Hydroxychloroquine (HCQ) exhibits better binding to the main protease (Mpro) compared to spike protein (S protein) of SARS-CoV-2: An in-silico analysis

Background: Despite various efforts in preventing and treating SARS-CoV-2 infections; transmission and mortality have been increasing at alarming rates globally. Since its first occurrence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV-2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns. Objective: The objective of this study is to identify the ability of HCQ for binding to the most widely studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main protease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ. Methods: X-ray crystallographic structures of spike glycoprotein and main protease of SARS-CoV-2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using C-Docker algorithm, and visualized using Discovery studio visualizer. Results: Data from molecular docking studies showed very strong binding of HCQ to the main protease compared to spike glycoprotein. Conclusion: The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.

Weight Gain and Loss In Cancer Patients Undergoing Chemotherapy: Importance of Dose Adjustment

Introduction: The established dose of chemotherapy is based on the values of the patient's body weight, where variations during treatment can increase the toxicity of chemotherapy, with the development of nephrotoxicity, among other toxicity profiles, as well as in cases of weight gain, patients may receive low doses and compromise the therapeutic response to the tumor. Objective: to evaluate weight gain and loss in cancer patients undergoing chemotherapy. Methods: Longitudinal analytical study with patients at the end of chemotherapy treatment of both genders. The type, location of the tumor and the antineoplastic agent used were collected from the medical records, as well as height and weight at the beginning of treatment. At the time of collection, anthropometric assessment was performed using body mass index, arm circumference, arm muscle circumference, triceps skinfold thickness and percentage of weight loss. Results: Among the patients included in the study, 47.5% had a weight gain of around 2.5 kg, while the remaining patients (52.5%) had a weight loss of around 2.8 kg. Of the patients who had GFR, 55.5% had severe PP, 33.4% had no significant loss and 11.1 had significant loss. In the current study, only 22% had a GFR <60ml/min/1.73m², but they would already need to readjust the medication calculation. Conclusion: It is important to evaluate body surface variations and also the GFR to adjust the dose of the antineoplastic agent and to prevent or minimize nephrotoxicity, as well as to reduce the risk of underdosing and inefficiency of the therapy.

Differential proliferative and cytotoxic effect of selected components of essential oils on human glioblastoma cells

Background: In the study of bioactive agents from traditional medicine, mono- and sesquiterpenes represent the main ingredients of essential oils. Till now, only thymoquinone and perillyl alcohol have been clinically tested on glioblastoma. Objective: In the present study, we examined the effect of ten different essential oils on three human glioblastoma cell lines and one healthy human cell line. Methods: We used confocal laser scanning microscopy, flow cytometry, and cell growth analysis to evaluate cell morphology changes, membrane disruption effects, acute cytotoxicity and effects on the proliferation rate caused by the essential oils pinene, geraniol, eucalyptol, perillaldehyde, limonene, and linalool, perillyl alcohol, myrcene, bisabolol and valencene on human cells. Caspase 3/7 activity was measured to observe apoptosis induced by the essential oils. Results: We found that the cytotoxicity concentrations varied not only between different essential oils but also among different cell lines. Acute cytotoxicity of essential oils was based on cell membrane disruption and that HEK cells were affected to a much higher degree than the Glioblastoma cells. Vacuoles found in surviving glioblastoma cells appeared to be a factor in this effect. Conclusion: Caspase activity did not correlate with the membrane damage observed in the flow cytometry experiments. This is especially evident in the HEK cells that only showed apoptosis with two out of ten essential oils.

Chemoresistance mechanisms in colon cancer: focus on conventional chemotherapy

Background: Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. Methods: In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. Results: The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. Conclusion: This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.

Inonotus obliquus aqueous extract suppresses carbon tetrachloride induced hepatic injury through modulation of antioxidant enzyme system and anti-inflammatory mechanism

Background: Chaga mushroom [Inonotus obliquus] is an edible macrofungus used in traditional and folk medicine for treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies including our anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-κB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The emergence of diverse inflammatory and carcinogenic agents like carbon tetrachloride [CCl4] is a potent hepatotoxic chemical that caused liver damage by inducing lipid peroxidation and other oxidative damages. Aims: The study was aimed to analyze the biochemical, cellular and molecular mechanism of CCl4 induced chronic liver inflammation and carcinoma and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms. Method: Physiological, histological and immunohistochemical the physiological functions and cellular functions. Biochemical assays for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for proposing the molecular interaction. Results: CCl4-exposed mice exhibited a significant decrease in the body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored towards normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level was increased to 447 IU/L in CCl4 treated mice as compared to control [236 IU/L]. Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control [52 μM], and induced the catalase enzyme activity to 259 U/mL as compared to control [124 U/L]. These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide suggests an inhibitory effect on these critical proinflammatory signaling proteins. Conclusions: The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanism which can be utilized in natural prevention of the liver toxicity.

Idarubicin and Ara-C treatment associated with fungal infection in acute leukemia patients with febrile neutropenia

Background: Acute leukemia with febrile neutropenia is at risk for infection. Fungal infection is a serious infection in this setting with a high mortality rate. There is limited data on clinical factors predictive of fungal infection in this setting. Objective: This study aimed to evaluate clinical predictive factors of fungal infection in acute leukemia patients with FN. Methods: This was a retrospective analytical study and included adult patients diagnosed with acute leukemia, who developed FN, and had positive culture on either bacterial or fungal infection. Predictors for fungal infection were calculated by using logistic regression analysis. A subgroup analysis in patients with acute myeloid leukemia (AML) was also performed. Results: There were 94 patients who met the study criteria. Of those, 29 patients had positive culture for fungus (30.82%): categorized as Aspergillus (19 patients; 65.51%) and Candida (10 patients; 34.49%). The mortality rate was significantly higher in the fungal infection group than the bacterial infection group (24.14% vs 6.15%; p 0.031). There were six factors in the final model predictive of fungal infection with one independent predictor: treatment regimen of Idarubicin plus Ara-C with an adjusted odds ratio of 5.188 (95% CI of 1.386, 19.419). A subgroup analysis for fungal infection in patients with AML showed that only the treatment regimen of Idarubicin plus Ara-C was a significant factor. Its adjusted odds ratio was 5.138 (95% CI of 1.156, 24.467). Conclusion: Treatment with idarubicin and Ara-C may increase the risk of fungal infection in acute leukemia patients with FN.

Efficacy of gefitinib in patients with advanced non-small cell carcinoma of the lung harboring common, uncommon and complex EGFR mutations

Background: As the commonest EGFR-TKI being used in Hong Kong, gefitinib has shown to be efficacious and safe as first line treatment for L858R mutation and exon 19 deletion with less gastrointestinal and cutaneous adverse events than erlotinib and afatinib. However, the evidence for therapeutic efficacy for uncommon and complex EGFR mutations is lacking. Whether gefitinib is efficacious for uncommon and complex EGFR mutations worth studying. Objectives: To assess the therapeutic efficacy of gefitinib, as measured by progression-free survival and overall survival, among advanced stage lung cancer patients with common, uncommon and complex EGFR mutations. Methods: This is a retrospective cohort study that included 241 Chinese patients with advanced non-small cell carcinoma of lung harboring EGFR mutations and received gefitinib 250 mg daily as first-line treatment. The progression-free survival [PFS] and overall survival [OS] for patients with different EGFR mutations, namely exon 19 deletion, L858R mutation in exon 21, uncommon EGFR mutations and complex EGFR mutations were analyzed. Results: Among the 241 patients, 118 [49%] had exon 19 deletion, 104 [43%] had L858R mutation in exon 21, 6 [2.5%] had uncommon EGFR mutations, 13 [5.4%] had complex EGFR mutations. The mean age was 69. 72% of the patients were female and with 81% being non-smoker. For patients with complex EGFR mutations, regardless of the presence of exon 19 deletion and L858R mutation as the component, have better PFS and OS than patients with single common EGFR mutations [Exon 19 deletion or L858R mutation]. Patients with uncommon EGFR mutations have inferior PFS and OS than those with common EGFR mutations. Conclusion: Gefitinib is a possible option for patients with complex EGFR mutations while it may not be the preferred treatment option in patients with single uncommon EGFR mutations.

Inhibition of ERN1 Signaling is Important for the Suppression of Tumor Growth

Background: Endoplasmic reticulum to nucleus signaling 1 (ERN1) is a major signaling pathway of endoplasmic reticulum stress and is crucial for malignant tumor growth Objective: The article aims to discuss the recent progress in the discovery of endoplasmic reticulum stress targets and their involvement in tumor growth. Methods: Literature from the PubMed database related to the endoplasmic reticulum stress involvement in the tumor growth and chemoresistance was searched and reviewed. Results: The endoplasmic reticulum stress plays an important part in malignant tumor growth and is involved in invasion and metastasis. Inhibition of protein kinase and endoribonuclease activities of the ERN1 signaling protein significantly reduces tumor growth through down-regulation of angiogenesis and cell proliferation but activates the invasion. ERN1 knockdown affects the expression of many genes associated with the regulation of apoptosis, cell proliferation and survival as well as reprograms the hypoxic regulation of most gene expressions. Simultaneously, inhibition of ERN1 endoribonuclease only has a stronger suppressive effect on tumor growth and decreases the invasiveness.. Conclusion: Present review summarizes the recent advances in the inhibition of ERN1 signaling that regulates tumor growth. Further understanding of the regulatory mechanisms of genome reprogramming upon inhibition of ERN1 signaling may help to discover new possibilities for developing novel effective therapeutics.

Diarylheptanoids: Potent Anticancer Agents

Diarylheptanoids are widely distributed among species belonging to the family Betulaceae. Being highly polar in nature, they can either be isolated from plants by using sophisticated chromatographic techniques or can be synthesized in the laboratory. They are found to exhibit a wide range of activities, from very simple analgesics to anticancer agents. Recently, they have gained considerable attention due to inhibitory activity against NF-κB activation, NO and TNF-α production, reduction in NO and COX-2 levels in a dose-dependent manner, and suppression of T-cell activation. The current review article highlights the role of diarylheptanoids as potent anticancer agents in a variety of cancers.