Targeting Nrf2 signaling pathway: new therapeutic strategy for cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of death globally, with oxidative stress (OS) identified as a primary contributor to their onset and progression. Given the elevated incidence and mortality rates associated with CVDs, there is an imperative need to investigate novel therapeutic strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), ubiquitously expressed in the cardiovascular system, has emerged as a promising therapeutic target for CVDs due to its role in regulating OS and inflammation. This review aims to delve into the mechanisms and actions of the Nrf2 pathway, highlighting its potential in mitigating the pathogenesis of CVDs.

Polycystic Ovary Syndrome and Oxidative Stress. Natural Treatments.

Polycystic ovary syndrome (PCOS) is one of the most frequent endocrinopathology affecting women in their reproductive ages. However, PCOS is also related to metabolic abnormalities such as metabolic syndrome (MS), insulin resistance (IR), and type 2 diabetes, among others. Consequently, an inflammatory and pro-oxidative status is also present in these patients, aggravating the syndrome's symptoms. This work aims to discuss some late treatments that focus on oxidative stress (OS) as a central feature related to primary PCOS abnormalities. Therefore, this review focuses on the evidence of anti-oxidant diets, natural compounds, mineralocorticoids, and combined therapies for PCOS management. Oxidative stress (OS) is important in PCOS pathogenesis. In this regard, increased levels of oxidative oxygen species and decreased levels of anti-oxidant agents' impact PCOS's reproductive and metabolic features. In the last years, non-pharmacological therapies have been considered a first line of treatment. For these reasons, several natural compounds such as Kelult honey (KH), Foeniculum Vulgare, Calendula officinalis Linn, Eugenia caryophyllus and Myristicafragrans, vitamin C, vitamin E, selenium, zinc, beta-carotene, magnesium, curcumin, mineralocorticoids and melatonin alone or in combination are powerful anti-oxidant agents being used for PCOS management. Data presented here suggest that natural therapies are essential in managing both reproductive and metabolic features in PCOS patients. Due to the results obtained, these incipient therapies deserve further investigation.

Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.

This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.

Core-Shell Structured Nanozyme with PDA-Mediated Enhanced Antioxidant Efficiency to Treat Early Intervertebral Disc Degeneration.

Early intervention during intervertebral disc degeneration (IDD) plays a vital role in inhibiting its deterioration and activating the regenerative process. Aiming at the high oxidative stress (OS) in the IDD microenvironment, a core-shell structured nanozyme composed of Co-doped NiO nanoparticle (CNO) as the core encapsulated with a polydopamine (PDA) shell, named PDA@CNO, was constructed, hoping to regulate the pathological environment. The results indicated that the coexistence of abundant Ni3+/Ni2+and Co3+/Co2+redox couples in CNO provided rich catalytic sites; meanwhile, the quinone and catechol groups in the PDA shell could enable the proton-coupled electron transfer, thus endowing the PDA@CNO nanozyme with multiple antioxidative enzyme-like activities to scavenge •O2-, H2O2, and •OH efficiently. Under OS conditions in vitro, PDA@CNO could effectively reduce the intracellular ROS in nucleus pulposus (NP) into friendly H2O and O2, to protect NP cells from stagnant proliferation, abnormal metabolism (senescence, mitochondria dysfunction, and impaired redox homeostasis), and inflammation, thereby reconstructing the extracellular matrix (ECM) homeostasis. The in vivo local injection experiments further proved the desirable therapeutic effects of the PDA@CNO nanozyme in a rat IDD model, suggesting great potential in prohibiting IDD from deterioration.

MiR-146b-5p regulates the scavenging effect of GPx-3 on peroxide in papillary thyroid cancer cells.

Background: Glutathione peroxidase (GPx) is an important antioxidant enzyme in thyroid follicular cells. Reduced levels of glutathione peroxidase 3 (GPx-3) expression in papillary thyroid cancer (PTC) are associated with poor prognosis. However, the reason for the decreased expression level of GPx-3 in PTC is unclear. Methods: The expression of GPx-3 in papillary thyroid carcinoma and adjacent normal tissue (n = 18) was detected by Western blotting. Bioinformatics was used to predict the relationship between the level of GPx-3 and gender, age, lymph node metastasis, stage, BRAFV600E mutation, and recurrence-free survival of patients. The possible upstream microRNAs of GPx-3 were analyzed by bioinformatics tools also. We verified the relationship between GPx-3 and upstream microRNA by dual luciferase reporter assay and enzyme-linked immunosorbent assay (ELISA). Results: The protein level of GPx-3 decreased in PTC, and analysis of public database datasets suggests that its decreased expression may be associated with the BRAFV600E mutation. MiR-146b-5p was significantly overexpressed in PTC. The dual luciferase reporter assay verified the effect of miR-146b-5p on 3'-UTR of GPx-3 mRNA. Knockdown of miR-146b-5p in thyroid cancer cell lines TPC-1 and BCPAP increased GPx-3 expression levels, accompanied by an increase in the conversion of glutathione (GSH) to oxidized glutathione (GSSG). Conclusions: In conclusion, the level of GPx-3 decreases in papillary thyroid carcinoma and impairs intracellular peroxide clearance, due to the inhibitory effect of miR-146b-5p. The accumulation of intracellular peroxides may contribute to the poor prognosis of thyroid cancer.

A Triterpenoid Lupeol as an Antioxidant and Anti-Neuroinflammatory Agent: Impacts on Oxidative Stress in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease illustrated by neuronal dysfunctions, leading to memory weaknesses and personality changes mostly in the aged population worldwide. The exact cause of AD is unclear, but numerous studies have addressed the involvement of oxidative stress (OS), induced by reactive oxygen species (ROS), to be one of the leading causes in developing AD. OS dysregulates the cellular homeostasis, causing abnormal protein and lipid metabolism. Nutrition plays a pivotal role in modulating the antioxidant system and decreases the neuronal ROS level, thus playing an important therapeutic role in neurodegenerative diseases, especially in AD. Hence, medicinal herbs and their extracts have received global attention as a commercial source of antioxidants Lupeol. Lupeol is a pentacyclic triterpenoid and has many biological functions. It is available in fruits, vegetables, and medicinal plants. It has shown effective antioxidant and anti-inflammatory properties, and higher blood-brain barrier permeability. Also, the binding and inhibitory potentials of Lupeol have been investigated and proved to be effective against certain receptor proteins and enzymes in AD studies by computational molecular docking approaches. Therefore, AD-related research has gained interest in investigating the therapeutic effects of Lupeol. However, despite its beneficial effects in AD, there is still a lack of research in Lupeol. Hence, we compiled in this analysis all preclinical research that looked at Lupeol as an antioxidant and anti-inflammatory agent for AD.

Antioxidant Supplementation Alleviates Mercury-Induced Cytotoxicity and Restores the Implantation-Related Functions of Primary Human Endometrial Cells.

Mercury (Hg) cytotoxicity, which is largely mediated through oxidative stress (OS), can be relieved with antioxidants. Thus, we aimed to study the effects of Hg alone or in combination with 5 nM N-Acetyl-L-cysteine (NAC) on the primary endometrial cells' viability and function. Primary human endometrial epithelial cells (hEnEC) and stromal cells (hEnSC) were isolated from 44 endometrial biopsies obtained from healthy donors. The viability of treated endometrial and JEG-3 trophoblast cells was evaluated via tetrazolium salt metabolism. Cell death and DNA integrity were quantified following annexin V and TUNEL staining, while the reactive oxygen species (ROS) levels were quantified following DCFDA staining. Decidualization was assessed through secreted prolactin and the insulin-like growth factor-binding protein 1 (IGFBP1) in cultured media. JEG-3 spheroids were co-cultured with the hEnEC and decidual hEnSC to assess trophoblast adhesion and outgrowth on the decidual stroma, respectively. Hg compromised cell viability and amplified ROS production in trophoblast and endometrial cells and exacerbated cell death and DNA damage in trophoblast cells, impairing trophoblast adhesion and outgrowth. NAC supplementation significantly restored cell viability, trophoblast adhesion, and outgrowth. As these effects were accompanied by the significant decline in ROS production, our findings originally describe how implantation-related endometrial cell functions are restored in Hg-treated primary human endometrial co-cultures by antioxidant supplementation.

Transcriptomic analysis reveals that the anti-PCOS effects of Zishen Qingre Lishi Huayu recipe may involve pathways and genes related to autophagy, steroidogenesis, oxidative stress, and inflammation in granulosa cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Zishen Qingre Lishi Huayu recipe (ZQLHR) is a Chinese medicine compound composed of nine herbs for the treatment of polycystic ovary syndrome (PCOS). It is used to nourish kidneys, clear heat, reduce dampness and dissipation blood stasis by promoting diuresis and blood circulation, dredging the meridians and harmonizing menstruation in the treatment of PCOS. Several clinical studies have shown that ZQLHR is effective in the treatment of PCOS, but the underlying mechanism remains unclear. AIM OF THE STUDY: In this study, we researched on the effects and mechanism of action of ZQLHR during treatment of human granulosa cells (hGCs) obtained from PCOS patients in order to provide a scientific basis for the clinical application of ZQLHR in the treatment of PCOS, emphasize the importance of some genes that have been reported to play a role in the pathogenesis or therapeutic mechanisms of PCOS from the perspective of disease treatment, and identify some new genes and signaling pathways that may play an important role in the treatment of PCOS. MATERIALS AND METHODS: KGN cells (a granulosa cell-like tumor cell line) were subjected to a cell counting kit-8 assay to explore the appropriate intervention concentration and duration of ZQLHR. Treated with or without ZQLHR (ZQLHR and control groups), the hGCs obtained from PCOS patients were sequenced using RNA sequencing, and the genes thus detected were further analyzed through Kyoto encyclopedia of genes and genomes enrichment analysis, gene set enrichment analysis, and individuation gene analysis. These genes were also compared with PCOS-related genes in other databases. To further verify the authenticity of the differentially expressed genes between the two groups, the expression of eight randomly selected vital genes and three proteins of interest was verified through real time quantitative polymerase chain reaction and Western blot experiment respectively. RESULTS: The best intervention concentration and duration for ZQLHR to promote the proliferation of KGN cells were 0.2% and 48 h respectively in this experiment. Multiple signaling pathways and 55 focus differentially expressed genes, both related to autophagy, steroidogenesis, oxidative stress-related longevity, inflammation, and complications of PCOS, may play an important role in the therapeutic mechanism of action of ZQLHR. The expression of eight genes is consistent with the result of RNA sequencing, and the expression of three proteins of interest is the same as expected. CONCLUSIONS: The promotion of hGCs proliferation upon treatment with ZQLHR may be a manifestation of ZQLHR in the treatment of PCOS patients. The positive effects of ZQLHR against PCOS may involve pathways and genes related to autophagy, steroidogenesis, oxidative stress-related longevity, and inflammation in hGCs. Some components of ZQLHR applied for the treatment of PCOS may also be effective for the treatment of some complications of PCOS.

Priming with caffeic acid enhances the potential and survival ability of human adipose-derived stem cells to counteract hypoxia.

The therapeutic effectiveness of stem cells after transplantation is hampered by the hypoxic milieu of chronic wounds. Prior research has established antioxidant priming as a thorough plan to improve stem cell performance. The purpose of this study was to ascertain how caffeic acid (CA) priming affected the ability of human adipose-derived stem cells (hASCs) to function under hypoxic stress. In order to study the cytoprotective properties of CA, hASCs were primed with CA in CoCl2 hypoxic conditions. Microscopy was used to assess cell morphology, while XTT, Trypan Blue, X-gal, LDH, Live Dead, scratch wound healing, and ROS assays were used to analyze viability, senescence, cell death, proliferation, and reactive oxygen species prevalence in the cells. According to our findings, CA priming enhances hASCs' ability to survive and regenerate in a hypoxic microenvironment more effectively than untreated hASCs. Our in-vitro research suggested that pre-treatment with CA of hASCs could be a unique way to enhance their therapeutic efficacy and ability to survive in hypoxic microenvironments.

Novel perspective in transplantation therapy of mesenchymal stem cells: targeting the ferroptosis pathway. / 间å 质干细胞移植治疗的新视角：靶向铁死亡通路.

Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. Ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.

Oxidative Stress and Natural Products in Orthodontic Treatment: A Systematic Review.

In recent years, orthodontics, a specialized branch of dentistry, has evolved considerably in terms of both techniques and materials used. Aimed at correcting dental malocclusions and craniofacial anomalies, it improves the functionality and aesthetics of the face and oral cavity. However, orthodontic treatment, in its developmental stages, may induce oxidative stress (O.S.) phenomena, with an increase in the production of reactive oxygen species (ROS), damaging the dental and periodontal tissues involved, affecting the short-, medium- and long-term results. Studies on the antioxidant effects of natural products (e.g., resveratrol, green tea, turmeric, etc.) in the medical field have aroused considerable interest in recent years. A systematic literature review was conducted on the PubMed, Scopus, and Web of Science databases using natural products (N.P.s), O.S., and orthodontic as keywords. The study aims to consider the determinants of the increase in ROS occurring during orthodontic treatment and the possibility of natural products being able to control and neutralize biochemical phenomena by restoring the physiological process in which the balance between the production of ROS and the ability of the body's antioxidant system to neutralize them is in favor of the latter.

Novel perspective in transplantation therapy of mesenchymal stem cells: targeting the ferroptosis pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. Ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.

Corrigendum: Arachidonic acid in follicular fluid of PCOS induces oxidative stress in a human ovarian granulosa tumor cell line (KGN) and upregulates GDF15 expression as a response.

[This corrects the article DOI: 10.3389/fendo.2022.865748.].

The protective effect of proanthocyanidins on the psoriasis-like cell models via PI3K/AKT and HO-1.

BACKGROUND: Inflammation and oxidative stress (OS) are important contributors to psoriasis pathogenesis. Proanthocyanidins (PCs) have anti-inflammatory and anti-oxidative activities. Previously, we discovered that PCs alleviated psoriasis-like mice symptoms, likely via mitigating inflammation and OS damage. OBJECTIVE: To elucidate the protective mechanism underlying PCs against the damage of TNF-ɑ-induced psoriasis-like cell models. METHODS: Psoriasis-like cell models were established with 7.5 ng/mL TNF-ɑ and then subjected to different-concentrations PCs treatment. Finally, inflammatory and oxidative parameters were determined. Besides, LY294002 (PI3K inhibitor) and ZnPP (HO-1 inhibitor) were employed to investigate the roles of PI3K/AKT and HO-1 in PCs against psoriasis-like cell models. RESULTS: After TNF-α treatment, cells organized tightly and proliferated greatly (P<0.01); HO-1 expression dropped obviously, along with the increased OS/inflammatory indicators and the decreased antioxidants (P<0.05); consequently, psoriasis-like cell models were well established. In the presence of PCs, nevertheless, the proliferation rate and number of psoriasis-like cells evidently decreased (P<0.01), accompanied with enhanced HO-1 and antioxidants, and lowered OS/inflammatory indicators as well as phosphorylated JAK2/STAT3/PI3/AKT (P<0.01). Similar changes appeared after LY294002 pretreatment, regardless of PCs or not. But after ZnPP pretreatment with or without PCs, the opposite occurred. CONCLUSION: The study reveals that PCs can suppress psoriasis-like cell proliferation and reduce inflammatory/OS damage through PI3K/AKT inhibition and HO-1 activation, thus promising a candidate for PCs in treating psoriasis.

Ultraviolet B irradiation induces senescence of human corneal endothelial cells in vitro by DNA damage response and oxidative stress.

The human corneal endothelial cells (HCEnCs) play a vital role in the maintenance of corneal transparency and visual acuity. In our daily life, HCEnCs are inevitably exposed to ultraviolet B (UVB) radiation leading to decreases of visual acuity and corneal transparency resulting in visual loss eventually. Therefore, understanding the UVB-induced cytotoxicity in HCEnCs is of importance for making efficient strategies to protect our vision from UVB-damage. However, in-depth knowledge about UVB-induced cytotoxicity in HCEnCs is missing. Herein, we pulse-irradiated the HCEnCs in vitro with 150 mJ/cm2 UVB (the environmental dose) at each subculture for 4 passages to explore the insights into UVB-induced phototoxicity. The results showed that the UVB-treated HCEnCs exhibit typical senescent characteristics, including significantly enlarged relative cell area, increased senescence-associated ß-galactosidase positive staining, and upregulated p16INK4A and senescence associated secretory phenotypes (SASPs) such as CCL-27, IL-1α/6/8/10, TGF-ß1 and TNF-α, as well as decreased cell proliferation and Lamin B1 expression, and translocation of Lamin B1. Furthermore, we explored the causative mechanisms of senescence and found that 150 mJ/cm2 UVB pulse-irradiation impairs DNA to activate DNA damage response (DDR) pathway of ATM-p53-p21WAF1/CIP1 with downregulated DNA repair enzyme PARP1, leading to cell cycle arrest resulting in DDR-mediated senescence. Meanwhile, UVB pulse-irradiation also elicits a consistent increase of ROS production to aggravate DNA damage and impose oxidative stress on energy metabolism leading to metabolic disturbance resulting in metabolic disturbance-mediated senescence. Altogether, the repeated pulse-irradiation of 150 mJ/cm2 UVB induces HCEnC senescence via both DDR pathway and energy metabolism disturbance.

Key LncRNAs Associated With Oxidative Stress Were Identified by GEO Database Data and Whole Blood Analysis of Intervertebral Disc Degeneration Patients.

Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain, but the onset and progression of IDD are unknown. Long non-coding RNA (lncRNA) has been validated to play a critical role in IDD, while an increasing number of studies have linked oxidative stress (OS) to the initiation and progression of IDD. We aim to investigate key lncRNAs in IDD through a comprehensive network of competing endogenous RNA (ceRNA) and to identify possible underlying mechanisms. Methods: We downloaded IDD-related gene expression data from the Gene Expression Omnibus (GEO) database and obtained differentially expressed-lncRNAs (DE-lncRNA), -microRNAs (DE-miRNA), and -messenger RNAs (DE-mRNA) by bioinformatics analysis. The OS-related lncRNA-miRNA-mRNA ceRNA interaction axis was constructed and key lncRNAs were identified based on ceRNA theory. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses on mRNAs regulated by lncRNAs in the ceRNA network. Single sample gene set enrichment analysis (ssGSEA) was used to reveal the immune landscape. Expression of key lncRNAs in IDD was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: In this study, 111 DE-mRNAs, 20 DE-lncRNAs, and 502 DE-miRNAs were identified between IDD patients and controls, and 16 OS-related DE-lncRNAs were also identified. The resulting lncRNA-miRNA-mRNA network consisted of eight OS-related DE-lncRNA nodes, 24 DE-miRNA nodes, 70 DE-mRNA nodes, and 183 edges. Functional enrichment analysis suggested that the ceRNA network may be involved in regulating biological processes related to cytokine secretion, lipid, and angiogenesis. We also identified four key lncRNAs, namely lncRNA GNAS-AS1, lncRNA MIR100HG, lncRNA LINC01359, and lncRNA LUCAT1, which were also found to be significantly associated with immune cells. Conclusion: These results provide novel insights into the potential applications of OS-related lncRNAs in patients with IDD.

Research progress on the mechanism of action of hesperetin in cerebral ischemia: a narrative review.

Background and Objective: Ischemic cerebrovascular disease is one of the main diseases threatening human health and survival and is a commonly occurring disease in neurology. Due to its high disability rate, ischemic cerebrovascular disease is one of the most important diseases to be prevented and treated at present. The risk factors of cerebral ischemia include atherosclerosis, hypertension, hyperlipidemia, and blood viscosity caused by thrombocytosis. After cerebral ischemia, cerebral ischemia-reperfusion injury may be induced by oxidative stress (OS), inflammatory reaction, nitric oxide damage, apoptosis, excitatory amino acid toxicity, calcium (Ca2+) overload, and other mechanisms. Hesperidin is a flavanone compound and is a key component in citrus plants. It is a kind of traditional Chinese medicine extract with high levels of Pericarpium, shell, fruit, and green peel. In recent years, Hesperidin has received great attention, compelling evidence has indicated Hesperidin plays a beneficial role in cerebral ischemia. Methods: We conducted a literature search for published manuscripts hesperidin in ischemia/reperfusion up to December 2021 in common English databases (i.e., PubMed, EMBASE, Web of Science, SpringerLink, Wiley, Cochrane Library) and Chinese databases [Chinese BioMedical Literature Service System (CBM), WANFANG database, China Knowledge Resource Integrated Database (CNKI)]. Key Content and Findings: In this article, we reviewed the mechanisms of action of hesperidin in the treatment of cerebral ischemia, including antioxidant stress, anti-inflammatory reaction, anti-atherosclerosis, anti-thrombosis, anti-apoptosis, and nitric oxide regulation. Conclusions: In this narrative review, Hesperidin exhibits antioxidant stress, anti-platelet aggregation, vasodilation, anti-atherosclerotic, anti-inflammatory, anti-apoptotic, hypolipidemic, anti-tumor, cardiovascular protection, and nitric oxide-release regulatory properties Such a comprehension of the recent progress of hesperidin will help identify biomarkers for diagnosis and therapeutic targets to cerebral ischemia.

The effect of immunomodulatory properties of naringenin on the inhibition of inflammation and oxidative stress in autoimmune disease models: a systematic review and meta-analysis of preclinical evidence.

BACKGROUND/OBJECTIVE: Naringenin is a member of the flavonoid family that can perform many biological processes to treat a wide range of inflammatory diseases and pathological conditions related to oxidative stress (OS). Naringenin immunomodulatory activities have been the subject of recent research as an effective alternative treatment for autoimmune disorders. The effects of naringenin on the levels of inflammatory biomarkers and OS factors in animal models of autoimmune disorders (ADs) were studied in this meta-analysis. METHODS: Up until January 2022, electronic databases such as Cochrane Library and EMBASE, PubMed, Web of Science, and Scopus were used to conduct a comprehensive literature search in English language. To evaluate the effect of naringenin on inflammatory mediators, such as TNF-α, IL-6, IL-ß, IFN-γ, NF-κB, and nitric oxide, and OS biomarkers, such as CAT, SOD, GPx, GSH and MDA, in AD models, we measured the quality assessment and heterogeneity test using the PRISMA checklist protocol and I2 statistic, respectively. A random-effects model was employed based on the heterogeneity test, and then pooled data were standardized as mean difference (SMD) with a 95% confident interval (CI). RESULTS: We excluded all clinical trials, cell experiment studies, animal studies with different parameters, non-autoimmune disease models, and an inadequate series of studies for quantitative synthesis. Finally, from 627 potentially reports, 12 eligible studies were included in the meta-analysis. Data were collected from several groups. Of these, 153 were in the naringenin group and 149 were in the control group. Our meta-analysis of the pooled data for the parameters of inflammation and OS indicated that naringenin significantly reduced the levels of NF-κB (SMD - 3.77, 95% CI [- 6.03 to - 1.51]; I2 = 80.1%, p = 0.002), IFN-γ (SMD - 6.18, 95% CI [- 8.73 to - 3.62]; I2 = 53.7%, p = 0.115), and NO (SMD - 3.97, 95% CI [- 5.50 to - 2.45]; I2 = 73.4%, p = 0.005), IL-1ß (SMD - 4.23, 95% CI [- 5.09 to - 3.37]; I2 = 0.0%, p = 0.462), IL-6 (SMD - 5.84, 95% CI [- 7.83 to - 3.85]; I2 = 86.5%, p < 0.001), and TNF-α (SMD - 5.10, 95% CI [- 6.34 to - 3.86]; I2 = 74.7%, p < 0.001). These findings also demonstrated the efficacy of naringenin on increasing the levels of CAT (SMD 4.19, 95% CI [1.33 to 7.06]; I2 = 79.9%, p = 0.007), GSH (SMD 4.58, 95% CI [1.64 to 7.51]; I2 = 90.5%, p < 0.001), and GPx (SMD 9.65, 95% CI [2.56 to 16.74]; I2 = 86.6%, p = 0.001) and decreasing the levels of MDA (SMD - 3.65, 95% CI [- 4.80 to - 2.51]; I2 = 69.4%, p = 0.001) than control groups. However, treatment with naringenin showed no statistically difference in SOD activity (SMD 1.89, 95% CI [- 1.11 to 4.89]; I2 = 93.6%, p < 0.001). CONCLUSION: Overall, our findings revealed the immunomodulatory potential of naringenin as an alternative treatment on inhibition of inflammation and OS in several autoimmune-related diseases. Nevertheless, regarding the limitation of clinical trials, strong preclinical models and clinical settings in the future are needed that address the effects of naringenin on ADs. Before large-scale clinical studies, precise human pharmacokinetic investigations are required to determine the dosage ranges and evaluate the initial safety profile of naringenin.

The effects of apigenin administration on the inhibition of inflammatory responses and oxidative stress in the lung injury models: a systematic review and meta-analysis of preclinical evidence.

BACKGROUND/OBJECTIVE: Apigenin is a member of the flavonoid family that can regulate various biological processes, which is characterized as a treatment of different inflammatory disorders and pathological problems associated with oxidative stress (OS). Recent research has focused on apigenin immunomodulatory properties as a potential treatment for different types of lung injuries. This meta-analysis was designed to determine the impact of apigenin treatment on inflammatory markers and OS parameters in animal models of lung injuries. METHODS: The comprehensive literature search was conducted using electronic databases such as Google Scholar, PubMed, Web of Science, Scopus, and Embase up to August 2021. To assess apigenin's effect on inflammatory mediators and OS biomarkers in lung injury animal models, we used the I2 statistic to determine the heterogeneity. We then pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Our meta-analysis of the pooled data for inflammatory biomarkers demonstrated that the apigenin administration significantly decreased the NF-κB expression (SMD - 1.60, 95% CI [- 2.93 to - 0.26]; I2 = 89.0%, p < 0.001), IL-1ß (SMD - 4.30, 95% CI [- 6.24 to - 2.37]; I2 = 67.3%, p = 0.047), IL-6 (SMD - 4.10, 95% CI [- 5.04 to - 3.16]; I2 = 72.6%, p < 0.001), TNF-α (SMD - 3.74, 95% CI [- 4.67 to - 2.82]; I2 = 84.1%, p < 0.001), and TNF-α gene expression (SMD - 3.44, 95% CI [- 4.44 to - 2.43]; I2 = 0.0%, p = 0.622). This study also indicated the efficacy of apigenin in increasing the level of CAT (SMD 4.56, 95% CI [3.57 to 5.55]; I2 = 15.3%, p = 3.15), GSH (SMD 5.12, 95% CI [3.53 to 6.70]; I2 = 77.6%, p < 0.001), and SOD (SMD 3.45, 95% CI [2.50 to 4.40]; I2 = 79.2%, p < 0.001), and decreasing the level of MDA (SMD - 3.87, 95% CI [- 5.25 to - 2.49]; I2 = 80.3%, p < 0.001) and MPO (SMD - 4.02, 95% CI [- 5.64 to - 2.40]; I2 = 88.9%, p < 0.001), TGF- ß (SMD - 3.81, 95% CI [- 4.91 to - 2.70]; I2 = 73.4%, p = 0.001) and W/D level (SMD - 3.22, 95% CI [- 4.47 to - 1.97]; I2 = 82.1%, p < 0.001) than control groups. CONCLUSION: Overall, our findings showed the immunomodulatory potential of apigenin as an alternative treatment for the suppression of inflammatory responses and OS in different types of lung injury diseases. Nevertheless, due to the paucity of clinical studies, reliable preclinical models, and clinical settings, evaluating the influence of apigenin on lung injury is required in the future. Before conducting large-scale clinical trials, detailed human pharmacokinetic studies are also needed to establish dosage ranges and determine the initial safety and tolerability of apigenin.

Osteomyelitis, Oxidative Stress and Related Biomarkers.

Bone is a very dynamic tissue, subject to continuous renewal to maintain homeostasis through bone remodeling, a process promoted by two cell types: osteoblasts, of mesenchymal derivation, are responsible for the deposition of new material, and osteoclasts, which are hematopoietic cells, responsible for bone resorption. Osteomyelitis (OM) is an invasive infectious process, with several etiological agents, the most common being Staphylococcus aureus, affecting bone or bone marrow, and severely impairing bone homeostasis, resulting in osteolysis. One of the characteristic features of OM is a strong state of oxidative stress (OS) with severe consequences on the delicate balance between osteoblastogenesis and osteoclastogenesis. Here we describe this, analyzing the effects of OS in bone remodeling and discussing the need for new, easy-to-measure and widely available OS biomarkers that will provide valid support in the management of the disease.