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.

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.

The effects of co-administration of artichoke leaf extract supplementation with metformin and vitamin E in patients with nonalcoholic fatty liver disease: A randomized clinical trial.

Medicinal plants are widely used as a complementary therapy to treat complex diseases, such as nonalcoholic fatty liver disease (NAFLD). Therefore, this study was done to investigate the effect of co-administration of artichoke leaf extract supplement (ALES) with conventional medicines on patients with NAFLD. The clinical trial was based on patients randomly divided into three groups involving metformin-vitamin E (ME), metformin-ALES (MA), and vitamin E-ALES (EA). The effectiveness of treatment in the treated groups was evaluated using liver ultrasonography and biochemical markers. After 12 weeks of treatment, the results showed that the rate of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was significantly reduced within all the study groups (p < .05). Liver ultrasonographic findings revealed that the rate of fat accumulation in liver of patients was decreased significantly within all the study groups and it was increased in the subjects with grade 0 fatty liver (without fat accumulation) in the MA and EA groups by 23.3 and 17.2%, respectively. In summary, the results of the present study showed that the concomitant use of ALES with metformin and vitamin E can have beneficial effects on amelioration of complications in patients with NAFLD. However, larger-scale clinical trial studies are required in this regard.

Genetics of intellectual disability in consanguineous families.

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

Bacterial starter cultures induce suitable changes in milk fatty acid profiles at different fermentation conditions.

This study aimed to compare the effect of different ratios of Streptococcus thermophilus to Lactobacillus bulgaricus (3 : 1, 1 : 1, and 1 : 3) under the various stressful temperatures (37 and 45°C) on the fatty acid profiles quality of Kermanshahi roghan (yogurt by-product) and sour cream to obtain a formula for producing a kind of animal fat healthier than milk and cream. Stresses such as fermentation play an important role in bacterial behavior and consequently in food quality. Our findings presented a significant difference between roghan and sour cream fatty acid levels only at 37°C. Furthermore, starter culture 3 : 1 was the best starter for producing products with a higher quality of fatty acid profile at 37°C, and a 1 : 1 S. thermophilus to L. bulgaricus ratio was optimal at 45°C. It seems that bacteria adapt to harsh growth conditions by changing the fatty acid profiles, and these changes warrant consideration in the production of a kind of animal fat with the best fatty acid profiles. In conclusion, the roghan fatty acid profile is more suitable than sour cream only at 37°C.

Study of gene expression and steviol glycosides accumulation in Stevia rebaudiana Bertoni under various mannitol concentrations.

Stevia rebaudiana produces sweet steviol glycosides that are 300 times sweeter than sugar and have the beneficial effects on human health including anti-hyperglycaemic. Tissue culture is the best method with high efficacy to propagate stevia. Abiotic stress has an impact on steviol glycoside contents in stevia. Therefore, we investigated the effect of mannitol on the expression of four genes involved in the biosynthesis of stevia including UGT74G1, UGT76G1, kaurene oxidase and kaurene synthase genes and steviol glycosides accumulation in stevia under in vitro conditions. The highest expression of UGT76G1 gene occurred in the plants grown under 20 g/l mannitol. While for the kaurene synthase gene, the highest amount of gene expression was observed at 40 g/l mannitol. The results were different about kaurene oxidase gene. As the highest and lowest gene expression were seen in 50 and 30 g/l mannitol conditions respectively. There were the same results for UGT74G1 that means the most appropriate and also the most inopportune treatment for the gene expression were same as the condition for the kaurene oxidase gene. Compared with control, adding mannitol to media in all concentrations increases the expression of UGT76G1 gene. Estimation of steviol glycosides contents under different treatments of mannitol carried out by HPLC. According to the results, the highest amount of stevioside was produced under 20 g/l mannitol treatment. However, rebaudioside A was accumulated in its maximum amounts under 30 g/l mannitol. It can be concluded that adding mannitol to media in the certain concentration increases steviol glycoside contents in the stevia.

Effect of Stevia rebaudiana Bertoni extract on sexual dysfunction in Streptozotocin-induced diabetic male rats.

Stevia rebaudiana Bertoni has been used locally as a non-calorie sweetener in medicine and diabetic diet which claimed to have aphrodisiac properties, although no scientific data of this function have been reported. The aim of this study was to investigate the effect of S. rebaudiana extract on sexual dysfunction, testosterone levels and number of Leydig cells in Streptozotocin (STZ)-induced diabetic male rats. A total of 28 diabetic male rats were randomly divided into 4 groups: diabetic group without any extract and 3 extract groups (5, 50 and 100 mg/kg). Seven normal control rats were treated with vehicle mount latency and frequency of (ML, MF), intromission latency and frequency (IL, IF), ejaculation latency and frequency of (EL, EF), the mount latency post ejaculation (MPE), the intromission latency post ejaculation (ILE), the intromission frequency post ejaculation (IFE) were recorded during 30 min on days 0, 14, 28. The serum testosterone levels, blood glucose, sex organs weight, number of leydig cells and histology of testicular tissue were measured. The stevia group (5 mg/kg) had a significant (p<0.05) increase in EF and IF. The number of Leydig cells in the diabetic group were significantly (p<0.05) reduced compared to the normal group and diabetic groups with extract (5 and 50 mg/kg). The serum testosterone levels and other sexual behaviors did not show any significant differences. The low- dose stevia extract with attention to antioxidant, vasodilator and anti-diabetic properties can be aphrodisiac in STZ- induced diabetic male rats.

Effect of fermentation temperature and different Streptococcus thermophilus to Lactobacillus bulgaricus ratios on Kermanshahi roghan and yoghurt fatty acid profiles.

The objective of the study reported in this Research Communication was to investigate the effect of fermentation temperature (37 and 45 °C) and different ratios of Streptococcus thermophilus to Lactobacillus bulgaricus (3 : 1, 1 : 1 and 1 : 3) on Kermanshahi roghan and yoghurt fatty acid profiles (FAP) in order to obtain a product with optimized fatty acid profiles. Kermanshahi roghan is a yoghurt by-product in western Iran (Kermanshah). The results revealed that incubation temperature at 37 °C as compared to 45 °C had a better effect on fatty acid profiles of roghan and yoghurt. Furthermore, the results showed that fatty acid profile of roghan is better than yoghurt at two experimental temperatures. On the other hand, the roghan products made by equal ratio of S. thermophilus and L. bulgaricus (1 : 1) had the best quality of fatty acid profiles. Although a lower incubation temperature increases incubation time, our finding suggests that inoculation ratio 1 : 1 at 37 °C as compared to 45 °C can affect the quality of roghan and yoghurt fatty acid profiles.

Quantification of sofosbuvir in human serum by liquid chromatography with negative ionization mass spectrometry using the parent peak and its source-induced fragment: Application to a bioequivalence study.

In the mass spectrometry of sofosbuvir, a new orally administered antihepatitis C drug, a weak peak is detected at the m/z value of the parent ion (m/z 530) as a result of in-source dissociation and current methods to its quantification, is based on monitoring of the parent peak using ultra high-performance liquid chromatography with tandem mass spectrometry. With these methods serum concentration of the drug is quantifiable only up to 4-5 h postdose. However, the fragmentation of the molecule generates a more stable ion at m/z 287 (base peak) with a signal intensity of about tenfold compared to the parent ion. Our study was aimed to improve sensitivity of analysis by acquisition of the m/z value of the daughter ion from which it originated instead of the parent molecule. This novelty allows us to measure serum concentrations of the drug for a longer time postdose and provides more opportunity for pharmacokinetic studies of sofosbuvir. Our method was linear over the concentration range of 2-2560 ng/mL of sofosbuvir in human serum with a limit of quantification of 2 ng/mL compared to 10 ng/mL reported previously. The coefficient variation values of both inter and intraday analysis were less than 13.8%, and the percentage error was less than 6.3.

Sensitive determination of atorvastatin in human plasma by dispersive liquid-liquid microextraction and solidification of floating organic drop followed by high-performance liquid chromatography.

A novel and sensitive dispersive liquid-liquid microextraction method based on the solidification of the floating organic drop combined with high-performance liquid chromatography and ultraviolet detection was used for the determination of atorvastatine in blood serum samples. The chromatographic separation of atorvastatin was carried out using methanol as the mobile phase organic modifier. Various parameters affecting the extraction efficiency were optimized, such as the kind and volume of extraction solvent (1-undecanol) and disperser solvent (acetonitrile), pH, and the extraction time. The calibration curve was linear in the range of 0.2-6000 µg/L of atorvastatin (r(2) = 0.995) with a limit of detection of 0.07 µg/L. The relative standard deviation for 100 µg/L of atorvastatin in human plasma was 8.4% (n = 4). The recoveries of plasma samples spiked with atorvastatin were in the range of 98.8-113.8%. The obtained results showed that the proposed method is fast, simple, and reliable for the determination of very low concentrations of atorvastatin in human plasma samples.

Sensitive determination of methadone in human serum and urine by dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet followed by HPLC-UV.

Dispersive liquid-liquid microextraction based on solidification of floating organic droplet was developed for the extraction of methadone and determination by high-performance liquid chromatography with UV detection. In this method, no microsyringe or fiber is required to support the organic microdrop due to the usage of an organic solvent with a low density and appropriate melting point. Furthermore, the extractant droplet can be collected easily by solidifying it at low temperature. 1-Undecanol and methanol were chosen as extraction and disperser solvents, respectively. Parameters that influence extraction efficiency, i.e. volumes of extracting and dispersing solvents, pH, and salt effect, were optimized by using response surface methodology. Under optimal conditions, enrichment factor for methadone was 134 and 160 in serum and urine samples, respectively. The limit of detection was 3.34 ng/mmL in serum and 1.67 ng/mL in urine samples. Compared with the traditional dispersive liquid-liquid microextraction, the proposed method obtained lower limit of detection. Moreover, the solidification of floating organic solvent facilitated the phase transfer. And most importantly, it avoided using high-density and toxic solvents of traditional dispersive liquid-liquid microextraction method. The proposed method was successfully applied to the determination of methadone in serum and urine samples of an addicted individual under methadone therapy.

Protective effect of a hydromethanolic extract from Fraxinus excelsior L. bark against a rat model of aluminum chloride-induced Alzheimer's disease: Relevance to its anti-inflammatory and antioxidant effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Fraxinus excelsior L. (FE), commonly known as the ash, belongs to the Oleaceae family and has shown several pharmacological and biological properties, such as antioxidant, immunomodulatory, neuroprotective, and anti-inflammatory effects. It has also attracted the most attention toward neuroinflammation. Moreover, FE bark and leaves have been used to treat neurological disorders, aging, neuropathic pain, urinary complaints, and articular pain in traditional and ethnomedicine. Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder resulting from the involvement of amyloid-beta, metal-induced oxidative stress, and neuroinflammation. AIM OF THE STUDY: The objective of the current study was to assess the neuroprotective effects of hydromethanolic extract from FE bark in an AlCl3-induced rat model of AD. MATERIALS AND METHODS: The maceration process was utilized to prepare the hydromethanolic extract of FE bark, and characterized by LC-MS/MS. To assess the anti-AD effects of the FE extract, rats were categorized into five different groups, AlCl3; normal control; FE-treated groups at 50, 100, and 200 mg/kg. Passive avoidance learning test, Y-maze, open field, and elevated plus maze behavioral tests were evaluated on days 7 and 14 to analyze the cognitive impairments. Zymography analysis, biochemical tests, and histopathological changes were also followed in different groups. RESULTS: LC-MS/MS analysis indicated the presence of coumarins, including isofraxidin7-O-diglucoside in the methanolic extract of FE as a new isofraxidin derivative in this genus. FE significantly improved memory and cognitive function, maintained weight, prevented neuronal damages, and preserved the hippocampus's histological features, as demonstrated by behavioral tests and histopathological analysis. FE increased anti-inflammatory MMP-2 activity, whereas it decreased that of inflammatory MMP-9. Moreover, FE increased plasma antioxidant capacity by enhancing CAT and GSH while decreasing nitrite levels in the serum of treated groups. In comparison between the treated groups, the rats that received high doses of the FE extract (200 mg/kg) showed the highest therapeutic effect. CONCLUSION: FE rich in coumarins could be an effective anti-AD adjunct agent, passing through antioxidant and anti-inflammatory pathways. These results encourage further studies for the development of this extract as a promising agent in preventing, managing, or treating AD and related diseases.

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.

Targeted protein modification as a paradigm shift in drug discovery.

Targeted Protein Modification (TPM) is an umbrella term encompassing numerous tools and approaches that use bifunctional agents to induce a desired modification over the POI. The most well-known TPM mechanism is PROTAC-directed protein ubiquitination. PROTAC-based targeted degradation offers several advantages over conventional small-molecule inhibitors, has shifted the drug discovery paradigm, and is acquiring increasing interest as over ten PROTACs have entered clinical trials in the past few years. Targeting the protein of interest for proteasomal degradation by PROTACS was the pioneer of various toolboxes for selective protein degradation. Nowadays, the ever-increasing number of tools and strategies for modulating and modifying the POI has expanded far beyond protein degradation, which phosphorylation and de-phosphorylation of the protein of interest, targeted acetylation, and selective modification of protein O-GlcNAcylation are among them. These novel strategies have opened new avenues for achieving more precise outcomes while remaining feasible and minimizing side effects. This field, however, is still in its infancy and has a long way to precede widespread use and translation into clinical practice. Herein, we investigate the pros and cons of these novel strategies by exploring the latest advancements in this field. Ultimately, we briefly discuss the emerging potential applications of these innovations in cancer therapy, neurodegeneration, viral infections, and autoimmune and inflammatory diseases.

Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways.

Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.

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.

Improving Animal Model of Induced Colitis by Acetic Acid in Terms of Fibrosis and Inflammation Incidence in the Colon.

METHODS: Fifty rats were randomly separated into five groups (n = 10) with different durations (30 s, 5, 10, and 20 min) of exposure of the colon to 4% acetic acid and colitis was investigated for 0-9 days. The extent of the mucosal ulcers, colon tissue thickening, and mucosal bleeding were scored by the Gerald classification system score. Slides of tissues were prepared for pathologic assay using the modified Wallace method. RESULTS: In all groups, inflammation was severe three days after the colitis induction, but no inflammation was observed in the 30 s group after five days. Acid contact with the colon surface did not result in fibrosis for the 30 s and the colon fibrosis was mild in 5 min group and severe in 10 and 20 min groups. The tissue damage was higher in groups of 20, 10, 5 min, and 30 s, respectively. Over time, the recovery rates in the 30 s and 5 min groups were higher than other groups. CONCLUSION: Our results showed that the evaluation of the disease process from 3 days to nine days after a 10 min contact of acid to the colon is a suitable model that mimics the histological features of the disease.

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.

Evaluation of the Cytotoxicity of Aqueous Extract and Oleo-Essential Oil of Dorema ammoniacum Plant Oleo-Gum Resin in Some Human Cancer Cell Lines.

Results: Aqueous extract and essential oil reduced the viability of A549 cancer cells in a concentration-dependent manner. The lowest inhibitory concentrations (IC50) for both samples of D. ammoniacum oleo-gum resin were 10 and 2.5 µg/ml for 24 hours in A549 cell line, respectively. After treatment with extract and essential oil of D. ammoniacum oleo-gum resin, ROS increased significantly compared to the control group. Although changes in caspase-3 did not show a significant increase in extract, the caspase-3 was found to be increased after exposure to essential oil and caspase-9 was downregulated after exposure to essential oil. Also, exposure to essential oil of D. ammoniacum caused a reduction in MMP level. Conclusion: Based on results, the cytotoxic effect of essential oil of D. ammoniacum can induce apoptosis toward A549 cell line via induction of oxidative stress, MMP depletion, and caspase-3 activation, which is independent to mitochondrial cytochrome c release and caspase-9 function.

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.