Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan.

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATM p. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

Preliminary insights on the mutational spectrum of BRCA1 and BRCA2 genes in Pakhtun ethnicity breast cancer patients from Khyber Pakhtunkhwa (KP), Pakistan.

Gene mutations are a source of genetic instability which fuels the progression of cancer. Mutations in BRCA1 and BRCA2 are considered as major drivers in the progression of breast cancer and their detection indispensable for devising therapeutic and management approaches. The current study aims to identify novel pathogenic and recurrent mutations in BRCA1 and BRCA2 in Pakhtun population from the Khyber Pakhtunkhwa. To determine the BRCA1 and BRCA2 pathogenic mutation prevalence in Pakhtun population from KP, whole exome sequencing of 19 patients along with 6 normal FFPE embedded blocks were performed. The pathogenicity of the mutations were determined and they were further correlated with different hormonal, sociogenetic and clinicopathological features. We obtained a total of 10 mutations (5 somatic and 5 germline) in BRCA1 while 27 mutations (24 somatic and 3 germline) for BRCA2. Five and seventeen pathogenic or deleterious mutations were identified in BRCA1 and BRCA2 respectively by examining the mutational spectrum through SIFT, PolyPhen-2 and Mutation Taster. Among the SNVs, BRCA1 p.P824L, BRCA2 p. P153Q, p.I180F, p.D559Y, p.G1529R, p.L1576F, p.E2229K were identified as mutations of the interaction sites as predicted by the deep algorithm based ISPRED-SEQ prediction tool. SAAFEQ-SEQ web-based algorithm was used to calculate the changes in free energy and effect of SNVs on protein stability. All SNVs were found to have a destabilizing effect on the protein. ConSurf database was used to determine the evolutionary conservation scores and nature of the mutated residues. Gromacs 4.5 was used for the molecular simulations. Ramachandran plots were generated using procheck server. STRING and GeneMania was used for prediction of the gene interactions. The highest number of mutations (BRCA1 7/10, 70 %) were on exon 9 and (BRCA2, 11/27; 40 %) were on exon 11. 40 % and 60 % of the BRCA2 mutations were associated Grade 2 and Grade 3 tumors respectively. The present study reveals unique BRCA1 and BRCA2 mutations in Pakhtun population. We further suggest sequencing of the large cohorts for further characterizing the pathogenic mutations.

Correction: Biogenic synthesis of silver nanoparticles using Rubus fruticosus extract and their antibacterial efficacy against Erwinia caratovora and Ralstonia solanacearum phytopathogens.

[This corrects the article DOI: 10.1039/D3RA06723H.].

Chitosan-Based Polymeric Nanoparticles as an Efficient Gene Delivery System to Cross Blood Brain Barrier: In Vitro and In Vivo Evaluations.

Significant progress has been made in the field of gene therapy, but effective treatments for brain tumors remain challenging due to their complex nature. Current treatment options have limitations, especially due to their inability to cross the blood-brain barrier (BBB) and precisely target cancer cells. Therefore options that are safer, more effective, and capable of specifically targeting cancer cells are urgently required as alternatives. This current study aimed to develop highly biocompatible natural biopolymeric chitosan nanoparticles (CNPs) as potential gene delivery vehicles that can cross the BBB and serve as gene or drug delivery vehicles for brain disease therapeutics. The efficiency of the CNPs was evaluated via in vitro transfection of Green Fluorescent Protein (GFP)-tagged plasmid in HEK293-293 and brain cancer MG-U87 cell lines, as well as within in vivo mouse models. The CNPs were prepared via a complex coacervation method, resulting in nanoparticles of approximately 260 nm in size. In vitro cytotoxicity analysis revealed that the CNPs had better cell viability (85%) in U87 cells compared to the chemical transfection reagent (CTR) (72%). Moreover, the transfection efficiency of the CNPs was also higher, as indicated by fluorescent emission microscopy (20.56% vs. 17.79%) and fluorescent-activated cell sorting (53% vs. 27%). In vivo assays using Balb/c mice revealed that the CNPs could efficiently cross the BBB, suggesting their potential as efficient gene delivery vehicles for targeted therapies against brain cancers as well as other brain diseases for which the efficient targeting of a therapeutic load to the brain cells has proven to be a real challenge.

Biogenic synthesis of silver nanoparticles using Rubus fruticosus extract and their antibacterial efficacy against Erwinia caratovora and Ralstonia solanacearum phytopathogens.

In the current research, we produced green, cost-effective, eco-friendly silver nanoparticles using a single-step approach. Plants are considered highly desirable systems for nanoparticle synthesis because they possess a variety of secondary metabolites with significant reduction potential. In the current research, the dried leaf extract of Rubus fruticosus was utilized as a capping and reducing agent for the fabrication of silver nanoparticles, to prepare reliable biogenic silver nanoparticles and subsequently to investigate their potential against some common phytopathogens. The prepared silver nanoparticles were exploited to quantify the total flavonoid content (TFC), total phenolic content (TPC) and DPPH-based antioxidant activity. Different concentrations of aqueous extracts of plant leaves and silver nitrate (AgNO3) were reacted, and the color change of the reactant mixture confirmed the formation of Rubus fruticosus leaf-mediated silver nanoparticles (RFL-AgNPs). A series of characterization techniques such as UV-vis spectroscopy, transmission electron microscopy, energy dispersive X-ray analysis and X-ray diffraction revealed the successful synthesis of silver nanoparticles. The surface plasmon resonance peak appeared at 449 nm. XRD analysis demonstrated the crystalline nature, EDX confirmed the purity, and TEM demonstrated that the nanoparticles are mostly spherical in form. Furthermore, the biosynthesized nanoparticles were screened for in vitro antibacterial activity, antioxidant activity, and total phenolic and flavonoid content. The nanoparticles were used in different concentrations alone and in combination with plant extracts to inhibit Erwinia caratovora and Ralstonia solanacearum. In high-throughput assays used to inhibit these plant pathogens, the nanoparticles were highly toxic against bacterial pathogens. This study can be exploited for planta assays against phytopathogens utilizing the same formulations for nanoparticle synthesis and to develop potent antibacterial agents to combat plant diseases.

Synthesis, spectral characterisation, biocidal investigation, in-silico and molecular docking studies of 4-[(2-chloro-4-methylphenyl)carbamoyl]butanoic acid derived triorganotin(IV) compounds.

Three triorganotin(IV) compounds, R3Sn(L), with R = CH3 (1), n-C4H9 (2) and C6H5 (3), and LH = 4-[(2-chloro-4-methylphenyl)carbamoyl]butanoic acid, were prepared and confirmed by various techniques. A five-coordinate, distorted trigonal-bipyramidal geometry was elucidated for tin(IV) centres both in solution and solid states. An intercalation mode was confirmed for the compound SS-DNA interaction by UV-visible, viscometric techniques and molecular docking. MD simulation revealed stable binding of LH with SS-DNA. Anti-bacterial investigation revealed 2 to be generally the most potent, especially against Sa and Ab, i.e. having the lowest MIC values (≤0.25 µg/mL) compared to the standard anti-biotics vancomycin-HCl (MIC = 1 µg/mL) and colistin-sulphate (MIC = 0.25 µg/mL). Similarly, the anti-fungal profile shows 2 exhibits 100% inhibition against Ca and Cn fungal strains and has MIC values (≤0.25 µg/mL) comparatively lower than standard drug fluconazole (0.125 and 8 µg/mL for Ca and Cn, respectively). Compound 2 has the greatest activity with CC50 ≤ 25 µg/mL and HC50 > 32 µg/mL performed against HEC239 and RBC cell lines. The anti-cancer potential was assessed against the MG-U87 cell line, using cisplatin as the standard (133 µM), indicates 2 displays the greatest activity (IC50: 5.521 µM) at a 5 µM dose. The greatest anti-leishmanial potential was observed for 2 (87.75 at 1000 µg/mL) in comparison to amphotericin B (90.67). The biological assay correlates with the observed maximum of 89% scavenging activity exhibited by 2. The Swiss-ADME data publicised the screened compounds generally follow the rule of 5 of drug-likeness and have good bioavailability potential.

Mutational Landscape and In-Silico Analysis of TP53, PIK3CA, and PTEN in Patients with Breast Cancer from Khyber Pakhtunkhwa.

Herein, we report the mutational spectrum of three breast cancer candidate genes (TP53, PIK3CA, and PTEN) using WES for identifying potential biomarkers. The WES data were thoroughly analyzed using SAMtools for variant calling and identification of the mutations. Various bioinformatic tools (SIFT, PolyPhen-2, Mutation Taster, ISPRED-SEQ, SAAFEQ-SEQ, ConSurf, PROCHECK etc.) were used to determine the pathogenicity and nature of the SNVs. Selected interaction site (IS) mutations were visualized in PyMOL after building 3D structures in Swiss-Model. Ramachandran plots were generated by using the PROCHECK server. The selected IS mutations were subjected to molecular dynamic simulation (MDS) studies using Gromacs 4.5. STRING and GeneMANIA were used for the prediction of gene-gene interactions and pathways. Our results revealed that the luminal A molecular subtype of the breast cancer was most common, whereas a high percentage of was Her2 negatives. Moreover, the somatic mutations were more common as compared to the germline mutations in TP53, PIK3CA, and PTEN. 20% of the identified mutations are reported for the first time from Khyber Pakhtunkhwa. In the enrolled cohort, 23 mutations were nonsynonymous SNVs. The frequency of mutations was the highest in PIK3CA, followed by TP53 and PTEN. A total of 13 mutations were found to be highly pathogenic. Four novel mutations were identified on PIK3CA and one each on PTEN and TP53. SAAFEQ-SEQ predicted the destabilizing effect for all mutations. ISPRED-SEQ predicted 9 IS mutations (6 on TP53 and 3 on PIK3CA), whereas no IS mutation was predicted on PTEN. The TP53 IS mutations were TP53R43H, TP53Y73X, TP53K93Q, TP53K93R, TP53D149E, and TP53Q199X; whereas for PIK3CA, the IS mutations were PIK3CAL156V, PIK3CAM610K, and PIK3CAH1047R. Analysis from the ConSurf Web server revealed five SNVs with a highly conserved status (conservation score 9) across TP53 and PTEN. TP53P33R was found predominant in the grade 3 tumors, whereas PTENp.C65S was distributed on ER+, ER-, PR+, PR-, Her2+, and Her2- patients. TP53p.P33R mutation was found to be recurring in the 14/19 (73.6%) patients and, therefore, can be considered as a potential biomarker. Finally, these mutations were studied in the context of their potential association with different hormonal and social factors.

Antiproliferative Activity of Lignans from Olea ferruginea: In Vitro Evidence Supported by Docking Studies.

BACKGROUND: The aim of the current study was to investigate the anticancer potential of bioactive compounds isolated from the leaves of Olea ferruginea (O. ferruginea). Lignans from O. ferruginea were previously described to possess antibacterial, antileishmanial, and antioxidant properties. Nevertheless, the antiproliferative activity of cycloolivil (1), ferruginan (2), and ferruginan A (3) have not been investigated in depth. METHODS: The compounds were isolated from the ethyl acetate fraction of the leaves extract of O. ferruginea. The isolated molecules were evaluated for their anticancer activity against U-87 MG malignant glioma cells. In parallel, molecular docking studies were also performed to investigate the interaction of the compounds with a duplex DNA sequence and epidermal growth factor receptor (EGFR). RESULTS: In vitro tests showed that all three compounds inhibit U-87 MG malignant glioma cell proliferation dose-dependently in the µM range, and ferruginan A (3) was highlighted as the most promising compound of the set. Molecular docking studies showed that the compounds could interfere with double stranded DNA possessing a cisplatin 1,2-d(GpG) intrastrand cross-link and EGFR. CONCLUSIONS: Overall, the findings suggest that the tested compounds from O. ferruginea may represent a starting point for the identification of novel tools to inhibit glioma cell proliferation.

Therapeutic Potential and Molecular Mechanisms of the Multitargeted Flavonoid Fisetin.

Flavonoids effectively treat cancer, inflammatory disorders (cardiovascular and nervous systems), and oxidative stress. Fisetin, derived from fruits and vegetables, suppresses cancer growth by altering cell cycle parameters that lead to cell death and angiogenesis without affecting healthy cells. Clinical trials are needed in humans to prove the effectiveness of this treatment for a wide range of cancers. According to the results of this study, fisetin can be used to prevent and treat a variety of cancers. Despite early detection and treatment advances, cancer is the leading cause of death worldwide. We must take proactive steps to reduce the risk of cancer. The natural flavonoid fisetin has pharmacological properties that suppress cancer growth. This review focuses on the potential drug use of fisetin, which has been extensively explored for its cancer-fighting ability and other pharmacological activities such as diabetes, COVID-19, obesity, allergy, neurological, and bone disorders. Researchers have focused on the molecular function of fisetin. In this review, we have highlighted the biological activities against chronic disorders, including cancer, metabolic illnesses, and degenerative illnesses, of the dietary components of fisetin.

Investigation of Newly Synthesized Bis-Acyl-Thiourea Derivatives of 4-Nitrobenzene-1,2-Diamine for Their DNA Binding, Urease Inhibition, and Anti-Brain-Tumor Activities.

Bis-acyl-thiourea derivatives, namely N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N'-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, 1H-NMR, and 13C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds' interactions with DNA. However, the values of binding constant (Kb), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (Do) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound-DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC50 value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40-120 µM.

Prevalence Of Human Adenovirus In Paediatric Patients Presenting With Acute Respiratory Symptoms At Different Hospitals Of Pakistan.

BACKGROUND: Human Adenovirus (HAdV) is one of the most common causes of infection in children. HAdV commonly affects respiratory system, however can also involve other parts of the body like nervous system, eyes and urinary tract. The virus usually causes a mild infection of the lower and upper respiratory tract. Objective of the study was to find the prevalence of HAdV in paediatric patients presenting with Influenza like symptoms and severe acute respiratory illness across Pakistan. METHODS: This cross-sectional study was conducted at the National Institute of Health, Islamabad. Respiratory swabs were collected from 389 children with age less than five years from 14 hospitals in different regions of Pakistan from October 1, 2017 to September 30, 2018. Patients' demographics, signs and symptoms were recorded through a predesigned proforma while Real-time polymerase chain reaction (RT-PCR) was performed for respiratory samples. RESULTS: Out of all 389 samples, HAdV was found in 25 (6.4%) cases. The proportion of HAdV obtained was greater in females 18 (4.6%) than male 7 (1.8%). The influenza-like illness in children attending outpatient department had a higher prevalence of HAdV 13 (3.3%) compared to admitted children 12 (3.1%). Similarly, patients from one to 6 months of age had higher positive outcome than older children. Majority of positive patients were from Islamabad (2.0%) followed by Gilgit (1.8%), Azad Jammu Kashmir (1.0%), Multan (0.5%), and Karachi (0.5%). The most frequent signs and symptoms were cough, fever, sore throat, nasal congestion and shortness of breath. CONCLUSIONS: The present study concludes that HAdV infection is common in Pakistan especially in female patients aged 1-6 months. It's crucial to improve the diagnosis of HAdV infections in our country to prevent complications associated with the virus. Furthermore, genetic analysis may help find different genotypes of HAdV circulating in Pakistan.

Effectiveness Of Pcr Pool Testing For Screening Of Covid-19 Infection In Pakistan.

BACKGROUND: We tested the utility of mini-pool PCR testing for the rational use of PCR consumables in screening for CoViD-19. METHODS: After pilot experiments, 3-samples pool size was selected. One step RT-PCR was performed. The samples in the mini-pool having COVID gene amplification were tested individually. RESULTS: 1548 samples tested in 516 mini-pools resulted 396 mini-pools as negative and 120 as positive. Upon individual testing, 110 samples tested positive and 9 were inconclusive. 876 PCR reactions were performed to test 1548 samples, saving 43% PCR reagents. Centres with low prevalence resulted in most saving on reagents (50%), while centres with high prevalence resulted in more test reactions. Testing of individual samples resulted in delays in reporting. CONCLUSIONS: Pooling can increase lab capacity, however, pooling delays results and cause degradation of samples.

Recent advances and limitations of mTOR inhibitors in the treatment of cancer.

The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

An Overview on Rumex dentatus L.: Its Functions as a Source of Nutrient and Health-Promoting Plant.

Rumex dentatus L. (Polygonaceae), also known as toothed dock or Aegean dock, is a medicinal plant with a high culinary value in addition to being used as an ethnomedicinal plant. This review focuses on the botanical, nutritional, phytochemical, and pharmacological activities of R. dentatus, as well as the future prospects for systematic investigations into these areas. R. dentatus has been subjected to scientific evaluation, which has confirmed its traditional uses and demonstrated a wide range of biological and pharmacological potentials, including antioxidant, anticancer, antifungal, antibacterial, anti-inflammatory, and other biological properties. Phytochemical analyses showed the presence of anthraquinones, chromones, flavonoids, and essential oils. As a result of this current review, the medicinal significance of R. dentatus has been confirmed, and future research on its unexplored aspects, such as the identification of pharmacologically active chemical constituents and related mechanisms and safety, may be stimulated, with the goal of developing it into a drug.

Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview.

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

Nanoparticles in clinical trials of COVID-19: An update.

Once the World Health Organization (WHO) declared the COVID-19 (Coronavirus Infectious Disease-19) outbreak to be pandemic, massive efforts have been launched by researchers around the globe to combat this emerging infectious disease. Strategies that must be investigated such as expanding testing capabilities, developing effective medicines, as well as developing safe and effective vaccines for COVID-19 disease that produce long-lasting immunity to human system. Now-a-days, bio-sensing, medication delivery, imaging, and antimicrobial treatment are just a few of the medical applications for nanoparticles (NPs). Since the early 1990s, nanoparticle drug delivery methods have been employed in clinical trials. Since then, the discipline of nanomedicine has evolved in tandem with expanding technological demands to better medicinal delivery. Newer generations of NPs have emerged in recent decades that are capable of performing additional delivery tasks, allowing for therapy via novel therapeutic modalities. Many of these next generation NPs and associated products have entered clinical trials and have been approved for diverse indications in the present clinical environment. For systemic applications, NPs or nanomedicine-based drug delivery systems have substantial benefits over their non-formulated and free drug counterparts. Nanoparticle systems, for example, are capable of delivering medicines and treating parts of the body that are inaccessible to existing delivery systems. As a result, NPs medication delivery is one of the most studied preclinical and clinical systems. NPs-based vaccines delivering SARS-CoV-2 antigens will play an increasingly important role in prolonging or improving COVID-19 vaccination outcomes. This review provides insights about employing NPs-based drug delivery systems for the treatment of COVID-19 to increase the bioavailability of current drugs, reducing their toxicity, and to increase their efficiency. This article also exhibits their capability and efficacy, and highlighting the future aspects and challenges on nanoparticle products in clinical trials of COVID-19.

Synthesis, characterization, antioxidant, antileishmanial, anticancer, DNA and theoretical SARS-CoV-2 interaction studies of copper(II) carboxylate complexes.

Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.

COVID-19 Infection in Pregnancy: A Review.

Coronavirus disease 2019 (COVID-19), which is a highly contagious viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a catastrophic effect on the world's demographics, resulting in more than 3.8 million deaths worldwide and establishing itself as the most serious global health crisis since the 1918 influenza pandemic. Several questions remain unanswered regarding the effects of COVID-19 disease during pregnancy. Although most infections are mild in high-risk populations, the severe disease frequently leads to intubation, intensive care unit admission, and, in some cases, death. Hormonal and physiological changes in the immune and respiratory systems, cardiovascular function, and coagulation may affect the progression of COVID-19 disease in pregnancy. However, the consequences of coronavirus infection on implantation, fetal growth and development, labor, and newborn health have yet to be determined, and, consequently, a coordinated global effort is needed in this respect. Principles of management concerning COVID-19 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and co-infection, fetal and uterine contraction monitoring, prevention, and / or treatment of thromboembolism early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. This review focuses on COVID-19 during pregnancy, its management, and the area where further investigations are needed to reduce the risk to mothers and their newborns.

Synthesis, anticancer evaluation and molecular docking studies of methotrexate's novel Schiff base derivatives against malignant glioma cell lines.

Recent years have witnessed advancement in cancer research that has led to the development of improved cytotoxic therapies with reduced side effects. Methotrexate (MTX) is a commonly used anticancer drug having robust activity, but with serious side effects. Several derivatives of MTX have been reported by modification at different sites to reduce its side effects and enhance efficacy. The current work describes the development of active MTX Schiff base derivatives by treating MTX with several aldehydes viz 2-chlorobenzaldehyde, 3-nitrobenzaldehyde, 5-chloro-2-hydroxybenz-aldehyde, 2-hydroxy-5-nitrobenzaldehyde, 2-thiocarboxyaldehyde, trans-2-pentenal and glutaraldehyde. Newly synthesized derivatives were evaluated for their anticancer potential against human malignant glioma U87 (MG-U87) cell lines at different concentrations of 200 µM, 100 µM, 50 µM, 25 µM, 12.5 µm, 6.25 µm and 0 µM. MTX derivatives with 2-Chlorobenzaldehyde (IC50 ∼100 µM), 2-Thiocarboxyaldehyde (IC50 <200 µM) and 2- Pentenal (IC50 ∼250 µM) showed much better activity at 100 µM compared to 400 µM concentration of MTX. Molecular docking studies were performed that showed a good correlation with the results obtained from in vitro experiments. The excellent agreement between molecular modeling and growth inhibition assay shows that the binding mode hypothesis is justly close to the experimentally biological values, therefore, may prove helpful for further lead optimization and clinical trials.Communicated by Ramaswamy H. Sarma.