Decoding dynamic interactions between EGFR-TKD and DAC through computational and experimental approaches: A novel breakthrough in lung melanoma treatment.

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.

Interplay of precision therapeutics and MD study: Calocybe indica's potentials against cervical cancer and its interaction with VEGF via octadecanoic acid.

The evolving landscape of personalized medicine necessitates a shift from traditional therapeutic interventions towards precision-driven approaches. Embracing this paradigm, our research probes the therapeutic efficacy of the aqueous crude extract (ACE) of Calocybe indica in cervical cancer treatment, merging botanical insights with advanced molecular research. We observed that ACE exerts significant influences on nuclear morphology and cell cycle modulation, further inducing early apoptosis and showcasing prebiotic attributes. Characterization of ACE have identified several phytochemicals including significant presence of octadeconoic acid. Simultaneously, utilizing advanced Molecular Dynamics (MD) simulations, we deciphered the intricate molecular interactions between Vascular Endothelial Growth Factor (VEGF) and Octadecanoic acid to establish C.indica's role as an anticancer agent. Our study delineates Octadecanoic acid's potential as a robust binding partner for VEGF, with comprehensive analyses from RMSD and RMSF profiles highlighting the stability and adaptability of the protein-ligand interactions. Further in-depth thermodynamic explorations via MM-GBSA calculations reveal the binding landscape of the VEGF-Octadecanoic acid complex. Emerging therapeutic innovations, encompassing proteolysis-targeting chimeras (PROTACs) and avant-garde nanocarriers, are discussed in the context of their synergy with compounds like Calocybe indica P&C. This convergence underscores the profound therapeutic potential awaiting clinical exploration. This study offers a holistic perspective on the promising therapeutic avenues facilitated by C. indica against cervical cancer, intricately woven with advanced molecular interactions and the prospective integration of precision therapeutics in modern oncology.

Attitude and Behavior of Parents of Children With Sickle Cell Disease Toward the Disease: An Observational Study in Saudi Arabia.

BACKGROUND: Sickle cell disease (SCD) is a significant hematological disorder affecting populations worldwide, with a notable prevalence in certain regions of Saudi Arabia. Despite extensive screening programs, there is a critical need for improved public health education to enhance understanding and management of SCD. This study examines the relationship between the attitudes and behaviors of parents toward their children's disease and its management. METHODS: We conducted a cross-sectional observational study at the King Fahd Medical Research Center in Jeddah. This research encompassed children aged 5-16 years with SCD and their parents. Comprehensive questionnaires assessed sociodemographic data, attitudes toward SCD, and behavioral responses to the illness and treatment. RESULTS: The study included 66 parents, predominantly in the age range of 30-39 years and earning below 5000 Saudi Riyals, who exhibited varying attitudes towards SCD, with a majority questioning the availability of a cure and expressing caution towards new treatments. Despite a cautious approach to invasive treatments, parents relied on information from healthcare providers. Attitudes towards treatment showed significant differences based on gender and education level, with females and less-educated parents exhibiting more hesitancy towards new treatment and blood transfusions. CONCLUSION: The study indicates that while parents show a positive and proactive attitude toward SCD, there is hesitancy towards new and invasive treatments, reflecting the need for continued educational support. The results underscore the importance of tailored healthcare communication strategies to address the diverse needs of families affected by SCD.

Challenges and insights: Methamphetamine analysis in post-mortem putrefied human tissues in a hot climate.

Background: The production and distribution of methamphetamine (meth) is often associated with illegal and clandestine laboratories, posing significant challenges for law enforcement and public health efforts. Global concern is growing over meth-related fatalities, as its high potential for abuse and detrimental impact on health make it an important issue in the realm of substance abuse and addiction. This concern has notably increased in Saudi Arabia, where the hot climate adds complexity to the analysis due to challenges posed by putrefaction. There is still an urgent need to enhance the screening capabilities of many toxicology laboratories to determine the cause of death, whether it be due to drug use or natural causes. Aim: This research aimed to investigate meth concentrations in post-mortem putrefied human solid tissues in a hot climate and comparing meth metabolite concentrations in cases where signs of putrefaction were observed versus those with no signs of putrefaction. The objective is to assist criminal investigations by analyzing meth and its metabolite concentrations. Methods: This retrospective cohort study involved postmortem samples from human subjects during autopsies conducted between 2016 and 2022. It focused on analyzing meth and its metabolite concentrations using LC-MS/MS analysis. Data on demographics, medical history, age, location, putrefaction, and other drug use were retrieved from medical records. Results: Out of the 27 reported samples of meth and its metabolite amphetamine in both putrefied and non-putrefied biological fluids and tissues, only 8 (30%) exhibited signs of putrefaction between 2016 and 2022. Despite decomposition, detectable concentrations of meth and amphetamine were sufficient to determine the cause of death and the source of amphetamines. Conclusion: This study found no significant difference in concentrations between putrefied and non-putrefied cases, underscoring the importance of multiple sample testing during autopsy for accurate interpretation. Each case is unique and must be considered individually.

The assessment of liver function test and fertility hormones in Saudi athletes using anabolic androgenic steroids.

Background: A growing number of athletes are using synthetic anabolic-androgenic steroids (AAS), comprised of testosterone and other derivatives, to enhance athletic performance and muscle mass. Over the years, numerous reports elucidated the side effects of the illegal use of AAS, such as infertility, and liver disorders. The effect of AAS on the hepatic and reproductive systems in Saudi athletes has not yet been studied. Therefore, this study examined the liver function and sex hormone parameters of AAS users as compared to non-users. Methods: Fasting blood samples were collected from 16 male Saudi athletes, 10 AAS-users (cases) and 6 non-users (controls) to measure liver function tests (ALT, AST, GGT, ALP, total protein, albumin, direct and total bilirubin) and muscle enzymes (CK, LDH), Fertility hormones (LH, FSH, total testosterone, estradiol, and prolactin) were included also. Furthermore, a self-reported questionnaire was obtained to identify the type of AAS used, the dosage, and the length of the course before sample collection. Results: The results show a statistically significant increase in ALT (P < 0.001), AST (P < 0.001), CK (P < 0.05), and a significant decrease (P < 0.05) in albumin (P < 0.001) and total bilirubin levels (P < 0.01) in AAS-users. Total testosterone increased significantly among AAS (P < 0.05), along with a significant decrease in LH (P < 0.01), and FSH (P < 0.001) levels, while serum prolactin and estradiol levels were significantly increased (P < 0.05). Conclusion: AAS can enhance physical performance and appearance, its potential adverse effects on the hepatic and reproductive systems necessitate careful consideration. Our research demonstrates an increase in the liver-specific enzyme ALT in AAS users relative to non-users and the possibility that short-term AAS usage increases the risk of liver injury.

Curcumin, its derivatives, and their nanoformulations: Revolutionizing cancer treatment.

Curcumin is a natural compound derived from turmeric and can target malignant tumor molecules involved in cancer propagation. It has potent antioxidant activity, but its effectiveness is limited due to poor absorption and rapid elimination from the body. Various curcumin derivatives have also shown anticancer potential in in-vitro and in-vivo models. Curcumin can target multiple signaling pathways involved in cancer development/progression or induce cancer cell death through apoptosis. In addition, curcumin and its derivatives could also enhance the effectiveness of conventional chemotherapy, radiation therapy and reduce their associated side effects. Lately, nanoparticle-based delivery systems are being developed/explored to overcome the challenges associated with curcumin's delivery, increasing its overall efficacy. The use of an imaging system to track these formulations could also give beneficial information about the bioavailability and distribution of the nano-curcumin complex. In conclusion, curcumin holds significant promise in the fight against cancer, especially in its nanoform, and could provide precise delivery to cancer cells without affecting normal healthy cells.

Evaluation of biogenically synthesized MgO NPs anticancer activity against breast cancer cells.

Background: Magnesium is recognized to have pharmacological potential, and its nanoformulation is anticipated to offer significant therapeutic effects, particularly against cancer. In this study, we analyzed the anticancer effect of biogenically synthesized magnesium oxide nanoparticles (MgO NPs) against breast cancer cells (MDA-MB-231). Methods: Different biological evaluations, such as cytotoxicity, cellular morphology, induction of apoptosis, generation of ROS, cell adhesion and cellular migration were estimated using well established methodology. Results: The biogenic MgO NPs exhibited increased cytotoxicity, induced apoptosis, enhanced formation of ROS, promoted cell adhesion and inhibited cellular migration in a dose-dependent manner, showing its therapeutic potential against MDA-MB-231 cells. Conclusion: The current study observed strong anticancer activity of MgO NPs against studied cancer cell lines. However, our study must be validated in an appropriate animal/xenograft model to authenticate the effectiveness of MgO NPs against breast cancer.

Structure-based virtual screening and molecular docking approaches to identify potential inhibitors against KIF2C to combat glioma.

Glioma, a kind of malignant brain tumor, is extremely lethal. Kinesin family member 2C (KIF2C) was found to have an aberrant expression in several cancer types, including lung cancer and glioma. KIF2C may therefore be a useful therapeutic target for the treatment of glioma. In the current study, new drug candidates that may function as KIF2C enzyme inhibitors were discovered. MTi OpenScreen was used to carry out the structure-based virtual screening of an inbuilt drug library containing 150,000 compounds. These compounds belong to different classes, such as natural product-based compounds (NP-lib), purchasable approved drugs (Drugs-lib), and food constituents compound collection (FOOD-lib). Based on their binding affinities, a total of 84 compounds were further pushed to calculate ADMET properties. The compounds (16) meeting the ADMET cutoff ranges were then further docked to the receptor to find their plausible binding modes using the Glide tool's standard precision (SP) technique. The docking results were examined using the Glide gscore, and the best binding compounds (Rimacalib and Sarizotan) were chosen to test their stability with KIF2C protein through molecular dynamics (MD) simulation. Similarly, Principal Component Analysis and cross-correlation matrix were also examined. The MM/GBSA binding free energies showed a considerable energy contribution in the binding of hits with the KIF2C. Collectively, these findings strongly suggest the potential of the lead compounds to inhibit the biological function of KIF2C, emphasizing the need for further investigation in this area.Communicated by Ramaswamy H. Sarma.

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics.

The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer's Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.

Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool.

Cancer has been one of the leading causes of mortality worldwide over the past few years. Some progress has been made in the development of more effective cancer therapeutics, resulting in improved survival rates. However, the desired outcome in the form of successful treatment is yet to be achieved. There is high demand for the development of innovative, inexpensive, and effective anticancer treatments using natural resources. Natural compounds have been increasingly discovered and used for cancer therapy owing to their high molecular diversity, novel biofunctionality, and minimal side effects. These compounds can be utilized as chemopreventive agents because they can efficiently inhibit cell growth, control cell cycle progression, and block several tumor-promoting signaling pathways. PI3K is an important upstream protein of the PI3K-Akt-mTOR pathway and a well-established cancer therapeutic target. This study aimed to explore the small molecules, natural flavonoids, viz. quercetin, luteolin, kaempferol, genistein, wogonin, daidzein, and flavopiridol for PI3Kγ kinase activity inhibition. In this study, the binding pose, interacting residues, molecular interactions, binding energies, and dissociation constants were investigated. Our results showed that these flavonoids bound well with PI3Kγ with adequate binding strength scores and binding energy ranging from (-8.19 to -8.97 Kcal/mol). Among the explored ligands, flavopiridol showed the highest binding energy of -8.97 Kcal/mol, dock score (-44.40), and dissociation constant term, pKd of 6.58 against PI3Kγ. Based on the above results, the stability of the most promising ligand, flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.

Screening of Cu4 O3 NPs efficacy and its anticancer potential against cervical cancer.

Cu4 O3 is the least explored copper oxide, and its nanoformulation is anticipated to have important therapeutic potential especially against cancer. The current study aimed to biosynthesize Cu4 O3 nanoparticles (NPs) using an aqueous extract of pumpkin seeds and evaluate its antiproliferative efficacy against cervical cells after screening on different cancer cell lines. The obtained NPs were characterized by different spectroscopic analyses, such as UV-vis, thermogravimetric, energy dispersive X-ray, and Fourier-transform infrared spectroscopy (FTIR). In addition, high-resolution transmission electron microscopes (HR-TEM) were used to observe the morphology of the biosynthesized NPs. The UV-vis spectra showed a peak at around 332 nm, confirming the formation of Cu4 O3 NPs. Moreover, FTIR and TAG analyses identified the presence of various bioactive phytoconstituents that might have worked as capping and stabilization agents and comparative stable NPs at very high temperatures, respectively. The HR-TEM data showed the spherical shape of Cu4 O3 NPs in the range of 100 nm. The Cu4 O3 NPs was screened on three different cancer cell lines viz., Hela, MDA-MB-231, and HCT-116 using cytotoxicity (MTT) reduction assay. In addition, Vero was taken as a normal epithelial (control) cell. The high responsive cell line in terms of least IC50 was further assessed for its anticancer potential using a battery of biological tests, including morphological alterations, induction of apoptosis/ROS generation, regulation of mitochondrial membrane potential (MMP), and suppression of cell adhesion/migration. Vero cells (control) showed a slight decline in % cell viability even at the highest tested Cu4 O3 NPs concentration. However, all the studied cancer cells viz., MDA-MB-231, HCT 116, and HeLa cells showed a dose-dependent decline in cell viability after the treatment with Cu4 O3 NPs with a calculated IC50 value of 10, 11, and 7.2 µg/mL, respectively. Based on the above data, Hela cells were chosen for further studies, that showed induction of apoptosis from 3.5 to 9-folds by three different staining techniques acridine orange/ethidium bromide (AO/EB), 4',6-diamidino-2-phenylindole (DAPI), and propidium iodide (PI). The enhanced production of reactive oxygen species (>3.5-fold), modulation in MMP, and suppression of cell adhesion/migration were observed in the cells treated with Cu4 O3 NPs. The current study obtained the significant antiproliferative potential of Cu4 O3 NPs against the cervical cancer cell line, which needs to be confirmed further in a suitable in vivo model. Based on our results, we also recommend the green-based, eco-friendly, and cost-effective alternative method for synthesizing novel nanoformulation.

Potential inflammatory targets in the integrative health care of patients with sickle cell disease.

Inflammation plays an integral role in the complications of sickle cell disease (SCD), which can lead to vaso-occlusive crisis and extreme pain. SCD is accompanied by numerous complications, including cardiovascular disease, cognitive decline and endothelial dysfunction, contributing to mortality. As disease severity increases with age, the present study aimed to assess if age is also correlated with a definite pattern of progression of the two inflammatory markers, high-sensitivity C-reactive protein (hsCRP) and total homocysteine (tHCY). The findings of the present study could lead to an improved understanding of the threshold levels of these inflammatory markers and timely interventions to delay complications. In an observational study, levels of hsCRP and tHCY were analyzed in 70 patients (35 male and 35 female patients) with SCD aged between 5 and 16 years. hsCRP levels were in the high-risk range in 64.29% (n=45) of all male and female patients. A sex-wise distribution showed that, of the 35 male patients, 74.28% (n=26) were in the high-risk range, and of the 35 female patients, 54.28% (n=19) were in the high-risk range. An age-wise distribution showed that of the 41 patients in the 5-10-years age group, 70.73% (n=29), were in the high-risk range. In comparison, of the 29 patients in the 11-16-years age group, 55.17% (n=16) were in the high-risk range. tHCY levels were observed to be in the normal range in 98.57% (n=69) of all children, as compared with 1.43% (n=1) in the high-risk range. Furthermore, a sex-wise distribution showed that female patients in the high-risk group of hsCRP had higher concentrations of tHCY as compared with the male patients in that risk group. An age-wise distribution of hsCRP concentration also showed that the risk of CVD in patients in the 11-16-years age group was higher with increased concentrations of tHCY. A weak negative correlation was observed between age and hsCRP concentrations (r-value=-0.280; P=0.026) and a weak positive correlation was detected between tHCY and age (r-value=0.259; P=0.036). In conclusion, the results of the present study indicated that higher levels of hsCRP could be a useful marker in children with SCD, and levels of tHCY may be an adjunct marker as the disease progresses with age.

11-Nor-9-Carboxy Tetrahydrocannabinol Distribution in Fluid from the Chest Cavity in Cannabis-Related Post-Mortem Cases.

In this study, the presence of 11-nor-Δ9-carboxy tetrahydrocannabinol (THC-COOH) in postmortem fluid obtained from the chest cavity (FCC) of postmortem cases collected from drug-related fatalities or criminal-related deaths in Jeddah, Saudi Arabia, was investigated to evaluate its suitability for use as a complementary specimen to blood and biological specimens in cases where no bodily fluids are available or suitable for analysis. The relationships between THC-COOH concentrations in the FCC samples and age, body mass index (BMI), polydrug intoxication, manner, and cause of death were investigated. METHODS: Fifteen postmortem cases of FCC were analyzed using fully validated liquid chromatography-positive-electrospray ionization tandem mass spectrometry (LC-MS/MS). RESULTS: FCC samples were collected from 15 postmortem cases; only THC-COOH tested positive, with a median concentration of 480 ng/mL (range = 80-3010 ng/mL). THC-COOH in FCC were higher than THC-COOH in all tested specimens with exception to bile, the median ratio FCC/blood with sodium fluoride, FCC/urine, FCC/gastric content, FCC/bile, FCC/liver, FCC/kidney, FCC/brain, FCC/stomach wall, FCC/lung, and FCC/intestine tissue were 48, 2, 0.2, 6, 4, 6, 102, 11, 5 and 10-fold, respectively. CONCLUSION: This is the first postmortem report of THC-COOH in the FCC using cannabinoid-related analysis. The FCC samples were liquid, easy to manipulate, and extracted using the same procedure as the blood samples. The source of THC-COOH detected in FCC could be derived from the surrounding organs due to postmortem redistribution or contamination due to postmortem changes after death. THC-COOH, which is stored in adipose tissues, could be a major source of THC-COOH found in the FCC.

Mirtazapine attenuated cadmium-induced neuronal intoxication by regulating Nrf2 and NF-κB/TLR4 signals.

Cadmium (Cd) is one of the most hazardous metals to the environment and human health. Neurotoxicity is of the most serious hazards caused by Cd. Mirtazapine (MZP) is a central presynaptic α2 receptor antagonist used effectively in treating several neurological disorders. This study investigated the anti-inflammatory and antioxidant activity of MZP against Cd-induced neurotoxicity. In this study, rats were randomly divided into five groups: control, MZP (30 mg/kg), Cd (6.5 mg/kg/day; i.p), Cd + MZP (15 mg/kg), and Cd + MZP (30 mg/kg). Histopathological examination, oxidative stress biomarkers, inflammatory cytokines, and the impact of Nrf2 and NF-κB/TLR4 signals were assessed in our study. Compared to Cd control rats, MZP attenuated histological abrasions in the cerebral cortex and CA1 and CA3 regions of the hippocampus as well as the dentate gyrus. MZP attenuated oxidative injury by upregulating Nrf2. In addition, MZP suppressed the inflammatory response by decreasing TNF-α, IL-1ß, and IL-6 mediated by downregulating TLR4 and NF-κB. It is noteworthy that MZP's neuroprotective actions were dose-dependent. Collectively, MZP is a promising therapeutic strategy for attenuating Cd-induced neurotoxicity by regulating Nrf2, and NF-κB/TLR4 signals, pending further study in clinical settings.

Renal mitochondrial restoration by gymnemic acid in gentamicin-mediated experimental nephrotoxicity: evidence from serum, kidney and histopathological alterations.

Background: Nephrotoxicity refers to the toxigenic impact of compounds and medications on kidney function. There are a variety of drug formulations, and some medicines that may affect renal function in multiple ways via nephrotoxins production. Nephrotoxins are substances that are harmful to the kidneys. Purpose: This investigation examines the renoprotective effect of gymnemic acid (GA) on Wistar rats in gentamicin-induced nephrotoxicity by analyzing serum, kidney, and histopathological markers. Study-design/methods: The current study investigated the protective effect of GA at doses of 20, 40, and 60 mg/kg against gentamicin-induced nephrotoxicity in rats. Vitamin E was administered to compare the antioxidant capacity and efficacy of GA. In addition to the treatment groups, 100 mg/kg of gentamicin was administered intraperitoneal for 14 days. At the end of the study protocol, kidney homogenate, blood, and serum were evaluated biochemically. Serum creatinine, blood urea, glomerular filtration rate (GFR), mitochondrial dysfunctions, inflammatory cytokines, and renal oxidative stress were examined to assess gentamicin-induced nephrotoxicity. In addition, the impact of GA on the above-mentioned nephrotoxic markers were evaluated and further confirmed by histological analysis. Results: This study establishes a correlation between antibiotic use, especifically aminoglycosides and acute renal failure. The research demonstrates the nephrotoxic effects of aminoglycosides, inducing mitochondrial ETC-complex dysfunction, and renal tissue inflammation in experimental rats. GA's antioxidant properties restored renal oxidative stress markers, reducing kidney inflammation and injury. Histopathological analysis revealed a significant reduction in renal injury with GA treatment. Additionally, GA demonstrated greater efficacy than Vitamin E in restoring antioxidant potential and mitochondrial enzymes. Conclusion: Consequently, our findings imply that long-term use of GA may be a suitable therapeutic strategy for reducing aminoglycoside toxicity. The current study suggests GA's potential in treating gentamicin-induced nephrotoxicity and acute renal failure, meriting further investigation using advanced techniques.

Metabolomics Analysis as a Tool to Measure Cobalt Neurotoxicity: An In Vitro Validation.

In this study, cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma (SH-SY5Y) cells using proliferation assays coupled with LC-MS-based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 µM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed cobalt cytotoxicity and decreased cell metabolism in a dose and time-dependent manner was observed by metabolomics analysis, in both cell lines. Metabolomic analysis also revealed several altered metabolites particularly those related to DNA deamination and methylation pathways. One of the increased metabolites was uracil which can be generated from DNA deamination or fragmentation of RNA. To investigate the origin of uracil, genomic DNA was isolated and analyzed by LC-MS. Interestingly, the source of uracil, which is uridine, increased significantly in the DNA of both cell lines. Additionally, the results of the qRT-PCR showed an increase in the expression of five genes Mlh1, Sirt2, MeCP2, UNG, and TDG in both cell lines. These genes are related to DNA strand breakage, hypoxia, methylation, and base excision repair. Overall, metabolomic analysis helped reveal the changes induced by cobalt in human neuronal-derived cell lines. These findings could unravel the effect of cobalt on the human brain.

Differential expression of programmed death 1 (PD-1) on various immune cells and its role in human leprosy.

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Leprosy patients have been found to have defects in T cells activation, which is critical to the clearance of the bacilli. Treg cell suppression is mediated by inhibitory cytokines such as IL10, IL-35 and TGF-ß and its frequency is higher in leprosy patients. Activation and overexpression of programmed death 1 (PD-1) receptor is considered to one of the pathways to inhibit T-cell response in human leprosy. In the current study we address the effect of PD-1 on Tregs function and its immuno-suppressive function in leprosy patients. Flow cytometry was used to evaluate the expression of PD-1 and its ligands on various immune cells T cells, B cells, Tregs and monocytes. We observed higher expression of PD-1 on Tregs is associated with lower production of IL-10 in leprosy patients. PD-1 ligands on T cells, B cells, Tregs and monocytes found to be higher in the leprosy patients as compared to healthy controls. Furthermore, in vitro blocking of PD-1 restores the Tregs mediated suppression of Teff and increase secretion of immunosuppressive cytokine IL-10. Moreover, overexpression of PD-1 positively correlates with disease severity as well as Bacteriological Index (BI) among leprosy patients. Collectively, our data suggested that PD-1 overexpression on various immune cells is associated with disease severity in human leprosy. Manipulation and inhibition of PD-1 signaling pathway on Tregs alter and restore the Treg cell suppression activity in leprosy patients.

Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment.

Cancer development is associated with the deregulation of various cell signaling pathways brought on by certain genetic and epigenetic alterations. Therefore, novel therapeutic strategies have been developed to target those pathways. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway is one major deregulated pathway in various types of cancer. Several anticancer drug candidates are currently being investigated in preclinical and/or clinical studies to target this pathway. Natural bioactive compounds provide an excellent source for anticancer drug development. Curcumin and plumbagin are two potential anticancer compounds that have been shown to target the PI3K/Akt/mTOR pathway individually. However, their combinatorial effect on cancer cells is still unknown. This study aims to investigate the synergistic effect of these two compounds on the PI3K/Akt/mTOR pathway by employing a sequential molecular docking and molecular dynamics (MD) analysis. An increase in binding affinity and a decrease in inhibition constant have been observed when curcumin and plumbagin were subjected to sequential docking against the key proteins PI3K, Akt, and mTOR. The MD simulations and molecular mechanics combined with generalized Born surface area (MM-GBSA) analyses validated the target proteins' more stable conformation when interacting with the curcumin and plumbagin combination. This indicates the synergistic role of curcumin and plumbagin against cancer cells and the possible dose advantage when used in combination. The findings of this study pave the way for further investigation of their combinatorial effect on cancer cells in vitro and in vivo models.

Biogenic Synthesis of Cu-Mn Bimetallic Nanoparticles Using Pumpkin Seeds Extract and Their Characterization and Anticancer Efficacy.

BACKGROUND: Cancer is a chronic, heterogeneous illness that progresses through a spectrum of devastating clinical manifestations and remains the 2nd leading contributor to global mortality. Current cancer therapeutics display various drawbacks that result in inefficient management. The present study is intended to evaluate the anticancer potential of Cu-Mn bimetallic NPs (CMBNPs) synthesized from pumpkin seed extract against colon adenocarcinoma cancer cell line (HT-29). METHODS: The CMBNPs were biosynthesized by continuously stirring an aqueous solution of pumpkin seed extract with CuSO4 and manganese (II) acetate tetrahydrate until a dark green solution was obtained. The characteristic features of biogenic CMBNPs were assessed by UV-visible spectrophotometry (UV-vis), X-ray powder diffraction (XRD), energy-dispersive X-ray (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). A battery of biological assays, viz. neutral red uptake (NRU) assay, in vitro scratch assay, and comet assay, were performed for anticancer efficacy evaluation. RESULTS: The formation of spherical monodispersed bimetallic nanoparticles with an average size of 50 nm was recorded using TEM. We observed dose-dependent cytotoxicity of CMBNPs in the HT-29 cell line with an IC50 dose of 115.2 µg/mL. On the other hand, CMBNPs did not show significant cytotoxicity against normal cell lines (Vero cells). Furthermore, the treatment of CMBNPs inhibited the migration of cancer cells and caused DNA damage with a significant increase in comet tail length. CONCLUSIONS: The results showed substantial anticancer efficacy of CMBNPs against the studied cancer cell line. However, it is advocated that the current work be expanded to different in vitro cancer models so that an in vivo validation could be carried out in the most appropriate cancer model.

Heroin-Related Fatalities in Jeddah, Saudi Arabia, between 2008 and 2018.

To date, epidemiological studies have not evaluated heroin-related deaths in the Middle East and North African regions, especially Saudi Arabia. All heroin-related postmortem cases reported at the Jeddah Poison Control Center (JPCC) over a 10-year period (21 January 2008 to 31 July 2018) were reviewed. In addition, liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was utilized to determine the 6-monoacetylmorphine (6-MAM), 6-acetylcodeine (6-AC), morphine (MOR), and codeine contents in unhydrolyzed postmortem specimens. Ninety-seven heroin-related deaths were assessed in this study, and they represented 2% of the total postmortem cases at the JPCC (median age, 38; 98% male). In the blood, urine, vitreous humor, and bile samples, the median morphine concentrations were 280 ng/mL, 1400 ng/mL, 90 ng/mL, and 2200 ng/mL, respectively; 6-MAM was detected in 60%, 100%, 99%, and 59% of the samples, respectively; and 6-AC was detected in 24%, 68%, 50%, and 30% of the samples, respectively. The highest number of deaths (33% of total cases) was observed in the 21-30 age group. In addition, 61% of cases were classified as "rapid deaths," while 24% were classified as "delayed deaths." The majority (76%) of deaths were accidental; 7% were from suicide; 5% were from homicide; and 11% were undetermined. This is the first epidemiological study to investigate heroin-related fatalities in Saudi Arabia and the Middle East and North African region. The rate of heroin-related deaths in Jeddah remained stable but increased slightly at the end of the study period. Most patients were heroin-dependent abusers and from the middle-aged group. The availability of urine, vitreous humor, and bile specimens provided valuable information regarding the opioids that were administered and the survival time following heroin injection.