Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.

BACKGROUND: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited. METHODS: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed. RESULTS: In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo. CONCLUSIONS: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Phenotypic variability to medication management: an update on fragile X syndrome.

This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Peri-levator Betamethasone Versus Triamcinolone Injection in Management of Thyroid Eye Disease-related Upper Eyelid Retraction Without Proptosis.

PURPOSE: To compare the efficacy of peri-levator injection of both betamethasone and triamcinolone in the management of thyroid eye disease-related upper eyelid retraction without proptosis. METHODS: This prospective, double-blind, randomized clinical trial was conducted at Assiut University Hospital, Upper Egypt in the period between December 2021 and October 2023. The study included 47 patients (56 eyes) and was divided into 2 groups. In group A, 1 ml betamethasone was injected into the peri-levator area, while in group B, 1 ml triamcinolone was injected. The injection was repeated every month for up to 5 injections if there was an improvement in margin reflex distance 1 (MRD1). The injection was stopped if MRD1 reached the normal value or if 2 successive injections caused no improvement in MRD1. The postinjection outcome was divided into: 1) effective if MRD1 reached the normal ≤4.5 mm; 2) partially effective if MRD1 was improved but did not reach the normal; and 3) ineffective if there was no improvement in MRD1. The follow up ranged from 6 to 20 months. RESULTS: In group A, the injection was effective in 26 eyes (92.9%) and partially effective in 2 eyes (7.1%). In group B, the injection was effective in 17 eyes (60.7%), partially effective in 6 eyes (21.4%), and ineffective in 5 eyes (17.9%). The mean number of injections was significantly lower in group A than in group B: 1.61 ± 0.50 versus 2.36 ± 1.16. CONCLUSIONS: This study results suggest that betamethasone is more effective with a smaller number of injections than triamcinolone in the management of thyroid eye disease-related upper eyelid retraction.

Efficacy of Buzzy Device Versus EMLA Cream for Reducing Pain During Needle-Related Procedures in Children: A Randomized Controlled Trial.

OBJECTIVES: Several pain management tools exist but with limitations in their efficacy or applicability. The EMLA (eutectic mixture of local anesthetics) cream is currently used for pain relief for needle-related procedures; however, it needs a minimum of 30 to 45 minutes to be effective. The Buzzy is a device that generates vibrations with cold leading to quicker pain relief. Our aim was to evaluate the effect of the Buzzy device in pain and anxiety reduction compared with EMLA cream in children requiring intravenous cannulation or venepuncture. METHODS: This was a randomized clinical trial comparing pain and anxiety reduction by Buzzy device with the standard care (EMLA cream) in children aged 2 to 14 years who required blood extraction or intravenous cannulation based on their clinical needs. Eligible patients were randomized to either Buzzy device as the intervention or EMLA cream as the control. The outcome measures were the degree of pain scores and anxiety ratings at different stages of the needle-related procedures. RESULTS: A total of 300 patients with a mean age of 6.5 ± 3.1 years were enrolled. Baseline characteristics were similar between the Buzzy device and EMLA cream groups. The observed pain scores by research nurses and a parent were significantly lower in the EMLA group compared with the Buzzy device group; however, the pain scores by the self-assessment scale were not statistically significant with mean difference of -0.332, 95% confidence interval, -0.635 to -0.028 ( P = 0.062). The level of anxiety was significantly lower in EMLA compared with Buzzy device ( P = 0. 0.0001). Both staff and parents' satisfaction, success rate of cannulation, type of blood tests, and comment on the physician on the results were similar in both groups. CONCLUSIONS: Pain and anxiety relief using the Buzzy device is not as effective as EMLA cream in children requiring venepuncture. However, rapid onset of action of the Buzzy device is valuable in decreasing waiting time in a busy emergency department. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT05354739.

Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives.

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

Biodegradation and antimicrobial capability-induced heavy metal resistance of the marine-derived actinomycetes Nocardia harenae JJB5 and Amycolatopsis marina JJB11.

Currently, heavy metal-resistant (HMR) marine actinomycetes have attracted much attention worldwide due to their unique capabilities. In this study, 27 marine-derived actinomycetes were isolated from coastal beaches in the Arabian Gulf of Al-Jubail in Saudi Arabia and screened for resistance to 100 mg/L of the heavy metals Cd2+, Cr6+, Cu2+, Fe2+, Pb2+, and Ni2+ using different assay techniques. Six isolates were selected as HMRs, of which two isolates, JJB5 and JJB11, exhibited the highest maximum tolerance concentrations (200- > 300 mg/L). Both isolates were the highest among six-HMR screened for their biodegradation potential of plastics low-density polyethylene, polystyrene, and polyvinyl chloride, recording the highest weight loss (15 ± 1.22 - 65 ± 1.2%) in their thin films. They also showed the highest biodegradability of the pesticides acetamiprid, chlordane, hexachlorocyclohexane, indoxacarb and lindane, indicating promising removal capacities (95.70-100%) for acetamiprid and indoxacarb using HPLC analysis. Additionally, the cell-free filtrate (CFF) of both isolates displayed the highest antimicrobial activity among the six-HMR screened against a variety of microbial test strains, recording the highest inhibition zone diameters (13.76 ± 0.66 - 26.0 ± 1.13 mm). GC‒MS analyses of the ethyl acetate extract of their CFFs revealed the presence of diverse chemical compounds with a multitude of remarkable biological activities. Based on their spore morphology and wall-chemotype, they were assigned to the nocardioform-actinomycetes. Furthermore, their phenotypic characteristics, together with 16S rRNA gene sequencing (OR121525-OR121526), revealed them as Nocardia harenae JJB5 and Amycolatopsis marina JJB11. Our results suggest that marine HMR actinomycetes are promising candidates for various biotechnological applications.

A simplified technique for correction of complete ptosis secondary to palpebral neurofibromatosis.

PURPOSE: To present a simplified technique in management of complete ptosis secondary to neurofibromatosis. METHODS: This prospective, non-comparative, clinical interventional study included 13 patients with complete ptosis secondary to histologically proved plexiform neurofibromas. It was conducted at the Orbital Unit of Assiut University Hospital, the referral center of Upper Egypt in the period between June 2013 and October 2021. In all cases, a simplified technique of 5 surgical steps was applied: (A) Division of the involved eyelid surgically into three parts by drawing 2 curvilinear lines, the superior line 11 mm below and parallel to the lower eyebrow hairline and the inferior one 10 mm above the lid margin, (B) Resection (full-thickness) of the large middle part which involves the main pathology and lies between the 2 lines, (C) Preservation of the upper part with identification, dissection and clamping of the levator muscle, (D) Refinement of the lower part by removal of any tissue between the skin and the debulked tarsus and (E) Re-suturing of the upper and lower parts in layers; conjunctiva to conjunctiva, levator to tarsus (after resection of a part that corrects the ptosis) and skin to skin. RESULTS: Ptosis was completely corrected in 8 cases (61.5%) and residual mild ptosis occurred in 5 patients (38.5%). No exposure keratopathy or tumor growth was reported during the follow-up period of minimum 1 year. CONCLUSIONS: This simplified technique could be considered as a surgical basis for correction of complete ptosis in neurofibromatosis.

Chromoionophoric probe-anchored mesoporous silica nanospheres for rapid and reliable naked-eye detection of Ni(II) ions in petroleum products and removal from electroplating wastewater.

This paper presents the expansion of an optical, chemical sensor that can rapidly and reliably detect, quantify, and remove Ni(II) ions in oil products and electroplating wastewater sources. The sensor is based on mesoporous silica nanospheres (MSNs) that have an extraordinary surface area, uniform surface morphology, and capacious porosity, making them an excellent substrate for the anchoring of the chromoionophoic probe,3'-{(1E,1' E)-[(4-chloro-1,2 phenylene)bis (azaneylylidene)]-bis(methaneylylidene)}bis(2-hydroxybenzoic acid) (CPAMHP). The CPAMHP probe is highly selective and sensitive to Ni(II), enabling it to be used in naked-eye colorimetric recognition of Ni(II) ions. The MSNs provide several accessible exhibited sites for uniform anchoring of CPAMHP probe molecules, making it a viable chemical sensor even with the use of naked-eye sensing. The surface characters and structural analysis of the MSNs and CPAMHP sensor samples were examined using various techniques. The CPAMHP probe-anchored MSNs exhibit a clear and vivid color shift from pale yellow to green upon exposure to various concentrations of Ni(II) ions, with a reaction time down to approximately 1 minute. Furthermore, the MSNs can serve as a base to retrieve extremely trace amounts of Ni(II) ions, making the CPAMHP sensor a dual-functional device. The calculated limit of recognition for Ni(II) ions using the fabricated CPAMHP sensor samples is 0.318 ppb (5.43 × 10-9 M). The results suggest that the proposed sensor is a promising tool for the sensitive and reliable detection of Ni(II) ions in petroleum products and for removing Ni(II) ions in electroplating wastewater; the data indicate an excellent removal of Ni (II) up to 96.8%, highlighting the high accuracy and precision of our CPAMHP sensor.

Genetic etiology and clinical challenges of phenylketonuria.

This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 µmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, immunity, angiogenesis, vascular permeability, and lymphocyte trafficking through G-protein coupled S1P receptors. Reduction of the circulating S1P level correlates with COVID-19 severity. S1P binding to sphingosine-1-phosphate receptor 1 (S1PR1) elicits endothelial protection and anti-inflammatory effects during SARS-CoV-2 infection, by limiting excessive INF-α response and hindering mitogen-activated protein kinase and nuclear factor kappa B action. However, binding to S1PR2 opposes the effect of S1PR1 with vascular inflammation, endothelial permeability, and dysfunction as the concomitant outcome. This binding also promotes nod-like receptor pyrin 3 (NLRP3) inflammasome activation, causing liver inflammation and fibrogenesis. Thus, higher expression of macrophage S1PR2 contributes to the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines. In conclusion, S1PR1 agonists and S1PR2 antagonists might effectively manage COVID-19 and its severe effects. Further studies are recommended to elucidate the potential conflict in the effects of S1P in COVID-19.

Tolvaptan treatment is associated with altered mineral metabolism parameters and increased bone mineral density in ADPKD patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a unique bone and mineral phenotype. The impact of tolvaptan treatment on mineral metabolism and bone mineral density (BMD) is unknown. METHODS: We conducted an analysis in the Bern ADPKD Registry, a prospective observational cohort study. Mineral metabolism parameters were measured at baseline and every 12 months thereafter. BMD was determined by dual-energy X-ray absorptiometry at baseline and after 3 years. Multivariable mixed-effects regression models were applied to assess changes in mineral metabolism parameters and BMD associated with tolvaptan treatment. RESULTS: A total of 189 participants (122 without and 67 with subsequent tolvaptan treatment) were included in the analysis. During follow-up, tolvaptan treatment was associated with increased BMD at the femoral neck {ß = 0.092 [95% confidence interval (CI) 0.001-0.183], P = .047}. In addition, tolvaptan treatment was associated with higher plasma magnesium [ß = 0.019 (95% CI 0.001-0.037), P = .037], bicarbonate [ß = 0.972 (95% CI 0.242-1.702), P = .009] and urine pH [ß = 0.214 (95% CI 0.056-0.372), P = .008] and lower parathyroid hormone [ß = -0.191 (95% CI -0.328 to -0.053), P = .006], 1,25(OH)D3 [ß = -0.126 (95% CI -0.235 to -0.164), P = .024] and fractional urinary magnesium excretion [ß = -0.473 (95% CI -0.622 to -0.324), P < .001]. CONCLUSIONS: Chronic tolvaptan treatment is associated with increased femoral BMD and significant changes in both mineral metabolism and acid-base parameters in ADPKD patients.

Unlocking Endocrown Restoration Expertise Among Dentists: Insights from a Multi-Center Cross-Sectional Study.

BACKGROUND This study, employing an online questionnaire, aimed to assess and contrast the awareness, knowledge, and perceptions of dentists in Saudi Arabia (SA) regarding endocrowns (EC) as post-endodontic restorations with those of dentists educated in various other countries. MATERIAL AND METHODS We conducted a cross-sectional survey among dental interns and practicing dentists in government facilities, private dental centers, and dental colleges in SA, including participants of diverse nationalities. We disseminated validated, closed-ended questionnaires through WhatsApp via Google Forms. The Chi-square test was applied to assess associations between categorical variables, with a P-value of ≤0.05 indicating statistical significance. RESULTS The majority of participants (61.2%) indicated that EC restorations are best suited for molar teeth. Furthermore, 69.6% asserted that the primary objective of employing EC is to accomplish minimally invasive preparations while preserving the existing tooth structure. Among the responses, 68.3% pinpointed debonding of ECs as a significant cause of failure. Notably, substantial differences were observed in responses concerning the knowledge or practice of EC across various factors such as gender, educational attainment, country of graduation, and workplace. CONCLUSIONS The findings reveal a comparatively low adoption of ECs among the participants, irrespective of experience or country of education. This underscores the need for incorporating ECs into dental curricula through theoretical and clinical discussions or considering them as a subject for post-graduate continuing education programs.

Preparation of green colorimetric pH sensor using Humulus lupulus L. (common hop) biomolecular extract for sweat monitoring.

Novel smart cotton diagnostic assay was developed toward onsite sensing of sweat pH variations for possible medical applications such as drug test and healthcare purposes. Humulus lupulus L. extract was obtained according to previously reported procedure. As reported by high-performance liquid chromatography (HPLC), the extract demonstrated the presence of hop acids, prenylchalcones, and prenylflavanones, which is responsible for the colorimetric changes. The extract was applied to cellulose fibers employing potassium aluminum sulfate as mordant. This was observed by the formation of mordant/xanthohumol nanoparticles onto cotton surface. The absorption spectra and CIE (Commission Internationale de l'Eclairage) Lab screening of the prepared cotton assay showed colorimetric changes in association with hypsochromic shift from 600 nm to 433 nm upon exposure to sweat simulant fluid (pH < 7). The biochromic activity of the xanthohumol-finished cotton depends mainly on the halochromic performance of the xanthohumol chromophore to show a colorimetric switch from yellow to white owing to intramolecular charge transfer in the xanthohumol molecule. No substantial defects were detected in gas-permeability and stiffness of the treated fabrics. Satisfactory fastness was approved for the xanthohumol-dyed diagnostic cotton assay.

In Vivo Wound-Healing Effect of Chemical and Green Synthesized Chitosan Nanoparticles Using Lawsonia inermis Ethanolic Extract.

Wounds can be a result of surgery, an accident, or other factors. There is still a challenge to find effective topical wound-healing agents. This study aims to investigate the wound-healing activity of chemical and green synthesized chitosan nanoparticles (Ch-NPs) using Lawsonia inermis leaves extract. The nanoparticles were morphologically and chemically characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and high-resolution transmission electron microscopy (HRTEM). Forty-five adult female albino rats were randomly divided into three groups. The cutaneous surgical wounds were topically treated with 0.9% normal saline (control group), green Ch-NPs (second group), and chemical Ch-NPs gels (third group), respectively. The clinical picture of wounds and histopathological changes were assessed on the 3rd, 7th, 14th, and 21st days post-treatment. X-ray diffraction analysis revealed great crystallinity and purity of nanoparticles. The studied nanoparticles increased the wound contraction percent (WC%), reduced healing time and wound surface area (WSA), and these results were backed up by histological findings that indicated improved epithelialization, dermal differentiation, collagen deposition, and angiogenesis in treated rats compared with control rats (p < 0.05). We concluded that the wound-healing effects of the studied nanoparticles are encouraging, and further studies for complete assessment are still needed.

Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors.

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1-6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19.

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Mitigation of Hepatotoxicity via Boosting Antioxidants and Reducing Oxidative Stress and Inflammation in Carbendazim-Treated Rats Using Adiantum Capillus-Veneris L. Extract.

Exposure to food contaminants continues to be a substantial source of human health risks all over the world, particularly in developing countries. Carbendazim (CBZ) is a chemical fungicide used to control the spread of various fungi and other pathogens in the agriculture and veterinary sectors. The hazardous effects of CBZ on human health occur due to the accumulation of its residues in agricultural food products. In this study, the possible hepatoprotective effects of Adiantum capillus-veneris L. (ACVL) extract were evaluated in CBZ-treated rats. A GC-MS analysis revealed that ACVL extract contained several bioactive hydrocarbon components and fatty acids, and that the components exerted hepatic protection by mitigating oxidative stress via upregulating antioxidant agents and neutralizing nitrogen and oxygen free radicals. Moreover, ACVL extracts relieved hepatic inflammation via decreasing NO, NF-κB, and pro-inflammatory cytokines (TNF-a, IL-6) in the liver of CBZ-treated rats, both at protein and mRNA levels. In addition, the protective effect of ACVL has appeared in the histopathological figures and function markers in the livers of CBZ-treated rats. According to the present results, ACVL extract can protect the hepatic tissue and restore its functions to a control level in CBZ-treated rats; this effect may be attributed to its antioxidant and anti-inflammatory activities.

Biogenic Preparation and Characterization of Silver Nanoparticles from Seed Kernel of Mangifera indica and Their Antibacterial Potential against Shigella spp.

Shigellosis is a serious foodborne diarrheal disease caused by the Shigella species. It is a critical global health issue. In developing countries, shigellosis causes most of the mortality in children below 5 years of age. Globally, around 165 million cases of diarrhea caused by Shigella are reported, which accounts for almost 1 million deaths, in which the majority are recorded in Third World nations. In this study, silver nanoparticles were synthesized using Mangifera indica kernel (MK-AgNPs) seed extracts. The biosynthesized M. indica silver nanoparticles (MK-AgNPs) were characterized using an array of spectroscopic and microscopic tools, such as UV-Vis, scanning electron microscopy, particle size analyzer, Fourier transform infrared spectroscopy, and X-ray diffractometer. The nanoparticles were spherical in shape and the average size was found to be 42.7 nm. The MK-AgNPs exhibited remarkable antibacterial activity against antibiotic-resistant clinical Shigella sp. The minimum inhibitory concentration (MIC) value of the MK-AgNPs was found to be 20 µg/mL against the multi-drug-resistant strain Shigella flexneri. The results clearly demonstrate that MK-AgNPs prepared using M. indica kernel seed extract exhibited significant bactericidal action against pathogenic Shigella species. The biosynthesized nanoparticles from mango kernel could possibly prove therapeutically useful and effective in combating the threat of shigellosis after careful investigation of its toxicity and in vivo efficacy.

Therapeutic Potential of Albumin Nanoparticles Encapsulated Visnagin in MDA-MB-468 Triple-Negative Breast Cancer Cells.

Breast cancer is among the most recurrent malignancies, and its prevalence is rising. With only a few treatment options available, there is an immediate need to search for better alternatives. In this regard, nanotechnology has been applied to develop potential chemotherapeutic techniques, particularly for cancer therapy. Specifically, albumin-based nanoparticles are a developing platform for the administration of diverse chemotherapy drugs owing to their biocompatibility and non-toxicity. Visnagin, a naturally derived furanochromone, treats cancers, epilepsy, angina, coughs, and inflammatory illnesses. In the current study, the synthesis and characterization of albumin visnagin (AV) nanoparticles (NPs) using a variety of techniques such as transmission electron microscopy, UV-visible, Fourier transform infrared, energy dispersive X-ray composition analysis, field emission scanning electron microscopy, photoluminescence, X-Ray diffraction, and dynamic light scattering analyses have been carried out. The MTT test, dual AO/EB, DCFH-DA, Annexin-V-FITC/PI, Propidium iodide staining techniques as well as analysis of apoptotic proteins, antioxidant enzymes, and PI3K/Akt/mTOR signaling analysis was performed to examine the NPs' efficacy to suppress MDA-MB-468 cell lines. The NPs decreased cell viability increased the amount of ROS in the cells, disrupted membrane integrity, decreased the level of antioxidant enzymes, induced cell cycle arrest, and activated the PI3K/Akt/mTOR signaling cascade, ultimately leading to cell death. Thus, AV NPs possesses huge potential to be employed as a strong anticancer therapy alternative.