The Effects of Curcumin on Astrocytes in Common Neurodegenerative Conditions.

Neurodegenerative diseases are age-related, multifactorial, and complicated conditions that affect the nervous system. In most cases, these diseases may begin with an accumulation of misfolded proteins rather than decay before they develop clinical symptoms. The progression of these diseases can be influenced by a number of internal and external factors, including oxidative damage, neuro-inflammation, and the accumulation of misfolded amyloid proteins. Astrocytes, with the highest abundance among the cells of the mammalian central nervous system, perform several important activities, such as maintaining brain homeostasis and playing a role in the neurodegenerative condition onset and progress. Therefore, these cells have been considered to be potential targets for managing neurodegeneration. Curcumin, with multiple special properties, has been effectively prescribed to manage various diseases. It has hepato-protective, anti-carcinogenic, cardio-protective, thrombo-suppressive, anti-inflammatory, chemo-therapeutic, anti-arthritic, chemo-preventive, and anti-oxidant activities. In the current review, the effects of curcumin on astrocytes in common neurodegenerative conditions, such as Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, are discussed. Hence, it can be concluded that astrocytes play a critical role in neurodegenerative diseases, and curcumin is able to directly modulate astrocyte activity in neurodegenerative diseases.

The association of in-utero exposure to polycyclic aromatic hydrocarbons and umbilical liver enzymes.

BACKGROUND: The adverse health influences of polycyclic aromatic hydrocarbons (PAHs) exposures have been examined in several previous research. However, the evidence on the health influences of PAHs exposure during pregnancy and childhood is scarce, with no study on the infant's liver function. Therefore, in this study, the association of in-utero exposure to particulate matter-bound PAHs (PM-bound PAHs) on the umbilical liver enzymes was investigated. METHODS: A total of 450 mother-pair samples were assessed in this cross-sectional study in Sabzevar, Iran (2019-2021). The concentrations of PM-bound PAHs were estimated based on spatiotemporal models at residential addresses. The umbilical cord blood alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were measured as indicators of infant's liver function. The association of PM-bound PAHs with umbilical liver enzymes was evaluated using multiple linear regression, controlled for relevant covariates. The quantile g-computation (g-comp) was used to investigate the combined impact of the 15 PAHs on liver function biomarkers. RESULTS: Higher levels of total 4-ring PAHs, Dibenzo[a,h]anthrancene, Anthracene, Pyrene, Benzo[a]anthracene, Phenanthrene, Fluorene, Acenaphthylene and Naphthalene were associated with higher umbilical ALP. An increase in total 5-ring PAHs, Benzo[g,h,i]perylene, Benzo[a]pyrene and Chrysene was associated with higher umbilical AST levels. Each 1 ng/m3 increase in exposure to Benzo[g,h,i]perylene was related with 182.21 U/L (95 % CI: 116.11, 248.31, P < 0.01) increase in umbilical GGT. PAHs mixture exposure was positively associated with higher umbilical AST and ALT, while no significant associations were noted for ALP and GGT. We observed a potentially stronger association for girls compared to boys based on umbilical ALT and AST. However, for GGT and ALP, these associations were stronger for boys compared to girls. CONCLUSION: Overall our findings suggested that exposure to PAHs during pregnancy had adverse effects on infant's liver function.

"To be or not to Be": Regulatory T cells in melanoma.

In spite of progresses in the therapy of different malignancies, melanoma still remains as one of lethal types of skin tumor. Melanoma is almost easily treatable by surgery alone with higher overall survival rates when it is diagnosed at early stages. However, survival rates are decreased remarkably upon survival if the tumor is progressed to advanced metastatic stages. Immunotherapeutics have been prosperous in the development of anti-tumor responses in patients with melanoma through promotion of the tumor-specific effector T cells in vivo; nonetheless, suitable clinical outcomes have not been satisfactory. One of the underlying causes of the unfavorable clinical outcomes might stem from adverse effects of regulatory T (Treg) cell, which is a prominent mechanism of tumor cells to escape from tumor-specific immune responses. Evidence shows that a poor prognosis and low survival rate in patients with melanoma can be attributed to a higher Treg cell number and function in these subjects. As a result, to promote melanoma-specific anti-tumor responses, depletion of Treg cells appears to be a promising approach; even though the clinical efficacy of different approaches to attain appropriate Treg cell depletion has been inconsistent. Here in this review, the main purpose is to assess the role of Treg cells in the initiation and perpetuation of melanoma and to discuss effective strategies for Treg cell modulation with the aim of melanoma therapy.

Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling.

1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole-phthalimide hybrid (PESMP) in high yields. The NMR (1H and 13C) spectroscopic analysis initially confirmed the structure of PESMP. Further spectral aspects were validated based on a single-crystal XRD analysis. Experimental findings were confirmed afterwards by executing a Hirshfeld surface (HS) analysis and quantum mechanical computations. The HS analysis showed the role of the π⋯π stacking interactions in PESMP. PESMP was found to have a high stability and lower reactivity in terms of global reactivity parameters. α-Amylase inhibition studies revealed that the PESMP was a good inhibitor of α-amylase with an s value of 10.60 ± 0.16 µg/mL compared with that of standard acarbose (IC50 = 8.80 ± 0.21 µg/mL). Molecular docking was also utilized to reveal the binding pose and features of PESMP against the α-amylase enzyme. Via docking computations, the high potency of PESMP and acarbose towards the α-amylase enzyme was unveiled and confirmed by docking scores of -7.4 and -9.4 kcal/mol, respectively. These findings shine a new light on the potential of PESMP compounds as α-amylase inhibitors.

In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.

Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of - 59.9, - 57.4, - 53.5, and - 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.

Protective Potentials of Alpha-Lipoic Acid against Ionizing Radiation-Induced Brain Damage in Rats.

Background: This study was aimed at determining the effects of alpha-lipoic acid on ionizing irradiation-induced oxidative damage and apoptosis in the brain of rats. Methods: The animals were exposed to whole-brain X-radiation with a 15 Gy single dose in the absence or presence of alpha-lipoic acid (200 mg/kg body weight) pretreatment for one week. The rats were divided into four groups (5 rats in each group): vehicle control, alpha-lipoic acid alone (ALA), radiation alone (RAD), and radiation plus alpha-lipoic acid (RAD+ALA). In the next stage, malondialdehyde (MDA), nitric oxide, catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the brain tissue of the rats were measured. Furthermore, the Western blot analysis technique was performed to assess the NOX2, NOX4, and caspase-3 protein expression levels. Results: Twenty-four hours after the irradiation, MDA and nitric oxide levels in the irradiated rats were significantly higher than those in the control group (p < 0.001); however, the pretreatment with alpha-lipoic acid resulted in a significant reduction in these stress oxidative markers (p < 0.05). Moreover, a significant decrease in CAT, SOD, and GPx levels was observed in the radiation group alone compared to the control group (p < 0.01); in contrast, the activities of these antioxidant enzymes significantly increased in the radiation plus alpha-lipoic acid group in comparison to the radiation group alone (p < 0.05). The results of Western blot analysis revealed that NOX2, NOX4, and caspase-3 protein expressions significantly elevated in the irradiated rats compared to the control group (p < 0.001). The pretreatment with alpha-lipoic acid could significantly decrease the expression levels of NOX2, NOX4, and caspase-3 in comparison with the radiation group alone (p < 0.05). Conclusion: According to the obtained findings, it can be mentioned that the alpha-lipoic acid pretreatment could mitigate the ionizing irradiation-induced oxidative damage and apoptosis in the brain of the rats.

Hospital wastewater treatment methods and its impact on human health and environments.

The scientific development and economic advances have led to the identification of many pathogenic agents in hospital effluents. Hospital wastewaters are qualitatively similar to municipal wastewaters, with the difference that these wastewaters contain toxic and infectious substances and compounds that can be dangerous for the health of the environment, employees of these centers, and the entire community. Therefore, in the last few years, it has been emphasized that all hospitals and medical and health centers should have a treatment facility for their produced wastewater so that the health of the society and people is not threatened. An issue that is not paid attention to has become one of the environmental problems and concerns of the world today. The present study focused on the investigate hospital wastewater treatment methods and its impact on human health and the environment. In this narrative study, the first literature search was performed with four hundred and twenty-three articles were retrieved based on PubMed, Elsevier, Web of science, Spring, and Google Scholar databases. The results of this study showed that wastewater from hospitals and medical centers can play a significant impress in polluting soil and aquatic environments and spreading infectious diseases. According to the mentioned contents, collection and treatment of hospital wastewater is essential. In addition, if hospital wastewater enters the wastewater collection network without knowing its characteristics or with incomplete treatment and finally enters the municipal wastewater treatment plant. It causes many problems, including disturbing the balance of the biological system of the treatment plant. Purification and disposal of hospital wastewater is considered a vital action based on environmental standards. The results of this study also showed that the treatment methods of this type of hospital wastewater can play a significant role in reducing the spread of diseases caused by hospital wastewater treatment, including infectious diseases. The results of this study can be very useful for politicians, the managers of the Ministry of Energy and Health and the Environmental Organization in choosing the appropriate methods and process to reduce hospital wastewater and increase the efficiency of hospital wastewater treatment plants.

The emerging crosstalk between atherosclerosis-related microRNAs and Bermuda triangle of foam cells: Cholesterol influx, trafficking, and efflux.

In atherosclerosis, the gradual buildup of lipid particles into the sub-endothelium of damaged arteries leads to numerous lipid alterations. The absorption of these modified lipids by monocyte-derived macrophages in the arterial wall leads to cholesterol accumulation and increases the likelihood of foam cell formation and fatty streak, which is an early characteristic of atherosclerosis. Foam cell formation is related to an imbalance in cholesterol influx, trafficking, and efflux. The formation of foam cells is heavily regulated by various mechanisms, among them, the role of epigenetic factors like microRNA alteration in the formation of foam cells has been well studied. Recent studies have focused on the potential interplay between microRNAs and foam cell formation in the pathogenesis of atherosclerosis; nevertheless, there is significant space to progress in this attractive field. This review has focused to examine the underlying processes of foam cell formation and microRNA crosstalk to provide a deep insight into therapeutic implications in atherosclerosis.

Chetomin, a SARS-CoV-2 3C-like Protease (3CLpro) Inhibitor: In Silico Screening, Enzyme Docking, Molecular Dynamics and Pharmacokinetics Analysis.

The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues −namely, chetomin A-D− as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate.

Unraveling the role of natural killer cells in leishmaniasis.

NK cells are known as frontline responders that are efficient in combating several maladies as well as leishmaniasis caused by Leishmania spp. As such they are being investigated to be used for adoptive transfer therapy and vaccine. In spite of the lack of antigen-specific receptors at their surface, NK cells can selectively recognize pathogens, accomplished by the activation of the receptors on the NK cell surface and also as the result of their effector functions. Activation of NK cells can occur through interaction between TLR-2 expressed on NK cells and. LPG of Leishmania parasites. In addition, NK cell activation can occur by cytokines (e.g., IFN-γ and IL-12) that also lead to producing cytokines and chemokines and lysis of target cells. This review summarizes several evidences that support NK cells activation for controlling leishmaniasis and the potentially lucrative roles of NK cells during leishmaniasis. Furthermore, we discuss strategies of Leishmania parasites in inhibiting NK cell functions. Leishmania LPG can utilizes TLR2 to evade host-immune responses. Also, Leishmania GP63 can directly binds to NK cells and modulates NK cell phenotype. Finally, this review analyzes the potentialities to harness NK cells effectiveness in therapy regimens and vaccinations.

The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer.

Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.

Interactions of Apigenin and Safranal with the 5HT1A and 5HT2A Receptors and Behavioral Effects in Depression and Anxiety: A Molecular Docking, Lipid-Mediated Molecular Dynamics, and In Vivo Analysis.

BACKGROUND: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. METHODS: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. RESULTS: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. CONCLUSIONS: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety.

Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism.

MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8+ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.

Nanovaccines in cancer immunotherapy: Focusing on dendritic cell targeting.

Cancer immunotherapy is proposed to eradicate tumors by stimulating host anti-tumor immunity through utilizing various therapeutic approaches. Cancer vaccines have become a promising approach for cancer immunotherapy among the proposed platforms, either alone or in combination with other therapeutic agents. Due to the suboptimal efficacy of cancer vaccines in clinical trials and the advent of nanotechnology in the biomedicine field, scientists developed nanoplatforms, such as various nanoparticles (NPs), cell-derived components, and nanocomplexes, to deliver vaccine components to target cells and tissues, thereby supporting their anti-tumor efficacy and minimizing adverse side effects. To increase the therapeutic effects of nanovaccines in cancer therapy, dendritic cell (DC) targeting through the modulation of the structure of the vaccines, such as using DC-specific ligands, has attracted extensive interest. Here, we reviewed the various forms of nanovaccines in cancer therapy and their therapeutic effects; we highlighted the properties and functions of DCs as the main antigen-presenting cells in immune responses and focused on targeting DCs in developing nanovaccines.

Potential bioactivity of Phoenix dactylifera fruits, leaves, and seeds against prostate and pancreatic cancer cells.

The use of functional foods' phytochemicals in the chemoprevention of different cancer diseases has become one of the hot scientific areas in the clinical nutrition field. For instance, the Khalas palm cultivar (KPC; Phoenix dactylifera) is one of the natural sustainable resources that have high bioactivity and functionality. This study aimed to investigate the antiproliferative activity and mode of action of KPC's different parts on prostate (Pc3) and pancreatic (panc1) cancer cells at a molecular level. In the methods, KPC's leaves, seeds, and fruits' chemical composition and phytochemical analysis were analyzed. Also, the cytotoxic effects of each extract were assessed against pc3 and panc1 cell lines. Besides, induction of apoptosis, cell cycle analysis, and gene expression of both Cap3 and Cap9 were studied. The obtained results indicated that KPC leaves extract exhibited the highest significant (P < 0.01) anti-proliferation activity against the utilized cancer cell lines compared to fruits and seeds extracts. Also, there were significant (P < 0.05) differences in the phenolic contents, flavonoid of compounds, and antioxidant power of the leaves when compared to the seeds and fruits. Additionally, the highest cytotoxic effect (lowest IC50) was recorded with leave extract than seeds and fruits. Meanwhile, the seeds extract induced (P < 0.05) the apoptosis and arrested cells in the G2/M phase as well as up-regulated the gene expression of the apoptotic-related genes (Casp3 and Casp9) compared to the control group. In conclusion, this study showed that the presence of bioactive components in the KPC different parts extracts have the significant ability to induce the apoptotic pathway that could down-regulate the proliferation of prostate (pc3) and pancreatic (panc1) cancer cells. The pathway mechanism of action was induced by the phytol molecule presented in its leaves extract.

Integrated network pharmacology and experimental analysis unveil multi-targeted effect of 18α- glycyrrhetinic acid against non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most malignant types of cancer with soaring incidence rates worldwide, attributed to its heterogeneity and complex etiology. Evidently, alternative anti-cancer therapies comprising traditional medicines and natural products have gained attention for their ability to act as chemopreventive agents with minimal toxicities, either alone or in combination. Accumulating studies have substantiated the inevitability of network pharmacology studies for effectively mapping molecular targets of natural products against multifaceted diseases, including cancer. The 18α-Glycyrrhetinic acid (18α-GA), a triterpenoid found in licorice plants, has shown promising medicinal properties, although, its mechanism of action against NSCLC yet remains elusive. The present study was conducted to explore the anti- NSCLC potential of 18α-GA, employing integrative network pharmacology, molecular docking, and experimental research. Initially, network analysis revealed 181 common targets of 18α-GA in NSCLC as shown in the "compound-target- disease" network employing Cytoscape 3.8.2. Further analyses identified EGFR, AKT1, PI3KR1, MAPK1, IGF1, and SRC as the most crucial hub targets of 18α-GA against NSCLC. Moreover, molecular docking simulations and functional enrichment analyses indicated the involvement of multiple signaling pathways in suppressing NSCLC. Subsequent in-vitro studies verified the antiproliferative effect of 18α-GA on two NSCLC cancer cell lines, H1299 and A549. Mechanistically, 18α-GA arrested cell cycle at the G1 phase, induced apoptosis, decreased migratory potential, and protein expression levels of EGFR-PI3K/AKT, as examined by flow cytometry, morphological assessment, RT-PCR, and western blot. In conclusion, this study delineates the therapeutic potential and underlying mechanism(s) of 18α-GA as a putative novel drug against NSCLC. However, further studies are warranted to elucidate the complete molecular mechanism(s) using animal models of NSCLC.

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study.

The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

Comparative study of phenolic profile, antioxidant and antimicrobial activities of aqueous extract of white and green tea.

The sole difference between white tea (WT) and green tea (GT) is the former that made only from the buds and young leaves of the Camelia sinensis plant, whilst the latter is made from matured tea leaves. The phytochemical profiles, phenolic compounds, antioxidant, and antimicrobial activity of two varieties of Camellia sinensis teas, white and green, were compared in this study. Total antioxidant capacity, reducing power, DPPH radical scavenging, and Fe+2 chelating activities were used to determine antioxidant activities in water extract of GT and WT. The largest level of phenolic content was discovered in WGTE compared with the lowest amount was found in WWTE (290.67 mg/100 g tea and 185.96 mg/100 g tea, respectively). Phenoilc acids (gallic, benzoic, chlorogenic, ellagic, and ρ-coumaric acids) and flavonoids (rutin and kampherol) were found in the two extracts. The findings of DPPH radical scavenging assays were 84.06 and 82.37% inhibition. In vitro antimicrobial activity was indicated that (WWTE and WGTE) had a high level of activity against Staphylococcus aureus, and gave negative activity against Salmonella typhimurium, and Aspergillus Niger. The WT and GT extracts are a great source of natural antioxidants with biological effects on human health.

PI3K-AKT Pathway Modulation by Thymoquinone Limits Tumor Growth and Glycolytic Metabolism in Colorectal Cancer.

Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.

Dietary Thymol Improved Growth, Body Composition, Digestive Enzyme Activities, Hematology, Immunity, Antioxidant Defense, and Resistance to Streptococcus iniae in the Rainbow Trout (Oncorhynchus mykiss).

In this study, thymol (TYM) at dietary levels of 0, 1, 1.5, 2, and 2.5 g/kg diet was used to evaluate its effects on growth, digestive performance, immunity, and resistances to the infection induced by Streptococcus iniae in the rainbow trout, Oncorhynchus mykiss. A number of 450 fish (35.8 ± 4.4 g; Mean ± SD) were distributed to 15 tanks (30 fish/tank) in three replicates and fed TYM for 60 days. After feeding period, Fish fed 1.5-2.5 g TYM showed better growth, higher digestive enzyme activity, and body protein content compared to other diets (P < 0.05). Regression analysis indicated a polynomial relationship between growth parameters and dietary TYM levels. Based upon the varied growth parameters, the optimum dietary TYM level was 1.89% for FCR. TYM at dietary levels of 1.5-2.5 g significantly enhanced liver antioxidant enzyme activity [superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)], immune components in blood [alternative complement activity (C3), total immunoglobulin (Ig), lysozyme activity, bactericidal activity, and total protein], and in mucus [alkaline phosphatase (ALP), protease activity, lysozyme activity, bactericidal activity, and total protein] compared to other diets (P < 0.05). TYM at dietary levels of 2-2.5 g significantly decreased malondialdehyde (MDA) levels compared to other experimental groups (P < 0.05). In addition, use of TYM at dietary levels of 1.5-2.5 g upregulated the expression of the immune-related genes (C3, Lyz, and Ig) (P < 0.05). In contrast, the expression of inflammatory genes, tumor necrosis factor (TNF-α) and Interleukin-8 (IL-8) significantly were downregulated in response to 2-2.5 g TYM (P < 0.05). The hematology of the fish also altered in response to dietary TYM, where the values of corpuscular hemoglobin concentration (MCHC), hemoglobin (Hb), red blood cell (RBC), hematocrit (Hct), and white blood cell (WBC) significantly increased in fish fed 2-2.5 g TYM compared to other diets (P < 0.05). In addition, MCV significantly decreased in response to 2-2.5 g TYM (P < 0.05). After challenge with Streptococcus iniae, the survival rate was significantly higher in fish fed 2-2.5 g TYM compared to other diets (P < 0.05). The results of the present study concluded that TYM in the diet of rainbow trout can improve the fish growth and immunity and increase the resistance of the fish to Streptococcus iniae infection. The results of this study recommend an optimized dietary level of 2-2.5 g TYM for the fish.