographic analysis was performed on the C18 column (Blue Orchid, 1.8 µm, 50 × 2 mm) using 0.1 % formic acid in water (pH 2.6) and acetonitrile (60:40; v/v) as mobile phase at a flow rate of 0.5 mL/min. The UV detector was set at 328 nm and 260 nm for analysis of SOF and LED, respectively. To 400 µL of plasma, 100 µL of clonazepam as the internal standard (I.S, 7 µg/mL) was added and the mixture subjected to liquid-liquid extraction using 1000 µL diethyl ether. The calibration curves were linear with coefficients of variation less than 8% for all analyses. The limit of quantification (LOQ) was 20 and 5 ng/mL for SOF and LED, respectively. The results of inter-day and intra-day precision showed good reproducibility and the total analysis time was 1.2 min. This method successfully applied for determination SOF and LED in four healthy volunteers.

In vitro and in vivo antidiabetic activity of Tamarix stricta Boiss.: Role of autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (DM) is a complicated metabolic disorder with no definite treatment. Different species of the genus Tamarix (tamarisk) are used by local people to treat DM. Tamarix stricta Boiss. is an endemic species to Iran with several traditional therapeutic uses in Persian Medicine. This study aimed to assess the antidiabetic activity of T. stricta. MATERIALS AND METHODS: Hydroethanolic extract of the plant was prepared and analyzed by High-performance liquid chromatography (HPLC). The protective effect of the extract was evaluated in streptozotocin (STZ)-induced toxicity and markers of autophagy in pancreatic RIN-5F cells. The effect of intragastric 10 or 20 mg/kg of the extract was compared with negative control (water) or positive control (metformin) treatment during four weeks of administration in high-fat diet + STZ-induced DM in Balb/c mice. RESULTS: Results showed the presence of 8.436 mg of gallic acid in each gram of the extract. A significant cytoprotective effect was observed by T. stricta in STZ-induced toxicity in RIN-5F cells, partially due to the modulation of autophagy. Also, animals treated with the extract showed a significant improvement in glycemic and lipid profiles, liver function, and histopathologic features of pancreas and liver compared with the negative control. CONCLUSION: T. stricta demonstrated beneficial effects in animal model of DM; though, further studies are recommended to confirm the clinical use of this plant in DM.

Involvement of TGF-ß and Autophagy Pathways in Pathogenesis of Diabetes: A Comprehensive Review on Biological and Pharmacological Insights.

Despite recent advancements in clinical drugs, diabetes treatment still needs further progress. As such, ongoing research has attempted to determine the precise molecular mechanisms of the disorder. Specifically, evidence supports that several signaling pathways play pivotal roles in the development of diabetes. However, the exact molecular mechanisms of diabetes still need to be explored. This study examines exciting new hallmarks for the strict involvement of autophagy and TGF-ß signaling pathways in the pathogenesis of diabetes and the design of novel therapeutic strategies. Dysregulated autophagy in pancreatic ß cells due to hyperglycemia, oxidative stress, and inflammation is associated with diabetes and accompanied by dysregulated autophagy in insulin target tissues and the progression of diabetic complications. Consequently, several therapeutic agents such as adiponectin, ezetimibe, GABA tea, geniposide, liraglutide, guava extract, and vitamin D were shown to inhibit diabetes and its complications through modulation of the autophagy pathway. Another pathway, TGF-ß signaling pathway, appears to play a part in the progression of diabetes, insulin resistance, and autoimmunity in both type 1 and 2 diabetes and complications in diabetes. Subsequently, drugs that target TGF-ß signaling, especially naturally derived ones such as resveratrol, puerarin, curcumin, hesperidin, and silymarin, as well as Propolis, Lycopus lucidus, and Momordica charantia extracts, may become promising alternatives to current drugs in diabetes treatment. This review provides keen insights into novel therapeutic strategies for the medical care of diabetes.