Molecular interactions of cucurbitacins A and B with anaplastic lymphoma kinase for lung cancer treatment.

Lung cancer is a major global public health issue and the leading cause of cancer-related deaths. Several medications are commonly used to treat lung cancer, either alone or in combination with other treatments. The anaplastic lymphoma kinase (ALK) protein is one of several target proteins that are thought to be potential therapeutic targets in the context of lung cancer. Several ALK inhibitors have been identified, but many of these have been associated with side effects and toxicity concerns. In this study, we intend to computationally predict the binding potential of cucurbitacins (CBNs), A and B to the active pockets of ALK, in order to estimate their potential ALK inhibitors. Compared to CBN-A, which has a binding energy of -7.9 kcal/mol, CBN B exhibits significantly better binding efficacy with a binding energy of -8.1 kcal/mol. This is closely comparable to the binding energy of Crizotinib, which is -8.2 kcal/mol. The results of the molecular dynamics simulation indicated that the docked complexes remained stable for the duration of the 100 ns simulation period. CBN inhibited the proliferation of both non-small cell lung cancer cell lines, H1299 and A549, in a dose-dependent manner. CBN-B inhibited the proliferation of lung cancer cells, showing IC50 values of 0.08 µM for H1299 cells and 0.10 µM for A549 cells. The computational analyses provide strong evidence that CBN-B has the potential to act as a potent natural inhibitor against ALK, and could prove to be a valuable treatment option for lung cancer.Communicated by Ramaswamy H. Sarma.

Targeting Wnt/ß-Catenin Pathway by Flavonoids: Implication for Cancer Therapeutics.

The Wnt pathway has been recognized for its crucial role in human development and homeostasis, but its dysregulation has also been linked to several disorders, including cancer. Wnt signaling is crucial for the development and metastasis of several kinds of cancer. Moreover, members of the Wnt pathway have been proven to be effective biomarkers and promising cancer therapeutic targets. Abnormal stimulation of the Wnt signaling pathway has been linked to the initiation and advancement of cancer in both clinical research and in vitro investigations. A reduction in cancer incidence rate and an improvement in survival may result from targeting the Wnt/ß-catenin pathway. As a result, blocking this pathway has been the focus of cancer research, and several candidates that can be targeted are currently being developed. Flavonoids derived from plants exhibit growth inhibitory, apoptotic, anti-angiogenic, and anti-migratory effects against various malignancies. Moreover, flavonoids influence different signaling pathways, including Wnt, to exert their anticancer effects. In this review, we comprehensively evaluate the influence of flavonoids on cancer development and metastasis by focusing on the Wnt/ß-catenin signaling pathway, and we provide evidence of their impact on a number of molecular targets. Overall, this review will enhance our understanding of these natural products as Wnt pathway modulators.

Updates on the anticancer potential of garlic organosulfur compounds and their nanoformulations: Plant therapeutics in cancer management.

Garlic (Allium sativum L.) possesses numerous pharmacological potential, including antibacterial, antiarthritic, antithrombotic, anticancer, hypoglycemic, and hypolipidemic effects. The anti-cancer action of garlic is likely the best researched of the many advantageous pharmacological effects, and its use offers significant protection against the risk of developing cancer. A few active metabolites of garlic have been reported to be essential in the destruction of malignant cells due to their multi-targeted activities and lack of significant toxicity. The bioactive compounds in garlic having anticancer properties include diallyl trisulfide, allicin, allyl mercaptan diallyl disulfide, and diallyl sulphide. Different garlic-derived constituents and their nanoformulations have been tested for their effects against various cancers including skin, ovarian, prostate, gastric, breast, and lung, colorectal, liver, oral, and pancreatic cancer. The objective of this review is to summarize the antitumor activity and associated mechanisms of the organosulfur compounds of garlic in breast carcinoma. Breast cancer continues to have a significant impact on the total number of cancer deaths worldwide. Global measures are required to reduce its growing burden, particularly in developing nations where incidence is increasing quickly and fatality rates are still high. It has been demonstrated that garlic extract, its bioactive compounds, and their use in nanoformulations can prevent breast cancer in all of its stages, including initiation, promotion, and progression. Additionally, these bioactive compounds affect cell signaling for cell cycle arrest and survival along with lipid peroxidation, nitric oxide synthase activity, epidermal growth factor receptor, nuclear factor kappa B (NF-κB), and protein kinase C in breast carcinoma. Hence, this review deciphers the anticancer potential of garlic components and its nanoformulations against several breast cancer thereby projecting it as a potent drug candidate for efficient breast cancer management.

Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations.

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

Prospects of microbial-engineering for the production of graphene and its derivatives: Application to design nanosystms for cancer theranostics.

Cancer is known as one of the leading causes of morbidity and fatality, currently faced by our society. The prevalence of cancer related dieses is rapidly increasing around the world. To reduce the mortality rates, early diagnosis and subsequent treatment of cancer in timely manner is quite essential. Advancements have been made to achieve effective theranostics strategies to tackle cancerous dieses, yet very challenging to overcome this issue. Recently, advances made in the field of nanotechnology have shown tremendous potential for cancer theranostics. Different types of nanomaterials have been successfully employed to develop sophisticated diagnosis and therapy techniques. In this context, graphene and its derivatives e.g. graphene oxide (GO) and reduced graphene oxide (RGO) have been investigated as promising candidates to design graphene-based nanosystems for the diagnosis and therapeutic purpose. Further, to synthesize graphene and its derivatives different types of physicochemical methods are being adopted. However, each method has its own advantage and disadvantages. In this reference, among diverse biological methods, microbial technique can be one of the most promising and eco-friendly approach for the preparation of graphene and its derivatives, particularly GO and RGO. In this review, we summarize studies performed on the preparation of graphene and its derivatives following microbial routes meanwhile focus has been made on the preparation method and the possible mechanism involved therein. Thereafter, we have discussed applications of graphene and its derivatives to developed advanced nanosystem that can be imperative for the cancer theranostics. Results of recent studies exploring applications graphene based nanosystem for the preparation of different types of biosensors for early diagnosis; advanced therapeutic approaches by designing drug delivery nanosystems along with multifunctionality (e.g cancer imaging, drug delivery, photodynamic and photo thermal therapy) in cancer theranostics have been discussed. Particularly, emphasis has been given on the preparation techniques of graphene based nanosystems, being employed in designing of biosensing platforms, drug delivery and multifunctional nanosystems. Moreover, issues have been discussed on the preparation of graphene and its derivatives following microbial technique and the implementation of graphene based nanosystems in cancer theranostics.

Computational hunting of natural active compounds as an alternative for Remdesivir to target RNA-dependent polymerase.

The hunt for potential lead/drug molecules from different resources, especially from natural resources, for possible treatment of COVID-19 is ongoing. Several compounds have already been identified, but only a few are good enough to show potential against the virus. Among the identified druggable target proteins of SARS-CoV-2, this study focuses on non-structural RNA-dependent RNA polymerase protein (RdRp), a well-known enzyme for both viral genome replication and viral mRNA synthesis, and is therefore considered to be the primary target. In this study, the virtual screening followed by an in-depth docking study of the Compounds Library found that natural compound Cyclocurcumin and Silybin B have strong interaction with RdRp and much better than the remdesivir with free binding energy and inhibition constant value as êzŒ-6.29 kcal/mol and 58.39 µMêzŒ, and êzŒ-7.93kcal/mol and 45.3 µMêzŒ, respectively. The finding indicated that the selected hits (Cyclocurcumin and Silybin B) could act as non-nucleotide anti-polymerase agents, and can be further optimized as a potential inhibitor of RdRp by benchwork experiments.

COVID-19 in Pediatric Granulomatosis with Polyangiitis.

The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.

Occurrence of Second Primary Malignancies in Patients With Primary Optic Nerve Gliomas: A Surveillance, Epidemiology, and End Results Analysis.

Background/Aim: Advanced understanding of screening and therapeutic modalities acts as provision for increased survival in patients diagnosed with optic nerve gliomas. Secondary primary malignancies (SPMs) in patients diagnosed with primary optic nerve glioma (OPG) are currently an uncharacterized frontier. This US national database analysis highlights the incidences of SPMs in patients diagnosed with primary OPG. Materials and Methods: Standardized incidence ratios (SIR) and excess absolute risk (EAR) for SPMs were calculated using the SEER-specific multiple outcome analysis. 95% SIR confidence intervals were calculated with statistical significance achieved at p<0.05. Results: SPMs originating from soft tissues (including the heart) (SIR=33.23, CI=6.85-97.11; EAR=5.07), breast (SIR=4.99, CI=1.36-12.77; EAR=5.57), female breast (SIR=5.03, CI=1.37-12.89; EAR=5.58), brain (SIR=105.38, CI=65.23-161.08; EAR=36.23), cranial nerves (SIR=103.29, CI=12.51-373.12; EAR=3.45), non-lymphocytic leukemia (SIR=15.05, CI=1.82-54.37; EAR=3.25), myeloid and monocytic leukemia (SIR=16.26, CI=1.97-58.75; EAR=3.27), and Kaposi's sarcoma (SIR=79.88, CI=2.02-445.08; EAR=1.72) demonstrated significantly increased SIR. Overall, the values for cumulative SPM (SIR=6.04, CI=4.33-8.19; EAR=59.60) highlight the overall significance in incidence of SPM in patients diagnosed with OPG. Conclusion: Clinical decision-making should reconcile enhanced propensities for development of SPM.

Human Papillomavirus Induced Cervical and Oropharyngeal Cancers: From Mechanisms to Potential Immuno-therapeutic Strategies.

The human papillomavirus (HPV) associated infections are the hallmark of cervical and neck cancer. Almost all the cases of cervical cancer (CC) and 70% of oropharyngeal cancer (OC) are, more or less, caused by the persistent infection of HPV. CC is the fourth most common cancer globally, and is commenced by the persistent infection with human papillomaviruses (HPVs), predominantly HPV types; 16 and 18. In the light of the above facts, there is an immediate requirement to develop novel preventive and innovative therapeutic strategies that may help in lower occurrences of HPV mediated cancers. Currently, only radiation and chemical-based therapies are the treatment for HPV mediated neck cancer (NC) and CC. Recent advances in the field of immunotherapy are underway, which are expected to unravel the optimal treatment strategies for the growing HPV mediated cancers. In this review, we decipher the mechanism of pathogenesis with current immunotherapeutic advances in regressing the NC and CC, with an emphasis on immune-therapeutic strategies being tested in clinical trials and predominantly focus on defining the efficacy and limitations. Taken together, these immunological advances have enhanced the effectiveness of immunotherapy and promises better treatment results in coming future.

The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all childhood leukemias. Some prognostic factors determine the outcome of therapy [e.g. age, sex, initial white blood cell count (WBC), etc.]; however, it is believed that other mechanisms such as glutathione S-transferase (GST) gene mutation, the expression of lung resistance protein (LRP), and multidrug resistance-associated protein (MRP) also plays a role in treatment failure. In this study, GST gene mutations including GSTM1 and GSTT1 were evaluated in patients with leukemia. Thirty newly diagnosed ALL patients younger than 15 years of age participated in the present study. Bone marrow aspiration and biopsy were evaluated for immune phenotyping and DNA was extracted for GST genotyping. All data plus sex, age, initial WBC count, central nervous system (CNS) or testicular involvement, immune phenotype, and outcome (relapse or not) were analyzed statistically. Genotyping showed that 46% were double null, 50% were M1 null and 93.3% were T1 null for GST mutations. There was no statistically significant relationship between GSTT1 and GSTM1 mutations, or between double null status, prognostic factors and relapse (P > .05). So, although the results of GST mutations were consistent, it seems that these mutations are not statistically significant.

Natural products modulate Shigella-host-cell interaction.

This study focused on identifying possible new options derived from natural sources for the treatment of bacterial infections. Several natural products were investigated for their potential in modulating Shigella-host-cell interactions. The proliferation of Shigella sonnei was effectively inhibited inside HEp-2 cells in the presence of 4-methoxycinnamic acid and propolin D. Propolin D also significantly reduced the apoptosis of infected macrophage-like U937 cells and moderately reduced the secretion of interleukin (IL)-1ß and IL-18, which probably resulted from the inhibition of invasion plasmid antigen B secretion by this compound. Further characterization showed that propolin D did not prevent escape of Shigella from phagocytic vacuoles, as evidenced by actin-based motility and by the fact that addition of chloroquine did not further reduce the number of intracellular c.f.u. The role of propolin D in modulating autophagy could not be established under the experimental conditions used. As these compounds had no direct anti-Shigella activity in vitro, it was concluded that these compounds modulated Shigella-host-cell interactions by targeting yet-to-be defined mechanisms that provide benefits to host cells.

Interaction between Vibrio mimicus and Acanthamoeba castellanii.

Vibrio mimicus is a Gram-negative bacterium, which causes gastroenteritis and is closely related to Vibrio cholerae. The environmental reservoir of this bacterium is far from defined. Acanthamoeba as well as Vibrio species are found in diverse aquatic environments. The present study was aimed to investigate the ability of A. castellanii to host V. mimicus, the role of bacterial protease on interaction with A. castellanii and to disclose the ability of cysts to protect intracellular V. mimicus. Co-cultivation, viable counts, gentamicin assay, electron microscopy and statistical analysis showed that co-cultivation of wild type and luxO mutant of V. mimicus strains with A. castellanii did not inhibit growth of the amoeba. On the other hand co-cultivation enhanced growth and survival of V. mimicus strains. Vibrio mimicus showed intracellular behaviour because bacteria were found to be localized in the cytoplasm of amoeba trophozoites and remain viable for 14 days. The cysts protected intracellular V. mimicus from high level of gentamicin. The intracellular growth of V. mimicus in A. castellanii suggests a role of A. castellanii as a host for V. mimicus.

Acanthamoeba polyphaga is a possible host for Vibrio cholerae in aquatic environments.

Acanthamoeba is a genus of free-living amoebae found to be able to host many bacterial species living in the environment. Acanthamoebae and Vibrio cholerae are found in the aquatic environments of cholera endemic areas. Previously it has been shown that V. cholerae O1 and O139 can survive and grow in Acanthamoeba castellanii. The aim of this study was to examine the ability of Acanthamoeba polyphaga to host V. cholerae O1 and O139. The interaction between A. polyphaga and V. cholerae strains was studied by means of viable amoeba cell counts and viable count of the bacteria in the absence and presence of amoebae. The viable count of intracellularly growing bacteria was estimated by utilizing gentamicin assay. Electron microscopy was used to determine the localization of V. cholerae inside A. polyphaga. The results showed that A. polyphaga enhanced growth and survival of V. cholerae, which grew and survived inside the amoeba cells for 2weeks. The electron microscopy showed that A. polyphaga hosted intracellular V. cholerae localized in the vacuoles of amoeba cell. Neither the presence of V. cholerae together with A. polyphaga nor the intracellular localization of the bacteria inhibited growth and survival of A. polyphaga. The outcome of the interaction between these microorganisms may support strongly the role of A. polyphaga as host for V. cholerae O1 and O139.

Ante mortem diagnosis of amoebic encephalitis in a haematopoietic stem cell transplanted patient.

Acanthamoeba species are widely distributed free-living amoebae showing an increased role as human pathogens causing encephalitis, keratitis, pneumonitis and dermatitis. A haematopoietic stem cell transplanted (HSCT) patient developed purulent meningitis while awaiting regrafting. The meningitis was thought to be an endogenous infection arising from the mucous membranes primarily involving the cervicofacial regions, probably due to haematogenous spread facilitated by surgery. We diagnosed a fatal case of granulomatous amoebic encephalitis caused by Acanthamoeba castellanii by direct microscopy of a cerebrospinal fluid sample (CSF), Acanthamoeba cultivation, Giemsa staining, polymerase chain reaction and sequencing.

Vibrio cholerae O1 strains are facultative intracellular bacteria, able to survive and multiply symbiotically inside the aquatic free-living amoeba Acanthamoeba castellanii.

Vibrio cholerae species are extracellular, waterborne, gram-negative bacteria that are overwhelmed by predators in aquatic environments. The unencapsulated serogroup V. cholerae O1 and encapsulated V. cholerae O139 cause epidemic and pandemic outbreaks of cholera. It has recently been shown that the aquatic and free-living amoeba Acanthamoeba castellanii is not a predator to V. cholerae O139; rather, V. cholerae O139 has shown an intracellular compatibility with this host. The aim of this study was to examine the ability of V. cholerae O1 classical and El Tor strains to grow and survive in A. castellanii. The interaction between A. castellanii and V. cholerae O1 strains was studied by means of amoeba cell counts and viable counts of the bacteria in the absence or presence of amoebae. The viable count of intracellularly growing bacteria was estimated by utilizing gentamicin assay. Confocal microscopy and electron microscopy were used to determine the intracellular localization of V. cholerae in A. castellanii. The results showed that V. cholerae O1 classical and El Tor strains grew and survived intracellularly in the cytoplasm of trophozoites, and that the bacteria were also found in the cysts of A. castellanii. The interaction showed a facultative intracellular behaviour of V. cholerae O1 classical and El Tor strains and a possible role of A. castellanii as an environmental host of V. cholerae species.