HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction.

Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Evaluation of cytogenotoxic potential and embryotoxicity of KRS-Cauvery River water in zebrafish (Danio rerio).

In the Cauvery River (CR), indiscriminate discharge of waste causes unexplained skeletal deformity in some fish species present in the water. To investigate this phenomenon, we analyzed the biological, physical, and chemical parameters present in the water and then evaluated the toxicity effects on the zebrafish (Danio rerio) model. The zebrafish were treated with KRS-CR water samples collected from three stations (fast-flowing water [X], slow-flowing [Y], and stagnant [Z] water), before and after filtration. Firstly, we detected microscopic organisms (MO) such as Cyclops, Daphnia, Spirogyra, Spirochaeta, and total coliform (Escherichia coli), which are bioindicators of water pollution present in the samples. All physicochemical parameters analyzed, including heavy metals before and after filtration of the water with Millipore filter paper (0.45 µm), were within the acceptable limits set by standard organizations, except for decreased dissolved oxygen (DO), and increased biochemical oxygen demand (BOD), and chemical oxygen demand (COD), which are indicators of hypoxic water conditions, as well as the presence of microplastics (polybutene (< 15 µm), polyisobutene (≤ 20 µm), and polymethylpentene (≤3 mm)) and cyclohexyl in CR water samples. Zebrafish embryos treated with the water samples, both before and after filtration exerts the same cytogenotoxic effects by inducing increased reactive oxygen species (ROS) production, which triggers subcellular organelle dysfunctions, DNA damage, apoptosis, pericardial edema, skeletal deformities, and increased mortality. As a result, we observed that both water samples and zebrafish larvae had significantly less oxygen using SEM and EDS. Our findings show that KRS-CR water can induce cytogenotoxic and embryotoxic defects in zebrafish due to hypoxic water conditions triggered by the microplastics influx. The present study would provide valuable insights for health hazards evaluation and future river water treatment strategies.

Gma-miR408 Enhances Soybean Cyst Nematode Susceptibility by Suppressing Reactive Oxygen Species Accumulation.

Soybean cyst nematode (SCN, Heterodera glycine) is a serious damaging disease in soybean worldwide, thus resulting in severe yield losses. MicroRNA408 (miR408) is an ancient and highly conserved miRNA involved in regulating plant growth, development, biotic and abiotic stress response. Here, we analyzed the evolution of miR408 in plants and verified four miR408 members in Glycine max. In the current research, highly upregulated gma-miR408 expressing was detected during nematode migration and syncytium formation response to soybean cyst nematode infection. Overexpressing and silencing miR408 vectors were transformed to soybean to confirm its potential role in plant and nematode interaction. Significant variations were observed in the MAPK signaling pathway with low OXI1, PR1, and wounding of the overexpressing lines. Overexpressing miR408 could negatively regulate soybean resistance to SCN by suppressing reactive oxygen species accumulation. Conversely, silencing miR408 positively regulates soybean resistance to SCN. Overall, gma-miR408 enhances soybean cyst nematode susceptibility by suppressing reactive oxygen species accumulation.

Recent Advances in Molecular Research on Hydrogen Sulfide (H2S) Role in Diabetes Mellitus (DM)-A Systematic Review.

Abundant experimental data suggest that hydrogen sulfide (H2S) is related to the pathophysiology of Diabetes Mellitus (DM). Multiple molecular mechanisms, including receptors, membrane ion channels, signalingmolecules, enzymes, and transcription factors, are known to be responsible for the H2S biological actions; however, H2S is not fully documented as a gaseous signaling molecule interfering with DM and vascular-linked pathology. In recent decades, multiple approaches regarding therapeutic exploitation of H2S have been identified, either based on H2S exogenous apport or on its modulated endogenous biosynthesis. This paper aims to synthesize and systematize, as comprehensively as possible, the recent literature-related data regarding the therapeutic/rehabilitative role of H2S in DM. This review was conducted following the "Preferred reporting items for systematic reviews and meta-analyses" (PRISMA) methodology, interrogating five international medically renowned databases by specific keyword combinations/"syntaxes" used contextually, over the last five years (2017-2021). The respective search/filtered and selection methodology we applied has identified, in the first step, 212 articles. After deploying the next specific quest steps, 51 unique published papers qualified for minute analysis resulted. To these bibliographic resources obtained through the PRISMA methodology, in order to have the best available information coverage, we added 86 papers that were freely found by a direct internet search. Finally, we selected for a connected meta-analysis eight relevant reports that included 1237 human subjects elicited from clinical trial registration platforms. Numerous H2S releasing/stimulating compounds have been produced, some being used in experimental models. However, very few of them were further advanced in clinical studies, indicating that the development of H2S as a therapeutic agent is still at the beginning.

Archaea Microbiome Dysregulated Genes and Pathways as Molecular Targets for Lung Adenocarcinoma and Squamous Cell Carcinoma.

The human microbiome is a vast collection of microbial species that exist throughout the human body and regulate various bodily functions and phenomena. Of the microbial species that exist in the human microbiome, those within the archaea domain have not been characterized to the extent of those in more common domains, despite their potential for unique metabolic interaction with host cells. Research has correlated tumoral presence of bacterial microbial species to the development and progression of lung cancer; however, the impacts and influences of archaea in the microbiome remain heavily unexplored. Within the United States lung cancer remains highly fatal, responsible for over 100,000 deaths every year with a 5-year survival rate of roughly 22.9%. This project attempts to investigate specific archaeal species' correlation to lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) incidence, patient staging, death rates across individuals of varying ages, races, genders, and smoking-statuses, and potential molecular targets associated with archaea microbiome. Archaeal species abundance was assessed across lung tissue samples of 527 LUAD patients, 479 LUSC patients, and 99 healthy individuals. Nine archaeal species were found to be of significantly altered abundance in cancerous samples as compared to normal counterparts, 6 of which are common to both LUAD and LUSC subgroups. Several of these species are of the taxonomic class Thermoprotei or the phylum Euryarchaeota, both known to contain metabolic processes distinct from most bacterial species. Host-microbe metabolic interactions may be responsible for the observed correlation of these species' abundance with cancer incidence. Significant microbes were correlated to patient gene expression to reveal genes of altered abundance with respect to high and low archaeal presence. With these genes, cellular oncogenic signaling pathways were analyzed for enrichment across cancer and normal samples. In comparing gene expression between LUAD and adjacent normal samples, 2 gene sets were found to be significantly enriched in cancers. In LUSC comparison, 6 sets were significantly enriched in cancer, and 34 were enriched in normals. Microbial counts across healthy and cancerous patients were then used to develop a machine-learning based predictive algorithm, capable of distinguishing lung cancer patients from healthy normal with 99% accuracy.

Origanum majorana essential oil improves the rat's sexual behavior and testicular oxidative damage induced by imidacloprid via modulating the steroidogenesis pathways.

The neonicotinoid insecticide imidacloprid has been linked to significant reproductive damage in mammals. Origanum majorana essential oil (OME) is a natural herbal product used in the management of many diseases due to its strong antioxidant effects. The oil was hydrodistilled from O. Majorana and analyzed using GC/MS then its possible protective mechanisms against IMI-induced reprotoxicity in male rats were investigated. 28-adult male Wistar rats were divided into 4 groups as follows: group (1) control group, group (2) OME, group (3) IMI, and group (4) IMI + OME. The treatments were applied daily via oral gavage for 60 days. Remarkable abnormalities in both territorial aggressive and sexual behaviors were observed in IMI-treated rats with a significant elevation of serum FSH and LH as well as altered testicular redox status. Along with inhibition of the testicular expression of StAR and aromatase genes and serum total testosterone in addition to abnormal sperm count, viability, motility, and morphology. Histopathological examination showed severe degeneration and necrosis in both germ cells and Leydig cells with atrophy in most of the seminiferous tubules. Co-administration of OME with IMI notably improved all the above-mentioned studied parameters, and restored rats' spermatogenesis, sexual behavior, and favorably modulates the levels of both testosterone and gonadotropic hormones via its potent antioxidant effect. These findings support the use of OME as a fertility enhancer and suggest that it could be used to manage pesticide-induced male infertility.

Empagliflozin attenuates neurodegeneration through antioxidant, anti-inflammatory, and modulation of α-synuclein and Parkin levels in rotenone-induced Parkinson's disease in rats.

Sodium-glucose co-transporter 2 (SGLT 2) inhibitors are a relatively new antidiabetic drug with antioxidant and anti-inflammatory properties. Therefore, this study aimed to investigate whether SGLT 2 inhibitors have a neuroprotective effect in PD. Twenty-four Wistar rats were randomized into four groups. The first one (control group) received dimethyl sulfoxide (DMSO) as a vehicle (0.2 mL/48 hr, S.C). The second group (positive control) received rotenone (ROT) (2.5 mg/kg/48 hr, S.C) for 20 successive days, whereas the third and fourth groups received empagliflozin (EMP) (1 and 2 mg/kg/day, orally), respectively. The two groups received rotenone (2.5 mg/kg/48 hr S.C) concomitantly with EMP for another 20 days on the fifth day. By the end of the experimental period, behavioral examinations were done. Subsequently, rats were sacrificed, blood samples and brain tissues were collected for analysis. ROT significantly elevated oxidative stress and proinflammatory markers as well as α-synuclein. However, dopamine (DP), antioxidants, tyrosine hydroxylase (TH), and Parkin were significantly decreased. Groups of (EMP + ROT) significantly maintained oxidative stress and inflammatory markers elevation, maintained α-synuclein and Parkin levels, and elevated TH activity and dopamine level. In both low and high doses, EMP produced a neuroprotective effect against the PD rat model, with the high dose inducing a more significant effect.

Reno-protective effect of mangiferin against methotrexate-induced kidney damage in male rats: PPARγ-mediated antioxidant activity.

Methotrexate (MTX) is an immunosuppressant used for the treatment of cancer and autoimmune diseases. MTX has a major adverse effect, acute kidney injury, which limits its use. Mangiferin (MF) is a natural bioactive xanthonoid used as a traditional herbal supplement to boost the immune system due to its potent anti-inflammatory and antioxidant activity. The present study evaluates the protective effect of MF against MTX-induced kidney damage. Male Wistar rats received MTX to induce nephrotoxicity or were pretreated with MF for 10 constitutive days before MTX administration. MF dose-dependently improved renal functions of MTX-treated rats and this activity was correlated with increased renal expression of PPARγ, a well-known transcriptional regulator of the immune response. Pretreating rats with PPARγ inhibitor, BADGE, reduced the reno-protective activity of MF. Furthermore, MF treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NFκB, interleukin-1ß, TNF-α, and COX-2), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (nitric oxide and iNOS) markers in the kidney. Importantly, BADGE treatment significantly reduced the anti-inflammatory and antioxidant activity of MF. Therefore, our data suggest that the reno-protective effect of MF against MTX-induced nephrotoxicity is due to inhibition of inflammation and oxidative stress in a PPAR-γ-dependent manner.

Recent advances in process engineering and upcoming applications of metal-organic frameworks.

Progress in metal-organic frameworks (MOFs) has advanced from fundamental chemistry to engineering processes and applications, resulting in new industrial opportunities. The unique features of MOFs, such as their permanent porosity, high surface area, and structural flexibility, continue to draw industrial interest outside the traditional MOF field, both to solve existing challenges and to create new businesses. In this context, diverse research has been directed toward commercializing MOFs, but such studies have been performed according to a variety of individual goals. Therefore, there have been limited opportunities to share the challenges, goals, and findings with most of the MOF field. In this review, we examine the issues and demands for MOF commercialization and investigate recent advances in MOF process engineering and applications. Specifically, we discuss the criteria for MOF commercialization from the views of stability, producibility, regulations, and production cost. This review covers progress in the mass production and formation of MOFs along with future applications that are not currently well known but have high potential for new areas of MOF commercialization.

The potential antiepileptic activity of astaxanthin in epileptic rats treated with valproic acid.

OBJECTIVES: Epilepsy is a neurological disease characterized by sudden, abnormal, and hyper- discharges in the central nervous system (CNS). Valproic acid (VPA) is commonly used as a broad-spectrum antiepileptic therapeutic. However, in many cases, patients develop resistance to VPA treatment due to overwhelming oxidative stress, which in turn might be a major catalyst for disease progression. Therefore, antioxidants can potentially become therapeutic agents by counteracting reactive oxygen species (ROS)-mediated damage. The present study is aimed to evaluate the potential antiepileptic effect of astaxanthin (ASTA) in pentylenetetrazol (PTZ) induced epileptic model rats that are chronically treated with VPA for 8 weeks. METHOD: Fifty-male Wistar rats were randomly divided into five groups: Non-PTZ group, PTZ, PTZ/VPA, PTZ/ASTA, and PTZ/VPA/ASTA treated groups. RESULTS: PTZ/VPA treated group showed a neuroprotective effect with improvement in antioxidant levels, behavioral test, and histopathological changes induced by PTZ. VPA also exhibited an anti-inflammatory effect as its treatment resulted in the reduction of tumor necrosis factor-α (TNF-α). ASTA exhibited an anticonvulsant effect and enhanced anti-inflammatory effect as compared to VPA. During the combined therapy, ASTA potentiated the antiepileptic effect of the VPA by reducing the oxidative stress and TNF-α as well as increased the glutathione (GSH) levels. Also, there were substantial improvements in the behavioral and histopathological changes in the VPA/ASTA treated group as compared to the VPA treated group. CONCLUSION: ASTA could have an antiepileptic and anti-inflammatory effect by reducing ROS generation. Therefore, co-administration of both the therapeutics (VPA/ASTA) has a synergistic effect in treating epilepsy and could potentially minimize recurrence and/or exacerbation of seizures.

Systematic analysis of potential targets of the curcumin analog pentagamavunon-1 (PGV-1) in overcoming resistance of glioblastoma cells to bevacizumab.

BACKGROUND: Glioblastoma is one of the most aggressive and deadliest malignant tumors. Acquired resistance decreases the effectiveness of bevacizumab in glioblastoma treatment and thus increases the mortality rate in patients with glioblastoma. In this study, the potential targets of pentagamavunone-1 (PGV-1), a curcumin analog, were explored as a complementary treatment to bevacizumab in glioblastoma therapy. METHODS: Target prediction, data collection, and analysis were conducted using the similarity ensemble approach (SEA), SwissTargetPrediction, STRING DB, and Gene Expression Omnibus (GEO) datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using Webgestalt and DAVID, respectively. Hub genes were selected based on the highest degree scores using the CytoHubba. Analysis of genetic alterations and gene expression as well as Kaplan-Meier survival analysis of selected genes were conducted with cBioportal and GEPIA. Immune infiltration correlations between selected genes and immune cells were analyzed with database TIMER 2.0. RESULTS: We found 374 targets of PGV-1, 1139 differentially expressed genes (DEGs) from bevacizumab-resistant-glioblastoma cells. A Venn diagram analysis using these two sets of data resulted in 21 genes that were identified as potential targets of PGV-1 against bevacizumab resistance (PBR). PBR regulated the metabolism of xenobiotics by cytochrome P450. Seven potential therapeutic PBR, namely GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110 were found to have genetic alterations in 1.2%-30% of patients with glioblastoma. Analysis using the GEPIA database showed that the mRNA expression of ADAM10, AKR1B1, and HSD17B10 was significantly upregulated in glioblastoma patients. Kaplan-Meier survival analysis showed that only patients with low mRNA expression of AKR1B1 had significantly better overall survival than the patients in the high mRNA group. We also found a correlation between PBR and immune cells and thus revealed the potential of PGV-1 as an immunotherapeutic agent via targeting of PBR. CONCLUSION: This study highlighted seven PBR, namely, GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110. This study also emphasized the potential of PBR as a target for immunotherapy with PGV-1. Further validation of the results of this study is required for the development of PGV-1 as an adjunct to immunotherapy for glioblastoma to counteract bevacizumab resistance.

Phytomodulatory proteins isolated from Calotropis procera latex promote glycemic control by improving hepatic mitochondrial function in HepG2 cells.

The medicinal uses of Calotropis procera are diverse, yet some of them are based on effects that still lack scientific support. Control of diabetes is one of them. Recently, latex proteins from C. procera latex (LP) have been shown to promote in vivo glycemic control by the inhibition of hepatic glucose production via AMP-activated protein kinase (AMPK). Glycemic control has been attributed to an isolated fraction of LP (CpPII), which is composed of cysteine peptidases (95%) and osmotin (5%) isoforms. Those proteins are extensively characterized in terms of chemistry, biochemistry and structural aspects. Furthermore, we evaluated some aspects of the mitochondrial function and cellular mechanisms involved in CpPII activity. The effect of CpPII on glycemic control was evaluated in fasting mice by glycemic curve and glucose and pyruvate tolerance tests. HepG2 cells was treated with CpPII, and cell viability, oxygen consumption, PPAR activity, production of lactate and reactive oxygen species, mitochondrial density and protein and gene expression were analyzed. CpPII reduced fasting glycemia, improved glucose tolerance and inhibited hepatic glucose production in control animals. Additionally, CpPII increased the consumption of ATP-linked oxygen and mitochondrial uncoupling, reduced lactate concentration, increased protein expression of mitochondrial complexes I, III and V, and activity of peroxisome-proliferator-responsive elements (PPRE), reduced the presence of reactive oxygen species (ROS) and increased mitochondrial density in HepG2 cells by activation of AMPK/PPAR. Our findings strongly support the medicinal use of the plant and suggest that CpPII is a potential therapy for prevention and/or treatment of type-2 diabetes. A common epitope sequence shared among the proteases and osmotin is possibly the responsible for the beneficial effects of CpPII.

Effects of neoadjuvant therapies on genetic regulation of targeted pathways in ER+ primary ductal breast carcinoma: A meta-analysis of microarray datasets.

Breast cancer arises as a result of multiple interactions between environmental and genetic factors. Conventionally, breast cancer is treated based on histopathological and clinical features. DNA technologies like the human genome microarray are now partially integrated into clinical practice and are used for developing new "personalized medicines" and "pharmacogenetics" for improving the efficiency and safety of cancer medications. We investigated the effects of four established therapies-for ER+ ductal breast cancer-on the differential gene expression. The therapies included single agent tamoxifen, two-agent docetaxel and capecitabine, or combined three-agents CAF (cyclophosphamide, doxorubicin, and fluorouracil) and CMF (cyclophosphamide, methotrexate, and fluorouracil). Genevestigator 8.1.0 was used to compare five datasets from patients with infiltrating ductal carcinoma, untreated or treated with selected drugs, to those from the healthy control. We identified 74 differentially expressed genes involved in three pathways, i.e., apoptosis (extrinsic and intrinsic), oxidative signaling, and PI3K/Akt signaling. The treatments affected the expression of apoptotic genes (TNFRSF10B [TRAIL], FAS, CASP3/6/7/8, PMAIP1 [NOXA], BNIP3L, BNIP3, BCL2A1, and BCL2), the oxidative stress-related genes (NOX4, XDH, MAOA, GSR, GPX3, and SOD3), and the PI3K/Akt pathway gene (ERBB2 [HER2]). Breast cancer treatments are complex with varying drug responses and efficacy among patients. This necessitates identifying novel biomarkers for predicting the drug response, using available data and new technologies. GSR, NOX4, CASP3, and ERBB2 are potential biomarkers for predicting the treatment response in primary ER+ ductal breast carcinoma.

Cinnamomum zeylanicum Blume (Ceylon cinnamon) bark extract attenuates doxorubicin induced cardiotoxicity in Wistar rats.

Anti-tumour efficacy of doxorubicin is hindered by the cumulative dose-dependent cardiotoxicity induced by reactive oxygen species during its metabolism. As Cinnamomum zeylanicum has proven antioxidant potential, objective of this study was to investigate the cardioprotective activity of Cinnamomum bark extract against doxorubicin induced cardiotoxicity in Wistar rats. Physicochemical and phytochemical analysis was carried out and dose response effect and the cardioprotective activity of Cinnamomum were determined in vivo. 180 mg/kg dexrazoxane was used as the positive control. Plant extracts were free of heavy metals and toxic phytoconstituents. In vivo study carried out in Wistar rats revealed a significant increase (p < 0.05) in cardiac troponin I, NT-pro brain natriuretic peptide, AST and LDH concentrations in the doxorubicin control group (18 mg/kg) compared to the normal control. Rats pre-treated with the optimum dosage of Cinnmamomum (2.0 g/kg) showed a significant reduction (p < 0.05) in all above parameters compared to the doxorubicin control. A significant reduction was observed in the total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activity while the lipid peroxidation and myeloperoxidase activity were significantly increased in the doxorubicin control group compared to the normal control (p < 0.05). Pre-treatment with Cinnamomum bark showed a significant decrease in lipid peroxidation, myeloperoxidase activity and significant increase in rest of the parameters compared to the doxorubicin control (p < 0.05). Histopathological analysis revealed a preserved appearance of the myocardium and lesser degree of cellular changes of necrosis in rats pre-treated with Cinnamomum extract. In conclusion, Cinnamomum bark extract has the potential to significantly reduce doxorubicin induced oxidative stress and inflammation in Wistar rats.

Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies.

Cancer therapy is a strategic measure in inhibiting breast cancer stem cell (BCSC) pathways. Naringenin, a citrus flavonoid, was found to increase breast cancer cells' sensitivity to chemotherapeutic agents. Bioinformatics study and 3D tumorsphere in vitro modeling in breast cancer (mammosphere) were used in this study, which aims to explore the potential therapeutic targets of naringenin (PTTNs) in inhibiting BCSCs. Bioinformatic analyses identified direct target proteins (DTPs), indirect target proteins (ITPs), naringenin-mediated proteins (NMPs), BCSC regulatory genes, and PTTNs. The PTTNs were further analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) networks, and hub protein selection. Mammospheres were cultured in serum-free media. The effects of naringenin were measured by MTT-based cytotoxicity, mammosphere forming potential (MFP), colony formation, scratch wound-healing assay, and flow cytometry-based cell cycle analyses and apoptosis assays. Gene expression analysis was performed using real-time quantitative polymerase chain reaction (q-RT PCR). Bioinformatics analysis revealed p53 and estrogen receptor alpha (ERα) as PTTNs, and KEGG pathway enrichment analysis revealed that TGF-ß and Wnt/ß-catenin pathways are regulated by PTTNs. Naringenin demonstrated cytotoxicity and inhibited mammosphere and colony formation, migration, and epithelial to mesenchymal transition in the mammosphere. The mRNA of tumor suppressors P53 and ERα were downregulated in the mammosphere, but were significantly upregulated upon naringenin treatment. By modulating the P53 and ERα mRNA, naringenin has the potential of inhibiting BCSCs. Further studies on the molecular mechanism and formulation of naringenin in BCSCs would be beneficial for its development as a BCSC-targeting drug.

A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products.

BACKGROUND: Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed, therefore, it is necessary to develop novel inhibitors for melanoma treatment. METHODS: We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma. RESULTS: We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells, revealing that this compound regulates various pathways, such as DNA replication, P53, apoptosis and the cell cycle. Additionally, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products, leading to DNA toxicity in melanoma cell lines. Moreover, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells, leading to DNA damage, which caused G2/M phase arrest and apoptosis. CONCLUSIONS: Taken together, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels, suggesting that this compound is a potential therapeutic drug for melanoma treatment.

Assessing acrolein for determination of the severity of brain stroke, dementia, renal failure, and Sjögren's syndrome.

It was found recently that acrolein (CH2=CH-CHO), mainly produced from spermine, is more toxic than ROS (reactive oxygen species, O2-·, H2O2, and ·OH). In this review, we describe how the seriousness of brain infarction, dementia, renal failure, and SjÓ§gren's syndrome is correlated with acrolein. In brain infarction and dementia, it was possible to identify incipient patients with high sensitivity and specificity by measuring protein-conjugated acrolein (PC-Acro) in plasma together with IL-6 and CRP in brain infarction and Aß40/42 in dementia. The level of PC-Acro in plasma and saliva correlated with the seriousness of renal failure and SjÓ§gren's syndrome, respectively. Thus, development of acrolein scavenger medicines containing SH-group such as N-acetylcysteine derivatives is important to maintain QOL (quality of life) of the elderly.

The potential role of sesquiterpene lactones isolated from medicinal plants in the treatment of the metabolic syndrome - A review.

Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.