Current Trends and Prospects for Application of Green Synthesized Metal Nanoparticles in Cancer and COVID-19 Therapies.

Cancer and COVID-19 have been deemed as world health concerns due to the millions of lives that they have claimed over the years. Extensive efforts have been made to develop sophisticated, site-specific, and safe strategies that can effectively diagnose, prevent, manage, and treat these diseases. These strategies involve the implementation of metal nanoparticles and metal oxides such as gold, silver, iron oxide, titanium oxide, zinc oxide, and copper oxide, formulated through nanotechnology as alternative anticancer or antiviral therapeutics or drug delivery systems. This review provides a perspective on metal nanoparticles and their potential application in cancer and COVID-19 treatments. The data of published studies were critically analysed to expose the potential therapeutic relevance of green synthesized metal nanoparticles in cancer and COVID-19. Although various research reports highlight the great potential of metal and metal oxide nanoparticles as alternative nanotherapeutics, issues of nanotoxicity, complex methods of preparation, biodegradability, and clearance are lingering challenges for the successful clinical application of the NPs. Thus, future innovations include fabricating metal nanoparticles with eco-friendly materials, tailor making them with optimal therapeutics for specific disease targeting, and in vitro and in vivo evaluation of safety, therapeutic efficiency, pharmacokinetics, and biodistribution.

Zinc(II) complexes in diabetes management: Plant-derived phenolics as understudied promising ligands.

Zinc mineral has been known as a supplement for diabetics due to its deficiency in diabetics. Its glycemic control and insulin mimetic properties have been reported. Thus, it has been complexed with numerous types of ligands to improve the glycemic control property of the ligands. Unfortunately, mostly synthetic ligands with little or no bioactive properties and toxicity concerns have been complexed with Zn, while plant-derived dietary phenolics have rarely been explored as ligand for Zn complexation, despite their medicinal credence and minimal toxicity concern. In this letter, plant-derived phenolics have been presented as promising ligands for Zn(II) in developing potent antidiabetic and antioxidative nutraceutical complexes with improved and multi-facet bioactivity profile, as well as minimal toxicity concerns. Thus, fostering the paradigm shift from synthetic medicine toward dietary and functional medicine. PRACTICAL APPLICATIONS: Potentially, complexing Zn(II) with bioactive plant-derived dietary phenolics could result in novel nutraceuticals and/or supplements with improved and multi-facet bioactivity profile, as well as minimal toxicity concerns.

Comparative effects of commonly used commercially available non-nutritive sweeteners on diabetes-related parameters in non-diabetic rats.

Studies of non-nutritive sweeteners (NNS) in diabetes models have been limited to their pure forms or NNS-sweetened products. Hence, we conducted a comparative study on the effects of commercial table-top NNS on diabetes-related parameters in non-diabetic rats. Normal animals were fed for 5 weeks with aqueous solutions of aspartame-, sucralose-, stevia-, sodium cyclamate- and saccharin-based commercial NNS at concentrations equivalent to the sweetness of 10% sucrose solution and thereafter food intake, blood glucose, lipid profile, and biochemical parameters were measured. Aspartame adversely affected blood cholesterols, while cyclamate increased food intake and weight gain. Stevia reduced weight gain and exhibited insulinotropic effects. These data in normal rats hypothetically suggest that stevia-based NNS may help in glycemic control and body weight management, while cyclamate- and aspartame-based NNS may increase body weight and risk of cardiovascular diseases. Further clinical studies are, however, required to confirm the results of this study. PRACTICAL APPLICATIONS: The use of NNS is becoming more popular, especially for individuals with diabetes. However, while there are several commercial table-top NNS available in the market, little is known about how they affect most diabetes-related parameters of consumers, as most of the previous studies on NNS have been limited to their pure forms or NNS-sweetened products. Therefore, we comparatively studied the effects of some commercially available table-top forms of the different NNS (aspartame, sucralose, cyclamate, saccharin, and stevia) on diabetes-related parameters in normal rats. These findings in normal rats suggested that some commercially available NNSs like stevia-based NNS may be suitable for glycemic control and body weight management, while cyclamate- and aspartame-based NNS may increase body weight and risk of cardiovascular diseases. However, these finding in normal rats is subject to additional corroborative clinical studies.

Evaluation of the in vitro ⍺-amylase inhibitory, antiglycation, and antioxidant properties of Punica granatum L. (pomegranate) fruit peel acetone extract and its effect on glucose uptake and oxidative stress in hepatocytes.

Punica granatum L. (pomegranate) is a widely eaten fruit. The antidiabetic, antioxidative, and antilipidemic properties of the hydroalcoholic extracts of the different plant's parts have been extensively studied, with scarce information on the acetone extract (ACE). This study investigated antidiabetic, antioxidative, and antiobesogenic properties of ACE of the fruit peel. Preliminary data showed that ACE showed stronger antioxidant (radical-scavenging IC50  = 1.56 µg/ml) and ⍺-amylase inhibitory (IC50  = 10.6 µg/ml) properties than the hydroalcoholic extracts and Acarbose. The ACE inhibited protein glycation and lipase activity. In hepatocytes, ACE impaired oxidative stress-induced lipid peroxidation and reduced glutathione depletion but increased glucose uptake without decreasing the cell viability. HPLC analysis showed predominant presence of bioactive phenolic acids (ferulic, caffeic, and gallic acids) in this extract. This study suggests that ACE of P. granatum fruit peel may be an understudied extract that contains potent antidiabetic and antioxidative bioactive principles with minimal toxicity. PRACTICAL APPLICATIONS: Plant derived medicines have been an affordable and effective alternative therapy for many metabolic diseases, including diabetes. The fruit juice and fruits of pomegranate is widely consumed for the palatable taste and cardiovascular benefits. This study provides preliminary experimental evidences confirming that of the acetone extracts of pomegranate fruit peel, which has been sparsely studied, may possess more potent antidiabetic and antioxidative property than to the routinely studied hydroalcoholic counterparts. Additionally, the acetone extract is rich in bioactive phenolic acids, suggesting that the acetone extract of pomegranate fruit peel may be a promising candidate for further antidiabetic study and a source of bioactive principles for the management of diabetes and oxidative complications.

A comprehensive review on zinc(II) complexes as anti-diabetic agents: The advances, scientific gaps and prospects.

Zinc has gained notable attention in the development of potent anti-diabetic agents, due to its role in insulin storage and secretion, as well as its reported insulin mimetic properties. Consequently, zinc(II) has been complexed with numerous organic ligands as an adjuvant to develop anti-diabetic agents with improved and/or broader scope of pharmacological properties. This review focuses on the research advances thus far to identify the major scientific gaps and prospects. Peer-reviewed published data on the anti-diabetic effects of zinc(II) complexes were sourced from different scientific search engines, including, but not limited to "PubMed", "Google Scholar", "Scopus" and ScienceDirect to identify potent anti-diabetic zinc(II) complexes. The complexes were subcategorized according to their precursor ligands. A critical analysis of the outcomes from published studies shows promising leads, with Zn(II) complexes having a "tri-facet" mode of exerting pharmacological effects. However, the promising leads have been flawed by some major scientific gaps. While zinc(II) complexes of synthetic ligands with little or no anti-diabetic pharmacological history remain the most studied (about 72 %), their toxicity profile was not reported, which raises safety concerns for clinical relevance. The zinc(II) complexes of plant polyphenols; natural ligands, such as maltol and hinokitiol; and supplements, such as ascorbic acid (a natural antioxidant), l-threonine and l-carnitine, showed promising insulin mimetic and glycemic control properties but remain understudied and lack clinical validation, in spite of their minimal safety concerns and health benefits. A paradigm shift toward probing (including clinical studies) supplements, plant polyphenol and natural ligands as anti-diabetic zinc(II) complex is, therefore, recommended. Also, promising anti-diabetic Zn(II) complexes of synthetic ligands should undergo critical toxicity evaluation to address possible safety concerns.

Evaluation of the nutritional composition of Myrothamnus flabellifolius (Welw.) herbal tea and its protective effect against oxidative hepatic cell injury.

The nutrient composition of Myrothamnus flabellifolius leaf tea extract (MLTE) and its protective effect against oxidative hepatic cell injury were evaluated. Gallic acid, caffeic acid, ferulic acid, methyl gallate, and epicatechin were identified in MLTE by high-performance liquid chromatography (HPLC). The tea extract showed an appreciable nutritional content of proximate, sugar, vitamin E, monounsaturated fatty acids, omega 6 and 9 unsaturated fatty acids, as well as considerable amounts of various mineral elements. Nineteen amino acids were found. Moreover, MLTE exhibited potent in vitro antioxidant activities, presumably because of its richness in polyphenols (gallic acid and ferulic acid) and vitamin E. In Chang liver cells, pretreatment with MLTE suppressed oxidative lipid peroxidation (IC50  = 113.11 µg/ml) and GSH depletion (IC50  = 70.49 µg/ml) without causing cytotoxicity. These data support the local consumption of M. flabellifolius herbal tea, which may be used against oxidative stress-induced diseases while providing the body with necessary nutrients. PRACTICAL APPLICATION: Herbal teas are one of the most consumed beverages in the world today, due to their refreshing taste and additional health benefits. Myrothamnus flabellifolius herbal tea is a widely used traditional herbal tea in Southern Africa with potentials for commercialization due to its pleasant flavor. This study, for the first time, reported the nutritional composition of the leaf decoction of M. flabellifolius and its protective effect on hepatic oxidative insults. These results can inform the dietary and nutritional use of the tea for optimum benefits, as well as provide preliminary scientific validation of the use of the herbal tea as an antioxidant beverage with good nutritional value.

Commercially available non-nutritive sweeteners modulate the antioxidant status of type 2 diabetic rats.

Non-nutritive sweeteners (NNS) are increasingly being used by diabetics, but little is known about their effects on antioxidant status. We investigated the effects of ad libitum consumption of commercially available NNS (aspartame, saccharin, sucralose, and cyclamate-based sweeteners) on antioxidative markers in a rat model of type 2 diabetes (T2D). NNS consumption reduced (p < 0.05) T2D-induced lipid peroxidation and boosted serum, hepatic, renal, cardiac, and pancreatic glutathione (GSH) levels. Catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase activity was increased in the serum and most organs upon diabetes induction, perhaps due to adaptative antioxidant response to the diabetes-induced lipid peroxidation. NNS showed varying effects on serum and tissue antioxidant enzymes of animals. An antioxidant capacity scores sheet of NNS, suggest that aspartame-based NNS may not exert antioxidant effects in diabetics, while saccharin-based NNS may be a potent antioxidative sweetener as seen in the animal model of T2D. PRACTICAL APPLICATIONS: The use of NNS is becoming more popular, especially for diabetic individuals. While there are several commercial NNS available in the market, little is known about how they affect the antioxidant status of consumers. We therefore investigated how some commercially available NNS affect the antioxidant status of diabetic rats. Observed data revealed varying effects of NNS on serum and different organs, which suggest that some NNS may be better than others for diabetic oxidative stress and thus may be recommended for consumers. However, this finding is subject to additional corroborative clinical studies.

Medicinal plants with concomitant anti-diabetic and anti-hypertensive effects as potential sources of dual acting therapies against diabetes and hypertension: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes and hypertension are pathophysiologically related diseases that co-exist with a wider complex of metabolic diseases having similar set of risk factors. There are numerous ethnopharmacological evidences on the anti-diabetic and/or anti-hypertensive properties of medicinal plants from various parts of the world, which are used as therapies to concomitantly manage diabetes and hypertension. AIM OF THE REVIEW: This article reviewed findings on medicinal plants with both anti-diabetic and anti-hypertensive effects reported in same experimental study to facilitate the development of dual-acting therapies against diabetes and hypertension. MATERIALS AND METHODS: A literature search was carried out on different scientific search engines including, but not limited to "PubMed", "Google Scholar", "Scopus" and ScienceDirect to identify published data in which plants in same experimental studies were reported to possess both anti-hyperglycemic and anti-hypertensive effects. Subsequently, the anti-diabetic/anti-hypertensive potency ratio (ψ) of the medicinal plants was computed. RESULTS: Sixty-four studies with 102 plant species matched the selection criteria. Members of the Fabaceae family were the most investigated plants, while the ψ greatly varied across the plants, with only 11 plants having a ψ ≃ 1. Withania somnifera Dunal was the only plant reported to show blood glucose-lowering and diuretic effects in humans, comparable to daonil. Caffeic acid, chlorogenic acid, caftaric acid, cichoric acid, verbascoside, leucosceptoside A, isoacteoside, fucoxanthin and nicotinamide were the reported dual acting anti-diabetic and anti-hypertensive compounds identified and/or isolated in the plants. CONCLUSIONS: This review suggests that medicinal plants possess varied therapeutic dynamics against hypertension and diabetes that could be exploited for the discovery of therapeutic preparation(s) or agent(s) for treating the two diseases.

Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

PURPOSE: Studies have reported that erythritol, a low or non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). METHODS: Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1 g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. RESULTS: Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. CONCLUSION: Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

Sorbitol increases muscle glucose uptake ex vivo and inhibits intestinal glucose absorption ex vivo and in normal and type 2 diabetic rats.

Previous studies have suggested that sorbitol, a known polyol sweetener, possesses glycemic control potentials. However, the effect of sorbitol on intestinal glucose absorption and muscle glucose uptake still remains elusive. The present study investigated the effects of sorbitol on intestinal glucose absorption and muscle glucose uptake as possible anti-hyperglycemic or glycemic control potentials using ex vivo and in vivo experimental models. Sorbitol (2.5% to 20%) inhibited glucose absorption in isolated rat jejuna (IC50 = 14.6% ± 4.6%) and increased glucose uptake in isolated rat psoas muscle with (GU50 = 3.5% ± 1.6%) or without insulin (GU50 = 7.0% ± 0.5%) in a concentration-dependent manner. Furthermore, sorbitol significantly delayed gastric emptying, accelerated digesta transit, inhibited intestinal glucose absorption, and reduced blood glucose increase in both normoglycemic and type 2 diabetic rats after 1 h of coingestion with glucose. Data of this study suggest that sorbitol exhibited anti-hyperglycemic potentials, possibly via increasing muscle glucose uptake ex vivo and reducing intestinal glucose absorption in normal and type 2 diabetic rats. Hence, sorbitol may be further investigated as a possible anti-hyperglycemic sweetener.

Maltitol inhibits small intestinal glucose absorption and increases insulin mediated muscle glucose uptake ex vivo but not in normal and type 2 diabetic rats.

This study investigated the effects of maltitol on intestinal glucose absorption and muscle glucose uptake using ex vivo and in vivo experimental models. The ex vivo experiment was conducted in isolated jejunum and psoas muscle from normal rats. The in vivo study investigated the effects of a single bolus dose of maltitol on gastric emptying, intestinal glucose absorption and digesta transit in normal and type 2 diabetic rats. Maltitol inhibited glucose absorption in isolated rat jejunum and increased glucose uptake in isolated rat psoas muscle in the presence of insulin but not in the absence of insulin. In contrast, maltitol did not significantly (p > 0.05) alter small intestinal glucose absorption or blood glucose levels as well as gastric emptying and digesta transit in normal or type 2 diabetic rats. The results suggest that maltitol may not be a suitable dietary supplement for anti-diabetic food and food products to improve glycemic control.

XYLITOL IMPROVES ANTI-OXIDATIVE DEFENSE SYSTEM IN SERUM, LIVER, HEART, KIDNEY AND PANCREAS OF NORMAL AND TYPE 2 DIABETES MODEL OF RATS.

The present study investigated the anti-oxidative effects of xylitol both in vitro and in vivo in normal and type 2 diabetes (T2D) rat model. Free radical scavenging and ferric reducing potentials of different concentrations of xylitol were investigated in vitro. For in vivo study, six weeks old male Sprague-Dawley rats were divided into four groups, namely: Normal Control (NC), Diabetic Control (DBC), Normal Xylitol (NXYL) and Diabetic Xylitol (DXYL). T2D was induced in the DBC and DXYL groups. After the confirmation of diabetes, a 10% xylitol solution was supplied instead of drinking water to NXYL and DXYL, while normal drinking water was supplied to NC and DBC ad libitum. After five weeks intervention period, the animals were sacri- ficed and thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) concentrations as well as superoxide dismutase, catalase glutathione reductase and glutathione peroxidase activities were determined in the liver, heart, kidney, pancreatic tissues and serum samples. Xylitol exhibited significant (p < 0.05) in vitro nitric oxide and hydroxyl radical scavenging and ferric reducing activities. In vivo study revealed significant (p < 0.05) reduction in TBARS concentrations in the xylitol consuming groups compared to their respective controls. Significant (p < 0.05) increase in GSH levels and antioxidant enzyme activities were observed in analyzed tissues and serum of xylitol-fed animals compared to their respective controls. Results of this study indicate that xylitol has strong anti-oxidative potential against T2D-associated oxidative stress. Hence, xylitol can be used as a potential supplement in diabetic foods and food products.

Myo-inositol inhibits intestinal glucose absorption and promotes muscle glucose uptake: a dual approach study

The present study investigated the effects of myo-inositol on muscle glucose uptake and intestinal glucose absorption ex vivo as well as in normal and type 2 diabetes model of rats. In ex vivo study, both intestinal glucose absorption and muscle glucose uptake were studied in isolated rat jejunum and psoas muscle respectively in the presence of increasing concentrations (2.5 % to 20 %) of myo-inositol. In the in vivo study, the effect of a single bolus dose (1 g/kg bw) of oral myo-inositol on intestinal glucose absorption, blood glucose, gastric emptying and digesta transit was investigated in normal and type 2 diabetic rats after 1 h of co-administration with 2 g/kg bw glucose, when phenol red was used as a recovery marker. Myo-inositol inhibited intestinal glucose absorption (IC50 = 28.23 ± 6.01 %) and increased muscle glucose uptake, with (GU50 = 2.68 ± 0.75 %) or without (GU50 = 8.61 ± 0.55 %) insulin. Additionally, oral myo-inositol not only inhibited duodenal glucose absorption and reduced blood glucose increase, but also delayed gastric emptying and accelerated digesta transit in both normal and diabetic animals. Results of this study suggest that dietary myo-inositol inhibits intestinal glucose absorption both in ex vivo and in normal or diabetic rats and also promotes muscle glucose uptake in ex vivo condition. Hence, myo-inositol may be further investigated as a possible anti-hyperglycaemic dietary supplement for diabetic foods and food products (AU)

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Myo-inositol inhibits intestinal glucose absorption and promotes muscle glucose uptake: a dual approach study.

The present study investigated the effects of myo-inositol on muscle glucose uptake and intestinal glucose absorption ex vivo as well as in normal and type 2 diabetes model of rats. In ex vivo study, both intestinal glucose absorption and muscle glucose uptake were studied in isolated rat jejunum and psoas muscle respectively in the presence of increasing concentrations (2.5 % to 20 %) of myo-inositol. In the in vivo study, the effect of a single bolus dose (1 g/kg bw) of oral myo-inositol on intestinal glucose absorption, blood glucose, gastric emptying and digesta transit was investigated in normal and type 2 diabetic rats after 1 h of co-administration with 2 g/kg bw glucose, when phenol red was used as a recovery marker. Myo-inositol inhibited intestinal glucose absorption (IC50 = 28.23 ± 6.01 %) and increased muscle glucose uptake, with (GU50 = 2.68 ± 0.75 %) or without (GU50 = 8.61 ± 0.55 %) insulin. Additionally, oral myo-inositol not only inhibited duodenal glucose absorption and reduced blood glucose increase, but also delayed gastric emptying and accelerated digesta transit in both normal and diabetic animals. Results of this study suggest that dietary myo-inositol inhibits intestinal glucose absorption both in ex vivo and in normal or diabetic rats and also promotes muscle glucose uptake in ex vivo condition. Hence, myo-inositol may be further investigated as a possible anti-hyperglycaemic dietary supplement for diabetic foods and food products.

Effects of xylitol on carbohydrate digesting enzymes activity, intestinal glucose absorption and muscle glucose uptake: a multi-mode study.

The present study investigated the possible mechanism(s) behind the effects of xylitol on carbohydrate digesting enzymes activity, muscle glucose uptake and intestinal glucose absorption using in vitro, ex vivo and in vivo experimental models. The effects of increasing concentrations of xylitol (2.5%-40% or 164.31 mM-2628.99 mM) on alpha amylase and alpha glucosidase activity in vitro and intestinal glucose absorption and muscle glucose uptake were investigated under ex vivo conditions. Additionally, the effects of an oral bolus dose of xylitol (1 g per kg BW) on gastric emptying and intestinal glucose absorption and digesta transit in the different segments of the intestinal tract were investigated in normal and type 2 diabetic rats at 1 hour after dose administration, when phenol red was used as a recovery marker. Xylitol exhibited concentration-dependent inhibition of alpha amylase (IC50 = 1364.04 mM) and alpha glucosidase (IC50 = 1127.52 mM) activity in vitro and small intestinal glucose absorption under ex vivo condition. Xylitol also increased dose dependent muscle glucose uptake with and without insulin, although the uptake was not significantly affected by the addition of insulin. Oral single bolus dose of xylitol significantly delayed gastric emptying, inhibited intestinal glucose absorption but increased the intestinal digesta transit rate in both normal and diabetic rats compared to their respective controls. The data of this study suggest that xylitol reduces intestinal glucose absorption via inhibiting major carbohydrate digesting enzymes, slowing gastric emptying and fastening the intestinal transit rate, but increases muscle glucose uptake in normal and type 2 diabetic rats.