A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators.

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson's disease (PD), underscores the urgency of discovering novel therapeutic strategies. Given the limitations associated with available treatments for mitochondrial dysfunction-associated diseases, the search for new potent alternatives has become imperative. In this report, we embarked on an extensive screening of 4224 fractions from 384 Australian marine organisms and plant samples to identify natural products with protective effects on mitochondria. Our initial screening using PD patient-sourced olfactory neurosphere-derived (hONS) cells with rotenone as a mitochondria stressor resulted in 108 promising fractions from 11 different biota. To further assess the potency and efficacy of these hits, the 11 biotas were subjected to a subsequent round of screening on human neuroblastoma (SH-SY5Y) cells, using 6-hydroxydopamine to induce mitochondrial stress, complemented by a mitochondrial membrane potential assay. This rigorous process yielded 35 active fractions from eight biotas. Advanced analysis using an orbit trap mass spectrophotometer facilitated the identification of the molecular constituents of the most active fraction from each of the eight biotas. This meticulous approach led to the discovery of 57 unique compounds, among which 12 were previously recognized for their mitoprotective effects. Our findings highlight the vast potential of natural products derived from Australian marine organisms and plants in the quest for innovative treatments targeting mitochondrial dysfunction in neurodegenerative diseases.

Mitochondrial Modulators: The Defender.

Mitochondria are widely considered the "power hub" of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to calcium homeostasis, reactive oxygen species (ROS) balance, and cell apoptosis. The mitochondria also perform crucial multifaceted roles in biosynthetic pathways, serving as an important source of building blocks for the biosynthesis of fatty acid, cholesterol, amino acid, glucose, and heme. Since mitochondria play multiple vital roles in the cell, it is not surprising that disruption of mitochondrial function has been linked to a myriad of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In this review, we discuss the key physiological and pathological functions of mitochondria and present bioactive compounds with protective effects on the mitochondria and their mechanisms of action. We highlight promising compounds and existing difficulties limiting the therapeutic use of these compounds and potential solutions. We also provide insights and perspectives into future research windows on mitochondrial modulators.

Securidaca inappendiculata Polyphenol Rich Extract Counteracts Cognitive Deficits, Neuropathy, Neuroinflammation and Oxidative Stress in Diabetic Encephalopathic Rats via p38 MAPK/Nrf2/HO-1 Pathways.

Diabetic encephalopathy is one of the serious emerging complication of diabetes. Securidaca inappendiculata is an important medicinal plant with excellent antioxidant and anti-inflammatory properties. This study investigated the neuroprotective effects of S. inappendiculata polyphenol rich extract (SiPE) against diabetic encephalopathy in rats and elucidated the potential mechanisms of action. Type 2 diabetes mellitus (T2DM) was induced using high fructose solution/intraperitoneal injection of streptozotocin and the diabetic rats were treated with SiPE (50, 100 and 200 mg/kg) for 8 weeks. Learning and memory functions were assessed using the Morris water and Y maze tests, depressive behaviour was evaluated using forced swimming and open field tests, while neuropathic pain assessment was assessed using hot plate, tail immersion and formalin tests. After the experiments, acetylcholinesterase (AChE), oxidative stress biomarkers and proinflammatory cytokines, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) were determined by ELISA kits. In addition, the expression levels of p38, phospho-p38 (p-p38), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were determined by western blot analyses. The results indicated that SiPE administration significantly lowered blood glucose level, attenuated body weight loss, thermal/chemical hyperalgesia, improved behavioural deficit in the Morris water maze, Y maze test and reduced depressive-like behaviours. Furthermore, SiPE reduced AChE, caspase-3, NF-κB, malonaldehyde malondialdehyde levels and simultaneously increased antioxidant enzymes activity in the brain tissues of diabetic rats. SiPE administration also significantly suppressed p38 MAPK pathway and upregulated the Nrf2 pathway. The findings suggested that SiPE exerted antidiabetic encephalopathy effects via modulation of oxidative stress and inflammation.

Protective effects of ethyl acetate extract from Shorea roxburghii against diabetes induced testicular damage in rats.

Diabetic mellitus is a chronic metabolic disorder that is associated with several complications including testicular dysfunction. This research investigated the protective action of the ethyl acetate extract from Shorea roxburghii (SRE) on diabetes induced testicular damage in rats. Diabetic rats were orally administered with SRE at doses of 100 and 400 mg/kg for 4 weeks. SRE improved the body weight gain, testes weight, testes index and increased serum concentration of testosterone. Furthermore, SRE increased the testicular antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase. In addition, SRE ameliorated testicular inflammatory mediators such as myeloperoxidase, tumor necrosis factor alpha, interleukin 6, p38 MAPK and nuclear factor kappa B activation and decreased testicular cell apoptosis in the treated diabetic rats. SRE also raised sperm parameters after treatment of diabetic rats. Conclusively, our results suggested that SRE ameliorated diabetes induced testicular damage by inhibiting oxidative stress and inflammation.

Tiliacora triandra extract and its major constituent attenuates diabetic kidney and testicular impairment by modulating redox imbalance and pro-inflammatory responses in rats.

BACKGROUND: Literature has demonstrated that diabetes is associated with renal complication and testicular dysfunctions. The current study explored the potential of Tiliacora triandra extract and its major component against diabetic kidney and testicular damages in rats. METHODS: Diabetes was induced by high fat diet/streptozotocin (HFD/STZ) and treated orally with Tiliacora triandra extract (TTE, 100 and 400 mg kg-1 body weight) and its major component, 5,7-dihydroxy-6-oxoheptadecanoic acid (DHA, 25 mg kg-1 body weight) for 30 consecutive days. Testicular activities of testicular enzymes, serum levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), sperm parameters and urinalysis for protein and albumin levels were evaluated. Renal and testicular biomarkers of oxidative stress and pro-inflammation were analysed along with histology. RESULTS: The experimental diabetes induced significant alterations in the levels and activities of indices evaluated compared to non-diabetic normal rats. The 28-day treatment of diabetic rats with TTE and DHA markedly improved activities of testicular enzymes, restored levels of testosterone, LH and FSH and sperm parameters compared to untreated diabetic rats. TTE and DHA abrogated proteinuria and reversed urine albumin level. Testicular and renal oxidative stress and pro-inflammation were attenuated in diabetic rats treated with TTE and DHA. The diabetes-mediated histopathological damage was alleviated in the kidney and testis. CONCLUSION: The protective effect of TTE and DHA against diabetes induced kidney and testicular damages may be related to its antioxidant and anti-inflammatory activities. © 2020 Society of Chemical Industry.

Tiliacora triandra extract possesses antidiabetic effects in high fat diet/streptozotocin-induced diabetes in rats.

The antidiabetic properties of Tiliacora triandra ethanol extract in diabetic rats induced with high-fat diet (HFD)/streptozotocin (STZ) was investigated. Rats were fed with HFD for 4 weeks to induced insulin resistance, and thereafter administered with 35 mg/kg of STZ to induce diabetes. Diabetic rats received 100 and 400 mg/kg of T. triandra daily for 30 days. The body weight, blood glucose level, food and fluid intake were monitored. Furthermore, biochemical and histological assessment was performed to evaluate the hypoglycemic effect of the extract in the treated rats. T. triandra significantly decreased the blood glucose level, increased the body weight and insulin secretion. Furthermore, T. triandra attenuated hyperlipidemia, improved liver and kidney functions of treated diabetic rats. Thus, T. triandra could effectively attenuate diabetes and it complications. PRACTICAL APPLICATIONS: Tiliacora triandra is a common vegetable consumed in Thailand and Laos. It is traditionally employed in the treatment of fever, cancer, malaria, and diabetes. The extract from the aerial part was investigated for its antidiabetic properties. The results obtained provides important pharmacological information that supports the use of T. triandra in management of diabetes.

Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats.

This study investigated the hypoglycemic effect of the methanol extract of Shorea roxburghii leaves (SRL) in high fat diet/high fructose solution (HFDHF) and streptozotocin (STZ) induced type 2 diabetes mellitus (T2DM) in rats as well as evaluating its ameliorative potentials in altered biochemical and hematological parameters in the treated rats. T2DM was induced in Sprague Dawley (SD) rats by feeding with HFDHF for 4 weeks and administering STZ (35 mg/kg, i. p.). Diabetic rats were given SRL extract at doses of 100 and 400 mg/kg for 30 days. The food and water intake were monitored on a daily basis, while the fasting blood glucose (FBG) levels and body weight were measured weekly. Biochemical and hematological parameters as well as histopathological studies of the pancreas were also evaluated. SRL significantly decreased FBG and improved the body weight, food and water intake of treated diabetic rats. Furthermore, biochemical and hematological parameters including liver and kidney function enzymes, lipid profiles, white blood and red blood cells parameters were markedly ameliorated by SRL. Histopathological analyses of the pancreas indicated reconstitution of ß-cells architecture in SRL treated rats. The results of this study suggest that SRL has antidiabetic potential and can be considered for the treatment of T2DM.

Rhinacanthins-rich extract and rhinacanthin C ameliorate oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic nephropathy.

In this present study, rhinacanthins-rich extract (RRE) and rhinacanthin C (RC) the main bioactive constituent of Rhinacanthus nasutus was investigated for their protective effect against diabetic nephropathy (DN). Diabetes was induced by administering nicotinamide (100 mg/kg, i.p.)/streptozotocin (60 mg/kg, i.p.) and diabetic rats were orally administered with RRE and RC for 4 weeks. RRE and RC significantly reduced the kidney index, renal oxidative stress markers, and pro-inflammatory cytokines. Furthermore, RRE and RC increased renal levels of glutathione, superoxide dismutase, catalase, and attenuated diabetic induced renal damages. In conclusion, RRE and RC confer protective effect against DN through the inhibition of oxidative stress and inflammation and could be a potential medicinal or nutritional supplement for the prevention of DN. PRACTICAL APPLICATIONS: Rhinacanthus nasutus is a medicinal plant that is extensively used in Thai traditional medicine as an antibacterial, antifungal, antidiabetic, and anti-inflammatory agent. The plant is rich in naphthoquinones, which confer it with several excellent bioactivities. The rich extract of the leaves was prepared with three major bioactive components and the extract was evaluated for its renoprotective effect in diabetic rats. The results from this study provides valuable pharmacological information that supports the use of the plant, especially the rich extract in the prevention and treatment of diabetes and diabetic complications.