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Fulltext Metabolomics Profiling of Age-Associated Metabolites in Malay Population

Tan JK, Zakaria SNA, Gunasekaran G, Abdul Sani NF, Nasaruddin ML, Jaafar F, et al.

Oxid Med Cell Longev, 2023;2023:4416410.
PMID: 36785791 DOI: 10.1155/2023/4416410

Aging is a complex process characterized by progressive loss of functional abilities due to the accumulation of molecular damages. Metabolomics could offer novel insights into the predictors and mechanisms of aging. This cross-sectional study is aimed at identifying age-associated plasma metabolome in a Malay population. A total of 146 (90 females) healthy participants aged 28-69 were selected for the study. Untargeted metabolomics profiling was performed using liquid chromatography-tandem mass spectrometry. Association analysis was based on the general linear model. Gender-associated metabolites were adjusted for age, while age-associated metabolites were adjusted for gender or analyzed in a gender-stratified manner. Gender-associated metabolites such as 4-hydroxyphenyllactic acid, carnitine, cortisol, and testosterone sulfate showed higher levels in males than females. Deoxycholic acid and hippuric acid were among the metabolites with a positive association with age after being adjusted for gender, while 9(E),11(E)-conjugated linoleic acid, cortisol, and nicotinamide were negatively associated with age. In gender-stratified analysis, glutamine was one of the common metabolites that showed a direct association with age in both genders, while metabolites such as 11-deoxy prostaglandin F2β, guanosine monophosphate, and testosterone sulfate were inversely associated with age in males and females. This study reveals several age-associated metabolites in Malays that could reflect the changes in metabolisms during aging and may be used to discern the risk of geriatric syndromes and disorders later. Further studies are required to determine the interplay between these metabolites and environmental factors on the functional outcomes during aging.
Fulltext Effect of Administration of an Equal Dose of Selected Dietary Chemicals on Nrf2 Nuclear Translocation in the Mouse Liver

Alrawaiq NS, Atia A, Abdullah A

Oxid Med Cell Longev, 2023;2023:9291417.
PMID: 37077659 DOI: 10.1155/2023/9291417

Certain dietary chemicals influenced the expression of chemopreventive genes through the Nrf2-Keap1 pathway. However, the difference in Nrf2 activation potency of these chemicals is not well studied. This study is aimed at determining the difference in the potency of liver Nrf2 nuclear translocation induced by the administration of equal doses of selected dietary chemicals in mice. Male ICR white mice were administered 50 mg/kg of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol for 14 days. On day 15, the animals were sacrificed, and their livers were isolated. Liver nuclear extracts were prepared, and Nrf2 nuclear translocation was detected through Western blotting. To determine the implication of the Nrf2 nuclear translocation on the expression levels of several Nrf2-regulated genes, liver RNA was extracted for qPCR assay. Equal doses of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol significantly induced the nuclear translocation of Nrf2 with different intensities and subsequently increased the expression of Nrf2-regulated genes with an almost similar pattern as the Nrf2 nuclear translocation intensities (sulforaphane > butylated hydroxyanisole = indole-3-carbinol > curcumin > quercetin). In conclusion, sulforaphane is the most potent dietary chemical that induces the Nrf2 translocation into the nuclear fraction in the mouse liver.
Fulltext Effect of Silymarin as an Adjunct Therapy in Combination with Sofosbuvir and Ribavirin in Hepatitis C Patients: A Miniature Clinical Trial

Ahmed S, Ullah N, Parveen S, Javed I, Jalil NAC, Murtey MD, et al.

Oxid Med Cell Longev, 2022;2022:9199190.
PMID: 35154575 DOI: 10.1155/2022/9199190

Silymarin is proclaimed to be a blend of flavonolignans or phytochemicals. An era of new generation of direct-acting antivirals (DAAs) has commenced to have facet effect in swaying of the hepatitis C virus (HCV). Nonetheless, this therapy has serious side effects that jeopardize its efficacy. This study is aimed at probing the effects of ribavirin (RBV) and sofosbuvir (SOF) along with silymarin as an adjunct therapy on hematological parameters and markers of obscured oxidative stress. The effect of DAAs along with silymarin was also examined on variable sex hormone level and liver function markers such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and bilirubin. The study was followed to determine viral load and viral genotypes. A total of 30 patients were randomly divided into two equal groups comprising the control group (n = 15) and treatment group (n = 15). The control group was solely administered with DAAs (SOF and RBV; 400 mg/800 mg each/day). Conversely, the treatment group was dispensed with DAAs, but with adjunct therapy of silymarin (400 mg/day) along with DAAs (400/800 mg/day) over period of 8 weeks. Sampling of blood was performed at pre- and posttreatment levels for the evaluation of different propound parameters. Our data showed that silymarin adjunct therapy enhances the efficiency of DAAs. A decrease in menace level of liver markers such as ALT, ALP, AST, and bilirubin was observed (p > 0.05). The adjunct therapy concurrently also demonstrated an ameliorative effect on hematological indices and oxidative markers, for instance, SOD, TAS, GSH, GSSG, and MDA (p < 0.05), diminishing latent viral load. The silymarin administration was also found to revamp the fluster level of sex hormones. Our outcomes provide evidence that systematic administration of silymarin effectively remits deviant levels of hematological, serological, hormonal, and antioxidant markers. This demonstrates a possibly unique role of silymarin in mitigating hepatitis C.
The Attenuation of Chronic Ulcerative Colitis by (R)-salbutamol in Repeated DSS-Induced Mice

Deng L, Guo H, Wang S, Liu X, Lin Y, Zhang R, et al.

Oxid Med Cell Longev, 2022;2022:9318721.
PMID: 35178163 DOI: 10.1155/2022/9318721

Racemic salbutamol ((RS)-sal), which consist of the same amount of (R)-sal and (S)-sal, has been used for asthma and COPD due to its bronchodilation effect. However, the effect of (R)-sal on repeated dextran sulfate sodium (DSS)-induced chronic colitis has not yet been investigated. In this study evaluated the potential effect of (R)-, (S)-, and (RS)-sal in mice with repeated DSS-induced chronic colitis and investigated the underlying mechanisms. Here, we verified that chronic colitis was significantly attenuated by (R)-sal, which was evidenced by notably mitigated body weight loss, disease activity index (DAI), splenomegaly, colonic lengths shortening, and histopathological scores. (R)-sal treatment noticeably diminished the levels of inflammatory cytokines (such as TNF-α, IL-6, IL-1β, and IFN-γ). Notably, the efficacy of (R)-sal was better than that of (RS)-sal. Further research revealed that (R)-sal mitigated colonic CD4 leukocyte infiltration, decreased NF-κB signaling pathway activation, improved the Nrf-2/HO-1 signaling pathway, and increased the expression of ZO-1 and occludin. In addition, (R)-sal suppressed the levels of TGF-β1, α-SMA, and collagen in mice with chronic colitis. Furthermore, the 16S rDNA sequences analyzed of the intestinal microbiome revealed that (R)-sal could mitigate the intestinal microbiome structure and made it more similar to the control group, which mainly by relieving the relative abundance of pathogens (such as Bacteroides) and increasing the relative abundance of probiotics (such as Akkermansia). Therefore, (R)-sal ameliorates repeated DSS-induced chronic colitis in mice by improving inflammation, suppressing oxidative stress, mitigating intestinal barrier function, relieving intestinal fibrosis, and regulating the intestinal microbiome community. These results indicate that (R)-sal maybe a novel treatment alternative for chronic colitis.
Fulltext Isosteviol Sodium Ameliorates Dextran Sodium Sulfate-Induced Chronic Colitis through the Regulation of Metabolic Profiling, Macrophage Polarization, and NF-κB Pathway

Wang S, Huang J, Tan KS, Deng L, Liu F, Tan W

Oxid Med Cell Longev, 2022;2022:4636618.
PMID: 35126813 DOI: 10.1155/2022/4636618

Inflammatory bowel diseases (IBDs) constitute a group of chronic intestinal conditions prominently featuring deranged metabolism. Effective pharmacological treatments for IBDs are lacking. Isosteviol sodium (STV-Na) exhibits anti-inflammatory activity and may offer therapeutic benefits in chronic colitis. However, the associated mechanism remains unclear. This study is aimed at exploring the therapeutic effects of STV-Na against chronic colitis in terms of metabolic reprogramming and macrophage polarization. Results show that STV-Na attenuated weight loss and colonic pathological damage and restored the hematological and biochemical parameters in chronic colitis mice models. STV-Na also restored intestinal permeability by increasing the goblet cell numbers, which was accompanied by lowered plasma lipopolysaccharide and diamine oxidase levels. Metabolomic analysis highlighted 102 candidate biomarkers and 5 vital pathways that may be crucial in the potential pharmacological mechanism of STV-Na in regulating intestinal inflammation and oxidative stress. These pathways were glycerophospholipid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, the pentose phosphate pathway, and phosphonate and phosphinate metabolism. Furthermore, STV-Na significantly decreased M1 macrophage polarization in the spleen and colon. The mRNA and protein levels of IL-1β, TNF-α, and NF-κB/p65 in colonic tissue from the colitis mice were decreased after the STV-Na treatment. Overall, STV-Na could alleviate chronic colitis by suppressing oxidative stress and inflammation levels, reprogramming the metabolic profile, inhibiting macrophage polarization, and suppressing the NF-κB/p65 signaling pathway. STV-Na remains a promising candidate drug for treating IBDs.
Fulltext Gliclazide in Binary and Ternary Systems Improves Physicochemical Properties, Bioactivity, and Antioxidant Activity

Ibrahim M, Munir S, Ahmed S, Chughtai AH, Ahmad W, Khan J, et al.

Oxid Med Cell Longev, 2022;2022:2100092.
PMID: 36466089 DOI: 10.1155/2022/2100092

The poor solubility of the antidiabetic drug gliclazide (Glc) is due to its hydrophobic nature. This research is aimed at improving Glc's solubility and drug release profile, as well as at investigating additional benefits such as bioactivity and antioxidant activity, by forming binary complexes with HPβCD at different w/w ratios (1 : 1, 1 : 2.5, 1 : 4, and 1 : 9) and ternary complexes with HPβCD and Tryp at 1 : 1 : 1, 1 : 1 : 0.27, 1 : 2.5 : 0.27, 1 : 3.6 : 3.6, 1 : 4 : 1, and 1 : 9 : 1, respectively. Complexes were prepared by the physical mixing (PM) and solvent evaporation (SE) methods. The prepared inclusion complexes were meticulously characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectra. To verify our findings, the inclusion complexes were evaluated by equilibrium solubility, in vitro drug release profile, kinetic models, and antidiabetic and antioxidant activities in animal models. Our results demonstrated that the solubility and drug release profile were found to be enhanced through binary as well as ternary complexes. Notably, ternary complexes with a ratio of 1 : 9 : 1 showed the highest solubility and drug release profile compared to all other preparations. Data on antioxidant activity indicated that the ternary complex had the higher total antioxidant status (TAS), superoxide dismutase (SOD), and catalase (CAT) activity than the binary complex and Glc alone, in contrast to the diabetic group. In vivo antidiabetic activity data revealed a high percentage reduction in the blood glucose level by ternary complexes (49-52%) compared to the binary complexes (45-46%; p ≤ 0.05). HPβCD and Tryp provide a new platform for overcoming the challenges associated with poorly soluble Glc by providing greater complexing and solubilizing capabilities and imparting ancillary benefits to improve the drug's antidiabetic and antioxidant activities.
Fulltext Polyphenols Targeting Oxidative Stress in Spinal Cord Injury: Current Status and Future Vision

Islam F, Bepary S, Nafady MH, Islam MR, Emran TB, Sultana S, et al.

Oxid Med Cell Longev, 2022;2022:8741787.
PMID: 36046682 DOI: 10.1155/2022/8741787

A spinal cord injury (SCI) occurs when the spinal cord is deteriorated or traumatized, leading to motor and sensory functions lost even totally or partially. An imbalance within the generation of reactive oxygen species and antioxidant defense levels results in oxidative stress (OS) and neuroinflammation. After SCI, OS and occurring pathways of inflammations are significant strenuous drivers of cross-linked dysregulated pathways. It emphasizes the significance of multitarget therapy in combating SCI consequences. Polyphenols, which are secondary metabolites originating from plants, have the promise to be used as alternative therapeutic agents to treat SCI. Secondary metabolites have activity on neuroinflammatory, neuronal OS, and extrinsic axonal dysregulated pathways during the early stages of SCI. Experimental and clinical investigations have noted the possible importance of phenolic compounds as important phytochemicals in moderating upstream dysregulated OS/inflammatory signaling mediators and axonal regeneration's extrinsic pathways after the SCI probable significance of phenolic compounds as important phytochemicals in mediating upstream dysregulated OS/inflammatory signaling mediators. Furthermore, combining polyphenols could be a way to lessen the effects of SCI.
Fulltext Targeted Diagnosis, Therapeutic Monitoring, and Assessment of Atherosclerosis Based on Mesoporous Silica Nanoparticles Coated with cRGD-Platelets

Zhang W, Lv Z, Zhang Y, Gopinath SCB, Yuan Y, Huang D, et al.

Oxid Med Cell Longev, 2022;2022:6006601.
PMID: 36211824 DOI: 10.1155/2022/6006601

OBJECTIVE: The off-target effects and severe side effects of PPARα and LXRα agonists greatly limit their application in atherosclerosis (AS). Therefore, this study intended to use mesoporous silica nanoparticles as carriers to generate MnO nanoparticles in situ with T1WI-MRI in mesoporous pores and simultaneously load PPARα and LXRα agonists. Afterward, cRGD-chelated platelet membranes can be used for coating to construct a new nanotheranostic agent.
METHODS: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were synthesized by a chemical method. Dynamic light scattering (DLS) was utilized to detect the size distribution and polydispersity index (PDI) of the nanoparticles. The safety of the nanoparticles was detected by CCK8 in vitro and HE staining and kidney function in vivo. Cell apoptosis was detected by flow cytometry detection and TUNEL staining. Oxidative stress responses (ROS, SOD, MDA, and NOX levels) were tested via a DCFH-DA assay and commercial kits. Immunofluorescence and phagocytosis experiments were used to detect the targeting of nanoparticles. Magnetic resonance imaging (MRI) was used to detect the imaging performance of cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles. Using western blotting, the expression changes in LXRα and ABCA1 were identified.
RESULTS: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were successfully established, with a particle size of approximately 150 nm and PDI less than 0.3, and showed high safety both in vitro and in vivo. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed good targeting properties and better MRI imaging performance in AS. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed better antioxidative capacities, MRI imaging performance, and diagnostic and therapeutic effects on AS by regulating the expression of LXRα and ABCA1.
CONCLUSION: In the present study, cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles with high safety and the capacity to target vulnerable plaques of AS were successfully established. They showed better performance on MRI images and treatment effects on AS by promoting cholesterol efflux through the regulation of ABCA1. These findings might address the problems of off-target effects and side effects of nanoparticle-mediated drug delivery, which will enhance the efficiency of AS treatment and provide new ideas for the clinical treatment of AS.
Fulltext Pharmacological Properties of Bergapten: Mechanistic and Therapeutic Aspects

Quetglas-Llabrés MM, Quispe C, Herrera-Bravo J, Catarino MD, Pereira OR, Cardoso SM, et al.

Oxid Med Cell Longev, 2022;2022:8615242.
PMID: 35509838 DOI: 10.1155/2022/8615242

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.
Fulltext The Differences in the Levels of Oxidative Status Marker and Soluble CD95 in Patients with Moderate to Severe COPD during an Exacerbation and a Stable Period

Soodaeva S, Kubysheva N, Klimanov I, Shutov A, Eliseeva T, Novikov V, et al.

Oxid Med Cell Longev, 2021;2021:2105406.
PMID: 34925689 DOI: 10.1155/2021/2105406

Studying the features of changes in markers of oxidative stress (OS) and inflammation indicators in COPD patients depending on the degree of bronchial obstruction is one of the priority directions for improving the prognosis and monitoring of the course of this pathology. We conducted a comparative investigation of changes in markers of OS and apoptosis at the systemic and local levels in patients with moderate to severe COPD during exacerbation and stable phase. 105 patients with COPD aged 46-67 and 21 healthy nonsmoking volunteers comparable in age were examined. COPD patients were divided into four groups: moderate COPD (GOLDII) during the exacerbation (GOLDIIex, n = 25) and in the stable phase (GOLDIIst, n = 27), severe COPD (GOLDIII) during the exacerbation (GOLDIIIex, n = 29), and in the stable phase (GOLDIIIst, n = 24). We studied the levels of such lipid peroxidation (LPO) products as diene conjugates (DC) and Schiff bases (SB) and parameters of induced chemiluminescence (Imax, total light sum-S, Imax/S) in blood serum, as well as sCD95 concentration in blood and exhaled breath condensate (EBC). The relationship between the values of the OS system indicators with sCD95, as well as with the parameters of lung function, was investigated. Multidirectional changes in OS indicator levels in COPD patients depending on the severity of obstructive airway disorders have been established. The maximum values of DC (0.26 ± 0.046 RU), Imax (0.265 ± 0.19 RLU), and Imax/S (0.13 ± 0.05) were typical for patients with moderate COPD, while the highest SB level (5.7 ± 2.3 RU) was observed in severe COPD during an exacerbation. The exacerbation of the disease was characterized by an increase in DC concentration in both GOLDIIex (0.26 ± 0.046 RU) and GOLDIIIex (0.209 ± 0.02 RU) compared to the stable moderate and severe COPD (0.202 ± 0.028 RU and 0.19 ± 0.03 RU, respectively, p < 0.05). The established decrease in high values of DC, Imax, Imax/S, and sCD95 and an increase in SB concentration in GOLD III can serve as quantitative indicators of the prognosis of the severity of the disease. The serum concentration of sCD95 in GOLDIIex (366.4 ± 70.5 U/ml) and GOLDIIst (361.4 ± 72.8 U/ml) did not differ from the control group (393.7 ± 80.9 U/ml, p > 0.05). In patients with FEV1 < 49% during the exacerbation and stable phase, the serum levels of Imax/S (0.058 ± 0.01 and 0.062 ± 0.01) and sCD95 (318.2 ± 66.3 U/ml and 321.4 ± 42.5 U/ml) were lower than the values of healthy volunteers (0.08 ± 0.01 and 393.7 ± 80.9 U/ml, respectively, p < 0.05). A positive correlation between sCD95 concentration and airway obstruction degree in all examined COPD patients was established. The revealed numerous associations between sCD95 and OS marker levels in GOLDIII indicate a relationship between systemic radical stress and apoptosis processes both in the respiratory tract and the whole body under conditions of severe inflammation. The established correlations between the values of DC, Imax, and sCD95 in the blood serum and the lung function parameters in all studied patients allow us to consider these indicators as additional prognostic indicators of disease intensification. Our work results help clarify the participation and detail of FRO and apoptosis processes in developing pathophysiological features in moderate to severe COPD in different periods and, accordingly, improve the efficiency of diagnosis and treatment of the disease.
Fulltext Glycyrrhiza Genus: Enlightening Phytochemical Components for Pharmacological and Health-Promoting Abilities

Sharifi-Rad J, Quispe C, Herrera-Bravo J, Belén LH, Kaur R, Kregiel D, et al.

Oxid Med Cell Longev, 2021;2021:7571132.
PMID: 34349875 DOI: 10.1155/2021/7571132

The Glycyrrhiza genus, generally well-known as licorice, is broadly used for food and medicinal purposes around the globe. The genus encompasses a rich pool of bioactive molecules including triterpene saponins (e.g., glycyrrhizin) and flavonoids (e.g., liquiritigenin, liquiritin). This genus is being increasingly exploited for its biological effects such as antioxidant, antibacterial, antifungal, anti-inflammatory, antiproliferative, and cytotoxic activities. The species Glycyrrhiza glabra L. and the compound glycyrrhizin (glycyrrhizic acid) have been studied immensely for their effect on humans. The efficacy of the compound has been reported to be significantly higher on viral hepatitis and immune deficiency syndrome. This review provides up-to-date data on the most widely investigated Glycyrrhiza species for food and medicinal purposes, with special emphasis on secondary metabolites' composition and bioactive effects.
Fulltext The Antioxidative Role of Natural Compounds from a Green Coconut Mesocarp Undeniably Contributes to Control Diabetic Complications as Evidenced by the Associated Genes and Biochemical Indexes

Das RR, Rahman MA, Al-Araby SQ, Islam MS, Rashid MM, Babteen NA, et al.

Oxid Med Cell Longev, 2021;2021:9711176.
PMID: 34367469 DOI: 10.1155/2021/9711176

The purpose of this study was to look into the effects of green coconut mesocarp juice extract (CMJE) on diabetes-related problems in streptozotocin- (STZ-) induced type 2 diabetes, as well as the antioxidative functions of its natural compounds in regulating the associated genes and biochemical markers. CMJE's antioxidative properties were evaluated by the standard antioxidant assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide radical, nitric oxide, and ferrous ions along with the total phenolic and flavonoids content. The α-amylase inhibitory effect was measured by an established method. The antidiabetic effect of CMJE was assayed by fructose-fed STZ-induced diabetic models in albino rats. The obtained results were verified by bioinformatics-based network pharmacological tools: STITCH, STRING, GSEA, and Cytoscape plugin cytoHubba bioinformatics tools. The results showed that GC-MS-characterized compounds from CMJE displayed a very promising antioxidative potential. In an animal model study, CMJE significantly (P < 0.05) decreased blood glucose, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, uric acid, and lipid levels and increased glucose tolerance as well as glucose homeostasis (HOMA-IR and HOMA-b scores). The animal's body weights and relative organ weights were found to be partially restored. Tissue architectures of the pancreas and the kidney were remarkably improved by low doses of CMJE. Compound-protein interactions showed that thymine, catechol, and 5-hydroxymethylfurfural of CMJE interacted with 84 target proteins. Of the top 15 proteins found by Cytoscape 3.6.1, 8, CAT and OGG1 (downregulated) and CASP3, COMT, CYP1B1, DPYD, NQO1, and PTGS1 (upregulated), were dysregulated in diabetes-related kidney disease. The data demonstrate the highly prospective use of CMJE in the regulation of tubulointerstitial tissues of patients with diabetic nephropathy.
Fulltext Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation

Ramachandran S, Verma AK, Dev K, Goyal Y, Bhatt D, Alsahli MA, et al.

Oxid Med Cell Longev, 2021;2021:5563746.
PMID: 34336101 DOI: 10.1155/2021/5563746

With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-β, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.
Fulltext Phytoantioxidant Functionalized Nanoparticles: A Green Approach to Combat Nanoparticle-Induced Oxidative Stress

Balkrishna A, Kumar A, Arya V, Rohela A, Verma R, Nepovimova E, et al.

Oxid Med Cell Longev, 2021;2021:3155962.
PMID: 34737844 DOI: 10.1155/2021/3155962

Nanotechnology is gaining significant attention, with numerous biomedical applications. Silver in wound dressings, copper oxide and silver in antibacterial preparations, and zinc oxide nanoparticles as a food and cosmetic ingredient are common examples. However, adverse effects of nanoparticles in humans and the environment from extended exposure at varied concentrations have yet to be established. One of the drawbacks of employing nanoparticles is their tendency to cause oxidative stress, a significant public health concern with life-threatening consequences. Cardiovascular, renal, and respiratory problems and diabetes are among the oxidative stress-related disorders. In this context, phytoantioxidant functionalized nanoparticles could be a novel and effective alternative. In addition to performing their intended function, they can protect against oxidative damage. This review was designed by searching through various websites, books, and articles found in PubMed, Science Direct, and Google Scholar. To begin with, oxidative stress, its related diseases, and the mechanistic basis of oxidative damage caused by nanoparticles are discussed. One of the main mechanisms of action of nanoparticles was unearthed to be oxidative stress, which limits their use in humans. Secondly, the role of phytoantioxidant functionalized nanoparticles in oxidative damage prevention is critically discussed. The parameters for the characterization of nanoparticles were also discussed. The majority of silver, gold, iron, zinc oxide, and copper nanoparticles produced utilizing various plant extracts were active free radical scavengers. This potential is linked to several surface fabricated phytoconstituents, such as flavonoids and phenols. These phytoantioxidant functionalized nanoparticles could be a better alternative to nanoparticles prepared by other existing approaches.
Fulltext Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

Mustapha S, Mohammed M, Azemi AK, Yunusa I, Shehu A, Mustapha L, et al.

Oxid Med Cell Longev, 2021;2021:8830880.
PMID: 33995826 DOI: 10.1155/2021/8830880

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.
Fulltext Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits

Sharifi-Rad J, Quispe C, Imran M, Rauf A, Nadeem M, Gondal TA, et al.

Oxid Med Cell Longev, 2021;2021:3268136.
PMID: 34336089 DOI: 10.1155/2021/3268136

Genistein is an isoflavone first isolated from the brooming plant Dyer's Genista tinctoria L. and is widely distributed in the Fabaceae family. As an isoflavone, mammalian genistein exerts estrogen-like functions. Several biological effects of genistein have been reported in preclinical studies, such as the antioxidant, anti-inflammatory, antibacterial, and antiviral activities, the effects of angiogenesis and estrogen, and the pharmacological activities on diabetes and lipid metabolism. The purpose of this review is to provide up-to-date evidence of preclinical pharmacological activities with mechanisms of action, bioavailability, and clinical evidence of genistein. The literature was researched using the most important keyword "genistein" from the PubMed, Science, and Google Scholar databases, and the taxonomy was validated using The Plant List. Data were also collected from specialized books and other online resources. The main positive effects of genistein refer to the protection against cardiovascular diseases and to the decrease of the incidence of some types of cancer, especially breast cancer. Although the mechanism of protection against cancer involves several aspects of genistein metabolism, the researchers attribute this effect to the similarity between the structure of soy genistein and that of estrogen. This structural similarity allows genistein to displace estrogen from cellular receptors, thus blocking their hormonal activity. The pharmacological activities resulting from the experimental studies of this review support the traditional uses of genistein, but in the future, further investigations are needed on the efficacy, safety, and use of nanotechnologies to increase bioavailability and therapeutic efficacy.
Fulltext Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress

Wee CL, Mokhtar SS, Singh KKB, Yahaya S, Leung SWS, Rasool AHG

Oxid Med Cell Longev, 2021;2021:3109294.
PMID: 33623633 DOI: 10.1155/2021/3109294

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 μg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.
Fulltext A Review on Oxidative Stress, Diabetic Complications, and the Roles of Honey Polyphenols

Pasupuleti VR, Arigela CS, Gan SH, Salam SKN, Krishnan KT, Rahman NA, et al.

Oxid Med Cell Longev, 2020;2020:8878172.
PMID: 33299532 DOI: 10.1155/2020/8878172

Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world's most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights.
Fulltext Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

Azemi AK, Mokhtar SS, Rasool AHG

Oxid Med Cell Longev, 2020;2020:7572892.
PMID: 32879653 DOI: 10.1155/2020/7572892

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.
Fulltext Detrimental Effects of UVB on Retinal Pigment Epithelial Cells and Its Role in Age-Related Macular Degeneration

Mahendra CK, Tan LTH, Pusparajah P, Htar TT, Chuah LH, Lee VS, et al.

Oxid Med Cell Longev, 2020;2020:1904178.
PMID: 32855763 DOI: 10.1155/2020/1904178

Retinal pigment epithelial (RPE) cells are an essential part of the human eye because they not only mediate and control the transfer of fluids and solutes but also protect the retina against photooxidative damage and renew photoreceptor cells through phagocytosis. However, their function necessitates cumulative exposure to the sun resulting in UV damage, which may lead to the development of age-related macular degeneration (AMD). Several studies have shown that UVB induces direct DNA damage and oxidative stress in RPE cells by increasing ROS and dysregulating endogenous antioxidants. Activation of different signaling pathways connected to inflammation, cell cycle arrest, and intrinsic apoptosis was reported as well. Besides that, essential functions like phagocytosis, osmoregulation, and water permeability of RPE cells were also affected. Although the melanin within RPE cells can act as a photoprotectant, this photoprotection decreases with age. Nevertheless, the changes in lens epithelium-derived growth factor (LEDGF) and autophagic activity or application of bioactive compounds from natural products can reverse the detrimental effect of UVB. Additionally, in vivo studies on the whole retina demonstrated that UVB irradiation induces gene and protein level dysregulation, indicating cellular stress and aberrations in the chromosome level. Morphological changes like retinal depigmentation and drusen formation were noted as well which is similar to the etiology of AMD, suggesting the connection of UVB damage with AMD. Therefore, future studies, which include mechanism studies via in vitro or in vivo and other potential bioactive compounds, should be pursued for a better understanding of the involvement of UVB in AMD.

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