Shielding Effect of Ryanodine Receptor Modulator in Rat Model of Autism.

Introduction: A neurodevelopmental disorder, autism is typically identified with three primary behavioral consequences, such as social impairment, communication problems, and limited or stereotypical behavior. Because of its co-morbidity and lack of therapeutic options, autism is a global economic burden. A short chain of fatty acid, propionic acid is formed biologically by the gut microbiome. Propionic acid levels that are too high can cause leaky intestines, which can lead to autism-like symptoms. Methods: To induce autism, male Albino Wistar rats were given propionic acid (250 mg/kg/po on the 21st, 22nd, and 23rd postnatal days). Rats also received a ryanodine receptor antagonist (Ruthenium red: 3 mg/kg/po; postnatal 21st to 50th day) to see what influence it had on propionic acid-induced autism. Anxiety, social behavior, and repeated behaviors were all assessed, as well as oxidative stress, inflammatory indicators, neuro signaling proteins, and blood-brain barrier permeability. Results: Ruthenium red was found to counter the propionic acid-induced increases in anxiety, repetitive behavior prefrontal cortex levels of IL-6, TNF-α, TBARS, Evans blue leakage, and water content along with decreases in social behavior, IL-10, and GSH followed by hippocampus CREB and BDNF levels. Conclusion: Ryanodine receptor antagonists presented a neuroprotective effect in propionic acid-induced conditions like autism by modulatory effects on social and repetitive behavior, oxidative stress, neuroinflammation, and neuroprotein changes. Ryanodine receptors can be further explored in depth to manage autism as a condition. Highlights: Ruthenium red can reduce the propionic acid-induced anxiety of rats with autism.Ruthenium red can improve the propionic acid-induced changes in repetitive behavior of rats with autism.Ruthenium red can reduce the propionic acid-induced social behavior dysfunction in rats with autism. Plain Language Summary: Autism is a complex heterogeneous neurodevelopmental disorder mainly diagnosed with social behavior dysfunction, communication problems, and repetitive behavior. Due to high comorbidity and multiple unknown factors involvement, its exact etiology remains unclear, and so no successful treatment is available. Among the environmentally produced models of autism in rats, the most common is created by propionic acid (PPA). With short-chain type fatty acid, PPA is one of the mediators for the cycle of cell metabolism. This study attempted to study the effect of a ryano-dine receptor antagonist (Ruthenium red) on PPA-induced Anxiety, social behavior dysfunction, and repeated behaviors in rats with autism. The results showed the modulatory effects of Ruthenium red PPA-induced conditions including social and repetitive behavior, oxidative stress, neuroinflammation, and neuroprotein changes in rats with autism.

Study Deciphering the Crucial Involvement of Notch Signaling Pathway in Human Cancers.

In recent years, dysregulation of the notch pathway has been associated with the development and progression of various cancers. Notch signaling is involved in several cellular processes such as proliferation, differentiation, apoptosis, and angiogenesis, and its abnormal activation can lead to uncontrolled cell growth and tumorigenesis. In various cancers, the Notch pathway has been shown to have both tumor-promoting and tumor-suppressive effects, depending on the context and stage of cancer development. In some cases, activation of the Notch pathway has been shown to promote tumor growth and progression, while in others it has been shown to inhibit tumor growth and induce cell death. The Notch pathway has been found to be particularly important in the development of leukaemia, breast cancer, lung cancer and pancreatic cancer. In leukaemia, the Notch pathway is often activated, which promotes the survival and proliferation of leukaemia cells. In breast cancer, Notch signaling has been implicated in tumor initiation and maintenance of cancer stem cells. In cervical cancer, the Notch signaling pathway has been shown to play a crucial role in the development of the disease. In lung cancer, Notch activation promotes cancer cell proliferation and migration, while in pancreatic cancer, Notch signaling is associated with tumor initiation and resistance to chemotherapy. Understanding the role of the Notch pathway in cancer development and progression may provide new opportunities for the development of targeted therapies for cancer treatment. Several drugs targeting the Notch pathway are currently in preclinical or clinical development and may hold promise for anticancer therapy in the future.

Synthesis of 1,2,3-triazole-1,3,4-thiadiazole hybrids as novel α-glucosidase inhibitors by in situ azidation/click assembly.

α-Glucosidase inhibition is widely used in the oral management of diabetes mellitus (DM), a disease characterized by high blood sugar levels (hyperglycemia) and abnormal carbohydrate metabolism. In this respect, a series of 1,2,3-triazole-1,3,4-thiadiazole hybrids 7a-j were synthesized, inspired by a copper-catalyzed one-pot azidation/click assembly approach. All the synthesized hybrids were screened for inhibition of the α-glucosidase enzyme, displaying IC50 values ranging from 63.35 ± 0.72 to 613.57 ± 1.98 µM, as compared to acarbose (reference) with IC50 of 844.81 ± 0.53 µM. The hybrids 7h and 7e with 3-nitro and 4-methoxy substituents at the phenyl ring of the thiadiazole moiety were the best active hybrids of this series with IC50 values of 63.35 ± 0.72 µM, and 67.61 ± 0.64 µM, respectively. Enzyme kinetics analysis of these compounds revealed a mixed mode of inhibition. Moreover, molecular docking studies were also performed to gain insights into the structure-activity-relationships of the potent compounds and their corresponding analogs.

Inhibition of α-glucosidase enzyme by 'click'-inspired pharmacophore framework 1,3,4-thiadiazole-1,2,3-triazole hybrids.

Aim: α-Glucosidase inhibitors are important oral antidiabetic drugs that are used alone or in combination therapy. Materials & methods: In this regard, 1,3,4-thiadiazoles-1,2,3-triazoles were designed, synthesized and evaluated for α-glucosidase enzyme inhibition. Results: The applied synthesis protocol involved a 'click' reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The hybrid (9n) bearing 2-methyl and 4-nitro substituents was the best inhibitor with an IC50 value of 31.91 µM (acarbose IC50 = 844.81 µM). The blind molecular docking study of the best derivative (9n) showed that it interacted with the allosteric site's amino acid residues of α-glucosidase. Conclusion: 'Click'-inspired potential α-glucosidase inhibitors (1,3,4-thiadiazole-1,2,3-triazole hybrids) were identified and structure-activity relationship and kinetic and molecular docking studies accomplished.

Oral antidiabetic drugs such as α-glucosidase inhibitors are used alone or in combination therapy. α-Glucosidase inhibitors are considered important for their localized site of action and limited side effects compared with other antidiabetic medications. In this regard, 1,3,4-thiadiazoles­1,2,3-triazoles were designed and synthesized and their antidiabetic potential (α-glucosidase enzyme inhibition) evaluated. The synthesis involved a 'click', or copper-catalyzed 1,3-dipolar cycloaddition, reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The synthesis was simple, easy and free of tedious separation processes. All synthesized thiadiazole­triazole hybrids were found to be active toward α-glucosidase (yeast origin). One of the thiadiazole­triazole hybrids showed excellent activity that was approximately 26-times greater than the standard drug acarbose. This study was further supported by computational analysis.

Protective Effect of Nimodipine Against Valproic-acid Induced Biochemical and Behavioral Phenotypes of Autism.

Objective: Present study was designed to investigate behavioral and biochemical role of nimodipine in prenatal valproic acid (Pre-VPA) induced autism in rats. Methods: Valproic acid was utilized to induce autistic phenotypes in Wistar rats. The rats were assessed for social behavior. Hippocampus and prefrontal cortex (PFC) were utilized for various biochemical assessments, whereas cerebellum was used to assess blood brain barrier (BBB) permeability. Results: Pre-VPA rats showed reduction social interaction. Pre-VPA administration were decreased PFC levels of interleukin- 10 (IL-10), and glutathione along with hippocampus cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Also, the animals have shown increase in PFC levels of IL-6, tumor necrosis factor-α, thiobarbituric acid reactive substance, Evans blue leakage and water content. Nimodipine countered Pre-VPA administered reduction in social interaction, CREB, BDNF, inflammation, oxidative stress, BBB permeability. Conclusion: Pre-VPA has induced autistic phenotype, which were attenuated by nimodipine in rats. Nimodipine and other calcium channel blockers should further investigate to check the management of autism.

Flavone-1,2,3-triazole derivatives as potential α-glucosidase inhibitors: Synthesis, enzyme inhibition, kinetic analysis and molecular docking study.

α-Glucosidase inhibitors are considered prime therapeutics in the management of type-2 diabetes and are preferred due to their localized action ushered by limited side effects. In this regard, nineteen new flavone-1,2,3-triazole derivatives have been designed and synthesized via utilizing an efficient click reaction protocol, and screened for the inhibition of the α-glucosidase enzyme. The reaction conditions were mild, good yielding and required easy work up. All the synthesized flavone-triazole derivatives were found more active against the yeast α-glucosidase with IC50 values ranging from 24.37 ± 0.55-168.44 ± 0.77 µ M as compared to standard inhibitor acarbose (IC50 = 844.81 ± 0.53 µM). The derivatives with 2,5­dichloro 9k (IC50 = 24.37 ± 0.55 µM) and 4­chloro 9d (IC50 = 24.77 ± 0.30 µM) substituent bearing an amide linkage were the most active. In the kinetic study of most active derivatives 9k and 9d, they were found to be mixed and uncompetitive inhibitors, respectively. In molecular docking studies, blind docking of the most active compounds was accomplished to find the interactions between the compounds and α-glucosidase that further confirms the mixed or uncompetitive nature of the inhibitors.

Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, commonly characterized by altered social behavior, communication, biochemistry and pathological conditions. One percent of the worldwide population suffers from autism and males suffer more than females. NMDA receptors have the important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. This study has been designed to investigate the role of memantine, a NMDA receptor modulator, in prenatal valproic acid-induced autism in rats. Animals with prenatal valproic acid have shown the reduction in social interaction (three-chamber social behavior apparatus), spontaneous alternation (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, prenatal valproic acid-treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood-brain barrier permeability. Treatment with memantine has significantly attenuated prenatal valproic acid-induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, memantine has also attenuated the prenatal valproic acid-induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood-brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behavior, biochemistry and blood-brain barrier impairment in animals, which were significantly attenuated by memantine. NMDA receptor modulators like memantine should be explored further for the therapeutic benefits in autism.

Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism.

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder.

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder.