A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Critical attributes of fine excipient materials in carrier-based dry powder inhalation formulations: The particle shape and surface properties.

The potential of fine excipient materials to improve the aerodynamic performance of carrier-based dry powder inhalation (DPI) formulations is well acknowledged but not fully elucidated. To improve the understanding of this potential, we studied two fine excipient materials: micronized lactose particles and silica microspheres. Inhalation formulations, each composed of a coarse lactose carrier, one of the two fine excipient materials (0.0-15.0 % w/w), and a spray-dried drug (fluticasone propionate) material (1.5 % w/w) were prepared. The physical structure, the flow behavior, the aerosolization behavior, and the aerodynamic performance of the formulations were studied. The two fine excipient materials similarly occupied carrier surface macropores. However, only the micronized lactose particles formed agglomerates and appeared to increase the tensile strength of the formulations. At 2.5 % w/w, the two fine excipient materials similarly improved drug dispersibility, whereas at higher concentrations, the micronized lactose material was more beneficial than the silica microspheres. The findings suggest that fine excipient materials improve drug dispersibility from carrier-based DPI formulations at low concentrations by filling carrier surface macropores and at high concentrations by forming agglomerates and/or enforcing fluidization. The study emphasizes critical attributes of fine excipient materials in carrier-based DPI formulations.

Physician's Knowledge and Attitudes on Antibiotic Prescribing and Resistance: A Cross-Sectional Study from Hail Region of Saudi Arabia.

BACKGROUND: Antibiotic (AB) resistance is caused partly by overuse, varies by region, and is influenced by prescriber perspectives. This study sought to determine physicians' knowledge and attitudes toward AB prescribing, particularly in the Hail region of Saudi Arabia. METHODS: An interdisciplinary team created and validated an electronic questionnaire via the test-retest method that measured reliability and consistency. The 19 questions covered the following subjects: demographic information (7), experience with AB resistance in daily work (3), AB prescribing behavior (2), communication with patients regarding AB resistance (3), and prescribing practices (4). The revised questionnaire was prepared and distributed to physicians in the Hail region via multiple electronic communication channels. Inferences were drawn based on descriptive statistics and multivariate regression analysis. RESULTS: The questionnaire responses of 202 participants were eligible for analysis. A total of 70 (34.80%) participants were general practitioners, 78 (38.12%) were engaged in daily work that was only mildly related to AB resistance, and 25 (12.37%) performed work that was substantially related to AB resistance. A total of 88 (43.56%) physicians believed that prescribing behavior contributed to the emergence of AB resistance, whereas 68 (33.66%) did not. Regarding exposure, 51 (25.24%) physicians reported encountering instances of AB resistance monthly, whereas 104 (51.48%) reported seeing cases of AB resistance very rarely. In terms of prescribing practices, 99 (49.0%) physicians prescribed ABs to patients daily and 73 (36.13%) weekly. Regarding AB-resistance-related communication with patients, 73 (36.13%) physicians frequently discussed AB resistance with patients suffering from infections, whereas 13 (6.4%) never discussed it with patients. CONCLUSION: General practitioners in the Hail region exhibited comprehensive awareness of the elements that contribute to AB resistance but only rarely communicated about the issue with their patients, presuming the latter to be oblivious to the science behind AB resistance. Our findings suggest that the features underlying practitioners' AB prescribing behavior could be a powerful strategy for lowering AB resistance.

Artemisia sieberi Besser essential oil inhibits the growth and migration of breast cancer cells via induction of S-phase arrest, caspase-independent cell death and downregulation of ERK.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia sieberi Besser is a medicinal herb that has been traditionally used across the Middle East for the treatment of cancer. Further pharmacological studies on its extracts revealed that they possess cytotoxic activity against certain cancer cells, however, there were no studies conducted on the anticancer potential of Artemisia sieberi essential oil (ASEO). AIM OF THE STUDY: To evaluate the anticancer potential of ASEO, elucidate the oil's mode of action for the first time and investigate its chemical composition. MATERIALS AND METHODS: Artemisia sieberi was collected from Hail, Saudi Arabia, and its essential oil was obtained via hydrodistillation. The oil's activity against HCT116, HepG2, A549 and MCF-7 cells was assessed using SRB assay, while its anti-metastatic potential was assessed via a migration assay. Cell-cycle analysis and apoptosis assay were conducted via flow cytometry, while protein expression levels were investigated using Western blotting. The oil's chemical constituents were identified using GCMS. RESULTS: ASEO exerted its highest cytotoxic activity against MCF-7 with an IC50 value of 38.7 µg/ml. Further studies showed that the oil inhibited MCF-7 cells' migration, induced S-phase arrest and apoptosis. Western blot analysis showed no change in the expression level of caspase-3 after treatment, indicating the induction of caspase-independent apoptosis-like cell death in MCF-7. Treatment of MCF-7 with the oil resulted in downregulation of the protein expression levels of total ERK and its downstream target, LC3, indicating that any potential activation of the ERK signalling pathway during the cancer cells' growth would be inhibited. Finally, GCMS analysis identified the oil's major components as cis-crysanthenyl acetate (48.56%), davanone (10.28%), 1,8-cineole (6.81%) and caryophyllene diepoxide (5.34%), whereby it is suggested that these compounds might be responsible for the oil's bioactivity. CONCLUSION: ASEO possessed in vitro anticancer activity and modulated the ERK signalling pathway. This is the first study to explore the anticancer potential of ASEO in detail and reflects the significance of investigating essential oils from medicinal plants that have been traditionally used against cancer. This work might pave the way for further in vivo studies that could result in developing the oil into a natural effective anticancer treatment.

A comprehensive phytochemical, biological, and toxicological studies of roots and aerial parts of Crotalaria burhia Buch.-Ham: An important medicinal plant.

This study was designed to seek the phytochemical analysis, antioxidant, enzyme inhibition, and toxicity potentials of methanol and dichloromethane (DCM) extracts of aerial and root parts of Crotalaria burhia. Total bioactive content, high-performance liquid chromatography-photodiode array detector (HPLC-PDA) polyphenolic quantification, and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) analysis were utilized to evaluate the phytochemical composition. Antioxidant [including 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH)], 2,2'-azino-bis[3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power assay (FRAP), cupric reducing antioxidant capacity CUPRAC, phosphomolybdenum, and metal chelation assays] and enzyme inhibition [against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, α-amylase, and tyrosinase] assays were carried out for biological evaluation. The cytotoxicity was tested against MCF-7 and MDA-MB-231 breast cell lines. The root-methanol extract contained the highest levels of phenolics (37.69 mg gallic acid equivalent/g extract) and flavonoids (83.0 mg quercetin equivalent/g extract) contents, and was also the most active for DPPH (50.04 mg Trolox equivalent/g extract) and CUPRAC (139.96 mg Trolox equivalent /g extract) antioxidant assays. Likewise, the aerial-methanol extract exhibited maximum activity for ABTS (94.05 mg Trolox equivalent/g extract) and FRAP (64.23 mg Trolox equivalent/g extract) assays. The aerial-DCM extract was noted to be a convincing cholinesterase (AChE; 4.01 and BChE; 4.28 mg galantamine equivalent/g extract), and α-glucosidase inhibitor (1.92 mmol acarbose equivalent/g extract). All of the extracts exhibited weak to modest toxicity against the tested cell lines. A considerable quantities of gallic acid, catechin, 4-OH benzoic acid, syringic acid, vanillic acid, 3-OH-4-MeO benzaldehyde, epicatechin, p-coumaric acid, rutin, naringenin, and carvacrol were quantified via HPLC-PDA analysis. UHPLC-MS analysis of methanolic extracts from roots and aerial parts revealed the tentative identification of important phytoconstituents such as polyphenols, saponins, flavonoids, and glycoside derivatives. To conclude, this plant could be considered a promising source of origin for bioactive compounds with several therapeutic uses.

SARS-CoV-2 vaccines: Clinical endpoints and psychological perspectives: A literature review.

BACKGROUND: About 270 million cases have been confirmed, and 5.3 million fatalities Worldwide due to SARS-CoV-2. Several vaccine candidates have entered phase 3 of the clinical trial and are being investigated to provide immunity to the maximum percentage of people. A safe and effective vaccine is required to tackle the current COVID-19 waves. There have been reports that clinical endpoints and psychological parameters are necessary to consider vaccine efficacy. This review examines the clinical endpoints required for a successful SARS-CoV-2 vaccine and the influences of psychological parameters on its efficacy. METHODS: The main research question was to find out the clinical endpoints that determine the vaccine efficacy? And what kind of psychological parameters affect the vaccine efficacy? The information was taken from several journals, databases, and scientific search engines like Googe scholar, Pubmed, Scopus, Web of Science, Science direct, WHO website, and other various sites. The research studies were searched using keywords; SAR-CoV-2 vaccine efficacy, psychological effect on SARS-CoV-2 vaccine, SARS-CoV-2 vaccine endpoints. RESULTS: This review has highlighted various clinical endpoints that are the main determinants of clinical vaccine efficacy. Currently, vaccinations are being carried out throughout the world; it is important to investigate the main determinants affecting vaccine efficacy. We have focused on the clinical endpoints and the influence of psychological parameters that affect the vaccine efficacy in clinical settings. The primary endpoints include the risk of infection, symptoms, and severity of COVID-19, while hospitalization length, supplemental oxygen requirement, and mechanical ventilation are secondary endpoints in the clinical endpoints. Some tangential endpoints were also considered, including organ dysfunction, stroke, and MI. Many psychological associated things have influenced the vaccine efficacy, like the lower antibody titers in the vaccinated people. In addition to that, Short- and long-term stress and sleep deprivation were also found to affect the vaccine efficacy. CONCLUSION: The review summarizes the important clinical endpoints required for a successful vaccine candidate. In addition to primary and secondary endpoints, auxiliary endpoints and the disease burden also play an important role in modulating vaccine efficacy. Moreover, the psychological perspective also influences vaccine efficacy. Effective follow-up of participants should follow to examine the clinical endpoints to reach any conclusion about vaccine efficacy.

Particle Engineering by Nano Spray Drying: Optimization of Process Parameters with Hydroethanolic versus Aqueous Solutions.

Nano spray drying has emerged as an outstanding platform for engineering micro- and nanoparticles, with growing applications in various areas of drug delivery. As a new technology involving distinct technical design, parameters of the nano spray drying process are not fully elucidated. In a quality-by-design approach, the aim of the current study was to gain thorough understanding of critical determinants of product characteristics in the Büchi Nano Spray Dryer B-90. Following a factorial experimental design, a series of spray drying experiments were conducted to gain new insights into the influences of the inlet temperature, the spray solvent, and the solute concentration in the spray solution on the yield, the moisture content, and the particle size of the nano spray-dried powder material. Special consideration was given to the potential of using hydroethanolic in comparison with aqueous solvent systems and to particle engineering for pulmonary drug delivery. Lactose and mannitol, widely used as excipients in dry powder inhalation formulations, were used as model materials. Lactose and mannitol are known to spray dry in amorphous and crystalline forms, respectively. The yields of spray drying of lactose and mannitol amounted generally to 71.1 ± 6.6% w/w and 66.1 ± 3.5% w/w, respectively. The spray-dried materials exhibited generally a number-weighted median particle diameter of 1.6 ± 0.2 µm and a volume-weighted median particle diameter of 5.1 ± 1.0 µm. A detailed analysis of the results improved understanding of the interplay between process parameters in the Nano Spray Dryer. The results demonstrate that optimization of spray generation is the key to yield optimization. On the other hand, particle size is determined by the spray mesh pore size and the spray solution degree of saturation. Selection of an appropriate spray solvent and using spray solution additives could optimize spray flow. In parallel, the spray solvent and the solute concentration in the spray solution determine the degree of saturation. Guidance on optimization of particle engineering by nano spray drying is provided.

Poly ε-Caprolactone Nanoparticles for Sustained Intra-Articular Immune Modulation in Adjuvant-Induced Arthritis Rodent Model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder with synovitis and articular pathology as its primary expositions. Leflunomide (Lfd) is an anti-rheumatic drug that is effective in the treatment of RA, but displays severe side effects upon prolonged systemic administration. Local therapy might represent a promising strategy to treat rheumatoid arthritis without eliciting systemic adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) nanoparticles (Lfd-NPs) were prepared and assessed as a local drug delivery system capable of alleviating RA-associated inflammation. Lfd-NPs were optimized using the Quality by Design (QbD) approach, applying a 32 full factorial design. In vitro drug release from NPs was examined in simulated synovial fluid. In addition, the in vivo efficacy of Lfd-NPs was evaluated in the Adjuvant Induced Arthritis (AIA) rodent model. Sustained drug release in simulated synovial fluid was observed for up to 168 h. A gradual reduction in paw volume and knee diameter was observed over the course of treatment, indicating the regression of the disease. In addition, significant reductions in serum proinflammatory markers and cytokines, including the C-reactive protein (CRP), rheumatoid factor (RF), TNF-α, IL1-ß, and IL-6, were verified upon treatment with Lfd-NPs, suggesting the modulation of immune responses at the pathological site. Most importantly, no remarkable signs of toxicity were observed in Lfd-NP-treated animals. Collectively, intra-articularly administered Lfd-NPs might represent a potential therapeutic alternative to systemically administered drugs for the treatment of rheumatoid arthritis, without eliciting systemic adverse effects.

Experimental Design and Optimization of Nano-Transfersomal Gel to Enhance the Hypoglycemic Activity of Silymarin.

Current advancements in the research investigations focused at using natural products to generate novel dosage forms with a potential therapeutic impact. Silymarin is a natural product obtained from the herb Silybum marianum that has been shown to have remarkable hypoglycemic activity. Owing to the low enteral absorption, instability in stomach secretion, and poor solubility of Silymarin, it was better to be produced as a topical dosage form. A three-factor, three-level Box Behnken (33 BB) design was constructed to develop 15 formulations using three independent variables (phospholipid concentration, surfactant concentration, and sonication time) and two dependent variables (encapsulation efficiency and in vitro drug release). The optimized formula was added to HPMC gel and the resulting transfersomal gel was investigated for its characteristics, in vitro, ex vivo and hypoglycemic behaviors. The pH of the Silymarin-loaded transfersomal gel was 7.05, the spreadability was 55.35 mm, and the viscosity was 6.27 Pa. Furthermore, Silymarin loaded transfersomal gel had the greatest transdermal flux (92.41 µg/cm2·h), which was much greater than all other formulations. In vivo observations revealed that Silymarin loaded transfersomal gel significantly reduced blood glucose levels, compared to either Silymarin gel or oral Silymarin suspension. The findings show that the developed transfersomal gel could be an effective carrier for Silymarin transdermal delivery.

Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients.

Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.

Screening of Apoptosis Pathway-Mediated Anti-Proliferative Activity of the Phytochemical Compound Furanodienone against Human Non-Small Lung Cancer A-549 Cells.

Furanodienone (FDN), a major bioactive component of sesquiterpenes produced from Rhizoma Curcumae, has been repeatedly acknowledged for its intrinsic anticancer efficacy against different types of cancer. In this study, we aimed to investigate the cytotoxic potential of furanodienone against human lung cancer (NSCLC A549) cells in vitro, as well as its underlying molecular mechanisms in the induction of apoptosis. Herein, we found that FDN significantly inhibited the proliferation of A549 cells in a dose-dependent manner. In addition, treatment with FDN potentially triggered apoptosis in A549 cells via not only disrupting the nuclear morphology, but by activating capsase-9 and caspase-3 with concomitant modulation of the pro- and antiapoptotic gene expression as well. Furthermore, FDN revealed its competence in inducing cell cycle arrest at G0/G1 phase in A549 cells, which was associated with decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), along with increased expression of CDK inhibitor p21Cip1. Intriguingly, FDN treatment efficiently downregulated the Wnt signaling pathway, which was correlated with increased apoptosis, as well as cell cycle arrest, in A549 cells. Collectively, FDN might represent a promising adjuvant therapy for the management of lung cancer.

Development and Evaluation of Clove and Cinnamon Supercritical Fluid Extracts-Loaded Emulgel for Antifungal Activity in Denture Stomatitis.

Denture stomatitis (DS), usually caused by Candida infection, is one of the common denture-related complications in patients wearing dentures. Clove and cinnamon oils have been acknowledged for their anti-inflammatory, antimicrobial activity, and antifungal effects in the oral cavity. The aim of this study, therefore, was to prepare clove/cinnamon oils-loaded emulgel and to assess its efficacy in treating Candida albicans-associated denture stomatitis. Central composite design was adopted to formulate and optimize clove/cinnamon extracts-loaded emulgel. The formulated preparations were assessed for their physical appearance, particle size, viscosity, spreadability, and in-vitro drug release. In addition, in-vivo therapeutic experiments were conducted on 42 patients with denture stomatitis. The prepared emulgel formulations showed good physical characteristics with efficient drug release within 3 h. In addition, in-vivo antifungal studies revealed that the optimized formula significantly (p < 0.001) reduced Candida colony counts from the denture surface, compared to commercially available gel (240.38 ± 27.20 vs. 398.19 ± 66.73 CFU/mL, respectively). Furthermore, the optimized formula and succeeded in alleviating denture stomatitis-related inflammation with a better clinical cure rate compared to commercially available gel Collectively, herbal extracts-loaded emulgel might be considered an evolution of polyherbal formulations and might represent a promising alternative to the existing allopathic drugs for the treatment of denture stomatitis, with better taste acceptability and no side effects.

Insights into the potential of rheological measurements in development of dry powder inhalation formulations.

Study of flow is a key to development of dry powder inhalation formulations. Various static (bulk) and dynamic rheological measurements are used to study different aspects of powder flow and packing. Among rheological measurements, the permeability and the fluidization energy are, conceptually, most relevant to dispersion of dry powder inhalation formulations. The aim of the current study was to test the robustness and the range of applications of the two measurements, among other rheological measurements. To this end, we prepared and studied a series of ternary, carrier-based dry powder inhalation formulations. The formulations were mixtures of coarse-fine excipient (α-lactose monohydrate) blends, with different fine excipient concentrations (0.0-15.0 % w/w), and a spray-dried drug (fluticasone propionate) material. The excipient blends were characterized in terms of morphology, size, crystallinity, and rheological properties. The formulations were evaluated in vitro using a low resistance inhalation device, the Cyclohaler®, and a high resistance inhalation device, the Handihaler®. The study design aimed to complement literature data. Bulk rheological measurements, specifically the bulk density, the compressibility, and the permeability, exhibited satisfactory precision and could demonstrate changes in powder composition and structure. They hold a potential for use as critical material attributes to aid monitoring and optimization of carrier-based dry powder inhalation formulations in quality-by-design systems. On the other hand, dynamic rheological measurements, specifically the basic flowability energy, the specific energy, and the fluidization energy, generally exhibited high variability, which obscured interpretation of the measurements and implied heterogeneous powder structures. The fluidization energy could, nevertheless, convey structural changes taking place during powder fluidization.

Thymoquinone provides structural protection of human hemoglobin against oxidative damage: Biochemical studies.

Hydroxyl radicals (OH.) are one of the most active reactive oxidants recognized for their deleterious effects to cause protein oxidative damage. Thymoquinone, a monoterpene molecule abundantly present in black cumin and known for its pharmacological activities, but its activity against the OH.-induced protein oxidative damage has never been explored. This study determined the therapeutic potential of thymoquinone against OH.-induced oxidative human hemoglobin damage. Novel data demonstrated that thymoquinone provides structural protection of hemoglobin against oxidative damage. Treatment of hemoglobin with OH. induces hypochromicity at 280 and 405 nm, whereas thymoquinone reversed these hypochromic effects. In addition, OH. cause significant reduction in tryptophan fluorescence, however thymoquinone also reversed these damaging effects. Thymoquinone also reduces OH.-induced hydrophobicity and also reduces OH.-induced carbonylation. Moreover, it also inhibits thermal stabilization of OH.-hemoglobin complex. SDS-PAGE of unmodified hemoglobin showed four bands, which disappeared upon OH. treatment and these changes were also retained by thymoquinone. In conclusion, this is the first study that shows the therapeutic potential of thymoquinone against OH.-induced oxidative damage in human hemoglobin.

Alteration of Salmonella enterica Virulence and Host Pathogenesis through Targeting sdiA by Using the CRISPR-Cas9 System.

Salmonella enterica is a common cause of many enteric infections worldwide and is successfully engineered to deliver heterologous antigens to be used as vaccines. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) RNA-guided Cas9 endonuclease is a promising genome editing tool. In the current study, a CRISPR-Cas9 system was used to target S.enterica sdiA that encodes signal molecule receptor SdiA and responds to the quorum sensing (QS) signaling compounds N-acylhomoserine lactones (AHLs). For this purpose, sdiA was targeted in both S.enterica wild type (WT) and the ΔssaV mutant strain, where SsaV has been reported to be an essential component of SPI2-T3SS. The impact of sdiA mutation on S. enterica virulence was evaluated at both early invasion and later intracellular replication in both the presence and absence of AHL. Additionally, the influence of sdiA mutation on the pathogenesis S. enterica WT and mutants was investigated in vivo, using mice infection model. Finally, the minimum inhibitory concentrations (MICs) of various antibiotics against S. enterica strains were determined. Present findings show that mutation in sdiA significantly affects S.enterica biofilm formation, cell adhesion and invasion. However, sdiA mutation did not affect bacterial intracellular survival. Moreover, in vivo bacterial pathogenesis was markedly lowered in S.enterica ΔsdiA in comparison with the wild-type strain. Significantly, double-mutant sdiA and ssaV attenuated the S. enterica virulence and in vivo pathogenesis. Moreover, mutations in selected genes increased Salmonella susceptibility to tested antibiotics, as revealed by determining the MICs and MBICs of these antibiotics. Altogether, current results clearly highlight the importance of the CRISPR-Cas9 system as a bacterial genome editing tool and the valuable role of SdiA in S.enterica virulence. The present findings extend the understanding of virulence regulation and host pathogenesis of Salmonellaenterica.

Quality by Design for Optimizing a Novel Liposomal Jojoba Oil-Based Emulgel to Ameliorate the Anti-Inflammatory Effect of Brucine.

One of the recent advancements in research is the application of natural products in developing newly effective formulations that have few drawbacks and that boost therapeutic effects. The goal of the current exploration is to investigate the effect of jojoba oil in augmenting the anti-inflammatory effect of Brucine natural alkaloid. This is first development of a formulation that applies Brucine and jojoba oil int a PEGylated liposomal emulgel proposed for topical application. Initially, various PEGylated Brucine liposomal formulations were fabricated using a thin-film hydration method. (22) Factorial design was assembled using two factors (egg Phosphatidylcholine and cholesterol concentrations) and three responses (particle size, encapsulation efficiency and in vitro release). The optimized formula was incorporated within jojoba oil emulgel. The PEGylated liposomal emulgel was inspected for its characteristics, in vitro, ex vivo and anti-inflammatory behaviors. Liposomal emulgel showed a pH of 6.63, a spreadability of 48.8 mm and a viscosity of 9310 cP. As much as 40.57% of Brucine was released after 6 h, and drug permeability exhibited a flux of 0.47 µg/cm2·h. Lastly, % of inflammation was lowered to 47.7, which was significant effect compared to other formulations. In conclusion, the anti-inflammatory influence of jojoba oil and Brucine was confirmed, supporting their integration into liposomal emulgel as a potential nanocarrier.

An overview of SARS-COV-2 epidemiology, mutant variants, vaccines, and management strategies.

BACKGROUND: Over the last two decades, humanity has observed the extraordinary anomaly caused by novel, weird coronavirus strains, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). As the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has made its entry into the world, it has dramatically affected life in every domain by continuously producing new variants. The vaccine development is an ongoing process, although some vaccines got marketed. The big challenge is now whether the vaccine candidates can provide long-lasting protection or prevention against mutant variants. METHODS: The information was gathered from various journals, electronic searches via Internet-based information such as PubMed, Google Scholar, Science Direct, online electronic journals, WHO landscape, world meters, WHO website, and News. RESULTS: This review will present and discuss some coronavirus disease 19 (COVID-19) related aspects including: the pathophysiology, epidemiology, mutant variants vaccine candidates, vaccine efficacy, and management strategies. Due to the high death rate, continuous spread, an inadequate workforce, lack of required therapeutics, and incomplete understanding of the viral strain, it becomes crucial to build the knowledge of its biological characteristics and make available the rapid diagnostic and vital therapeutic machinery for the combat and management of an infection. CONCLUSION: The data summarizes current research on the COVID 19 infection and therapeutic interventions, which will direct future decision-making on the effort-worthy phases of the COVID 19 and the development of critical therapeutics. The only possible solution is the vaccine development targeting against all variant strains to halt its progress; the identified theoretical and practical knowledge can eliminate the gaps to improve a better understanding of the novel coronavirus structure and its design of a vaccine. In addition, to that the long-lasting protection is another challenging objective that need to be looked into.

Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device.

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 µm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 µm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40-12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17-10.16% w/w).

Playground lead levels in rubber, soil, sand, and mulch surfaces in Boston.

Rubber surfacing is often used in playgrounds due to its potential injury prevention benefits and as a way to recycle waste tires. Available research on chemicals in recycled rubber has focused on synthetic turf applications, but is limited for playground rubber surfacing. Potential lead contamination from vulcanizing agents used in rubber surfacing are a possible concern; however this has not been researched. We examined levels of lead in poured-in-place rubber and compared them to levels in soil, sand, and wood mulch materials from 28 randomly selected playgrounds in Boston, MA, USA using X-ray fluorescence. To evaluate the association between material type and lead concentrations, we conducted a two-way ANOVA with repeated measures and built a linear regression model controlling for distance to major roadway, neighborhood-level status as an environmental justice area, peeling paint on the playground, and rubber condition. Average lead levels were 65.7 µg/g for soil, 22.0 µg/g for rubber, 8.5 µg/g for sand, and 9.0 µg/g for mulch. Our finding of lower concentrations of lead in sand and mulch compared to rubber and soil should be used to inform playground design to optimize children's health, alongside other chemical and safety considerations.

An intestinal paracellular pathway biased toward positively-charged macromolecules.

Lacking an effective mechanism to safely and consistently enhance macromolecular uptake across the intestinal epithelium, prospects for successful development of oral therapeutic peptide drugs remain unlikely. We previously addressed this challenge by identifying an endogenous mechanism that controls intestinal paracellular permeability that can be activated by a peptide, termed PIP 640, which can increase cellular levels of phosphorylated myosin light chain at position S19 (MLC-pS19). Apical application in vitro or luminal application in vivo was shown to increase macromolecular solute transport within minutes that recovered completely within a few hours after removal. We now examine the nature of PIP 640-mediated permeability changes. Confluent Caco-2 cell monolayers treated with PIP 640 enhanced apical-to-basolateral (AB) transport of 4-kDa, but not 10-kDa, dextran. Expression and/or cellular distribution changes of tight junction (TJ) proteins were restricted to increased claudin-2 over a time course that correlated with an apparent shift in its distribution from the nucleus to the membrane fraction of the cell. PIP 640-mediated epithelial changes were distinct from the combined actions of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). While TNF-α/IFN-γ treatment also increased MLC-pS19 levels, these cytokines enhanced AB transport for 70-kDa dextran and decreased occludin expression at TJs. Claudin-2-dependent changes induced by PIP 640 resulted in an AB transport bias for positively-charged macromolecules demonstrated in vitro using charge variants of 4-kDa dextrans and by comparing transport of salmon calcitonin to exenatide. Comparable outcomes of increased TJ localization of claudin-2 and enhanced transport of these therapeutic peptides that biased toward cationic characteristics was demonstrated in vivo following after intra-luminal injection into rat jejunum. Together, these data have shown a potential mechanism for PIP 640 to enhance paracellular permeability of solutes in the size range of small therapeutic peptides that is biased toward positively-charged solutes.