Exploring Natural Compounds Targeting the Bacterial SHV Protein to Combat Antibiotic Resistance: A Biocomputational Study

Background: Antibiotic-resistant (AR) bacteria are rapidly spreading worldwide, posing a serious threat to antibiotic efficacy. Bacterial infections have emerged as a persistent threat following decades of antibiotic use. Sulfhydryl variable (SHV) is a well-known bacterial enzyme linked to AR. SHV has a high degree of genetic diversity, resulting in the existence of numerous distinct variants. Methods: The PyRx AutoDock VINA was used to conduct in-silico screening of a natural compound library to assess their interaction with the SHV-1 protein. SwissADME web tools were used to predict the physicochemical, drug-likeness, and ADMET properties of the selected compounds.Result: The compounds PSCdb00708, PSCdb00149, PSCdb00698, and PSCdb00175 bind strongly to the SHV-1 protein and interact strongly with the SHV-1 active site residues, as well as having several amino acid residue interactions in common with avibactam. These compounds exhibited higher binding affinity values than avibactam. Furthermore, these compounds demonstrated no violation of drug-likeness.Conclusion: The compounds PSCdb00708, PSCdb00149, PSCdb00698, and PSCdb00175 can be employed as SHV-1 inhibitors in the management of AR. However, experimental validation is required to optimize them as SHV-1 inhibitors.Keywords: Antibiotic-resistant; Antibiotic; Virtual screening; AutoDock; SHV-1 protein

Identification of Novel Natural BACE1 Inhibitors for Alzheimer's Disease via In Silico Approach

Background: Alzheimer's disease (AD) is a neurological ailment that causes progressive memory loss as neurons die. Beta-secretase 1 (BACE1) is a key enzyme in the production of amyloid beta, which is a characteristic of Alzheimer's disease. Developing new BACE1 inhibitors with no cytotoxicity is a promising method to treat AD.Methods: The goal of this study was to find new BACE1 inhibitors by screening natural compounds in the ZINC database against the BACE1 active site. The compounds were screened against BACE1 using the PyRx 0.8 program. The SwissADME web server was used to determine the ADMET properties of hit compounds.Results: The hit compounds ZINC3875408, ZINC4098603, ZINC95561079, ZINC299817515, and ZINC67903362 exhibited higher binding affinities to BACE1 than the control compound AZD3293. The Asp32, Lys224, Tyr198, Thr329, Ile226, Val332, Arg128, Tyr71, Phe108, Lys107, Gly74, Gly13, Gly11, Gln12, Ile110, Trp115, Leu30, and Gly230 were the important binding residues of BACE1 protein with these compounds as well as the control compound. These compounds also have good drug-like qualities.Conclusion: The compounds ZINC3875408, ZINC4098603, ZINC95561079, ZINC299817515, and ZINC67903362 can be used as BACE1 inhibitors to manage AD. However, experimental validation is needed to optimize these compounds as BACE1 inhibitors.Keywords: Alzheimer's Disease; Amyloid Beta; Beta-Secretase 1; Natural Compound

An increased fraction of circulating miR-363 and miR-16 is particle bound in patients with chronic lymphocytic leukaemia as compared to normal subjects.

In vitro culture studies have shown that miR-363 is enriched in extracellular vesicles from chronic lymphocytic leukaemia cells. We wondered whether miR-363 was detectable in plasma, which is an essential precondition for further studies to assess its usefulness as a biomarker. Using samples from two clinical trials: one enrolling patients with advanced disease and the other asymptomatic patients with early stage disease, we determined plasma miR-363 levels and secondly investigated the distribution of this miRNA between plasma and particle bound fractions in patients and normal subjects.Advanced disease (n = 95) was associated with higher levels of miR-363 than early stage disease (n = 45) or normal subjects (n = 11) but there was no association with markers of prognosis. The distribution of specific miRNA between particle bound and plasma protein fractions was investigated using size exclusion chromatography on plasma from patients (n = 4) and normal subjects (n = 3). ~ 20% of total miR-16 and miR-363 is particle bound in patients while there was no detectable particle bound material in normal subjects. Our work demonstrates that miR-363 levels are raised in chronic lymphocytic leukaemia patients and raises the possibility that distribution of circulating miRNA between plasma fractions differs in health and disease

Surgical Dental Intervention For Implants, Responsibility Of Nursing, Pharmacist Radiology And Operation Room Technician: Review

Late dental implant issues include peri-implantitis, which is one of the most common dental implant complications. As a result of the fact that the disease is brought on by a bacterial infection, anti-infective peri-implantitis treatment options are necessary in order to halt the growing marginal bone loss and ensure that the damaged implant continues to function normally. Surgical therapies have frequently resulted in improved treatment outcomes, despite the fact that nonsurgical therapy options tend to have a limited degree of predictability. During the time that implant surgery has been utilized in clinical settings, numerous modifications of the surgical procedure that is used to install dental implants have been developed. Among these are variances in the timing of implant placement in relation to the removal of the tooth, as well as variations in the manner in which the bone site of the recipient is prepared. In addition, the members of the nursing staff, the pharmacist, the radiology technician, and the operation room technician work together to constitute an essential component of these processes

Retrieval of Cu2+ and Cd2+ ions from aqueous solutions using sustainable guar gum/PVA/montmorillonite nanocomposite films: effect of temperature and adsorption isotherms

Uncontrolled or improperly managed wastewater is considered toxic and dangerous to plants, animals, and people, as well as negatively impacting the ecosystem. In this research, the use of we aimed to prepare polymer nanocomposites (guar gum/polyvinyl alcohol, and nano-montmorillonite clay) for eliminating heavy metals from water-based systems, especially Cu2+ and Cd2+ ions. The synthesis of nanocomposites was done by the green method with different ratios of guar gum to PVA (50/50), (60/40), and (80/20) wt%, in addition to glycerol that acts as a cross-linker. Fourier-transform infrared spectroscopy (FT-IR) analysis of the prepared (guar gum/PVA/MMT) polymeric nano-composites’ structure and morphology revealed the presence of both guar gum and PVA’s functional groups in the polymeric network matrix. Transmission electron microscopy (TEM) analysis was also performed, which verified the creation of a nanocomposite. Furthermore, theromgravimetric analysis (TGA) demonstrated the biocomposites’ excellent thermal properties. For those metal ions, the extreme uptake was found at pH 6.0 in each instance. The Equilibrium uptake capacities of the three prepared nanocomposites were achieved within 240 min. The maximal capacities were found to be 95, 89 and 84 mg/g for Cu2+, and for Cd2+ were found to be 100, 91, 87 mg/g for guar gum (80/20, 60/40 and 50/50), respectively. The pseudo-2nd-order model with R2 > 0.98 was demonstrated to be followed by the adsorption reaction, according to the presented results. In less than 4 hours, the adsorption equilibrium was reached. Furthermore, a 1% EDTA solution could be used to revitalize the metal-ion-loaded nanocomposites for several cycles. The most promising nanocomposite with efficiency above 90% for the removal of Cu2+ and Cd2+ ions from wastewater was found to have a guar (80/20) weight percentage, according to the results obtained

Extracellular vesicles in chronic lymphocytic leukaemia: exploration of their miRNA cargo as biomarkers

The lymph node microenvironment provides essential signals for the proliferation and survival of chronic lymphocytic leukaemia (CLL) cells and contributes to resistance to chemotherapy. There is no readily available access to lymph node tissue and currently no markers of leukaemic cell activity specifically due to stimulation within lymph nodes. Extracellular vesicles (EVs) are produced by CLL cells and their cargo, which includes miRNA, mRNA and proteins, is important for intercellular signalling. Following CD40L/IL-4 stimulation EVs are enriched in miR-363-3p and miR-374b. These miRNA are only detectable at lower levels in plasma from normal subjects and in this thesis the idea that microRNAs might be predictive biomarkers reflecting leukaemic activity in the tumour microenvironment was investigated. To pursue the hypothesis that plasma levels of miR-363 might correlate with disease activity I established real-time PCR assays and showed that patients had higher miR-363 levels than normal subjects and confirmed this result in a repository study using samples from patients in the ARCTIC and CLEAR clinical trials. There were no associations between miR-363 levels and prognostic markers. Numbers of EVs, measured by dynamic light scattering are higher in CLL patients than normal subjects. To examine the source of circulating miRNA size exclusion chromatography was carried out followed by real-time PCR and showed that circulating miR-363 was derived from both plasma and particle bound fractions in healthy subjects but in patients a greater proportion was found in the particle fractions. Finally, I investigated the function of miR-363 in CLL. In contrast to T-cells miR-363 did not appear to have effects on the expression or function of CD69 in CLL B-cells. Overall, numbers of EVs and miR-363 levels associate with CLL but not with survival. An observation, which may have implications for identifying disease associated miRNA and can be followed up is that there appears to be a disease specific distribution of circulating miR-363 between plasma protein and particle bound fractions

Improvement of atopic dermatitis and alopecia universalis with dupilumab: a case report

Dupilumab is an interleukin (IL)-4 receptor alpha antagonist that showed significant improvement of atopic dermatitis (AD). Many reports have shown significant resolution of alopecia areata, alopecia universalis, and alopecia totalis after dupilumab treatment for AD. We present one of the few reported cases that showed improvement of underlying alopecia universalis treated with dupilumab.</jats:p

Effect of Combined Perftoran and Indocyanine Green-Photodynamic Therapy on HypoxamiRs and OncomiRs in Lung Cancer Cells

Indocyanine green (ICG) is a nontoxic registered photosensitizer used as a diagnostic tool and for photodynamic therapy (PDT). Hypoxia is one the main factors affecting PDT efficacy. Perfluorodecalin emulsion (Perftoran®) is a known oxygen carrier. This study investigated the effect of Perftoran® on ICG/PDT efficacy in presence and absence of Perftoran®via evaluation of phototoxicity by MTT; hypoxia estimation by pimonidazole, HIF-1α/β by ELISA, and 17 miRNAs (tumor suppressors, oncomiRs, and hypoxamiRs) were analyzed by qPCR. Compared to ICG/PDT, Perftoran®/ICG/PDT led to higher photocytotoxicity, inhibited pimonidazole hypoxia adducts, inhibited HIF-1α/β concentrations, induced the expression of tumor-suppressing miRNAs let-7b/d/f/g, and strongly inhibited the pro-hypoxia miRNA let-7i. Additionally, Perftoran®/ICG/PDT suppressed the expression of the oncomiRs miR-155, miR-30c, and miR-181a and the hypoxamiRs miR-210 and miR-21 compared to ICG/PDT. In conclusion, Perftoran® induced the phototoxicity of ICG/PDT and inhibited ICG/PDT-hypoxia via suppressing HIF-α/β, miR-210, miR-21, let-7i, miR-15a, miR-30c, and miR-181a and by inducing the expression of let-7d/f and miR-15b.</jats:p

Perftoran® Inhibits Hypoxia-Associated Resistance in Lung Cancer Cells to Carboplatin

Perftoran® (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran®, as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran® on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran®/carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC50 and inducing apoptosis. Perftoran® induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran® and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran® inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation.</jats:p