Production and bioprocessing of epothilone B from Aspergillus niger, an endophyte of Latania loddegesii, with a conceivable biosynthetic stability: anticancer, anti-wound healing activities and cell cycle analysis.

Epothilones are one of the common prescribed anticancer drugs for solid tumors, for their exceptional binding affinity with ß-tubulin microtubule, stabilizing their disassembly, causing an ultimate arrest to the cellular growth. Epothilones were initially isolated from Sornagium cellulosum, however, their extremely slow growth rate and low yield of epothilone is the challenge. So, screening for a novel fungal endophyte dwelling medicinal plants, with higher epothilone productivity and feasibility of growth manipulation was the objective. Aspergillus niger EFBL-SR OR342867, an endophyte of Latania loddegesii, has been recognized as the heady epothilone producer (140.2 µg/L). The chemical structural identity of the TLC-purified putative sample of A. niger was resolved from the HPLC, FTIR and LC-ESI-MS/MS analyses, with an identical molecular structure of the authentic epothilone B. The purified A. niger epothilone B showed a resilient activity against MCF-7 (0.022 µM), HepG-2 (0.037 µM), and HCT-116 (0.12 µM), with selectivity indices 21.8, 12.9 and 4, respectively. The purified epothilone B exhibited a potential anti-wound healing activity to HepG-2 and MCF-7 cells by ~ 54.07 and 60.0%, respectively, after 24 h, compared to the untreated cells. The purified epothilone has a significant antiproliferative effect by arresting the cellular growth of MCF-7 at G2/M phase by ~ 2.1 folds, inducing the total apoptosis by ~ 12.2 folds, normalized to the control cells. The epothilone B productivity by A. niger was optimized by the response surface methodology, with ~ 1.4 fold increments (266.9 µg/L), over the control. The epothilone productivity by A. niger was reduced by ~ 2.4 folds by 6 months storage as a slope culture at 4 °C, however, the epothilone productivity was slightly restored with ethylacetate extracts of L. loddegesii, confirming the plant-derived chemical signals that partially triggers the biosynthetic genes of A. niger epothilones. So, this is the first report emphasizing the metabolic potency of A. niger, an endophyte of L. loddegesii, to produce epothilone B, that could be a new platform for industrial production of this drug.

Hit me with your best shot: Integrated hit discovery for the next generation of drug targets.

Identification of high-quality hit chemical matter is of vital importance to the success of drug discovery campaigns. However, this goal is becoming ever harder to achieve as the targets entering the portfolios of pharmaceutical and biotechnology companies are increasingly trending towards novel and traditionally challenging to drug. This demand has fuelled the development and adoption of numerous new screening approaches, whereby the contemporary hit identification toolbox comprises a growing number of orthogonal and complementary technologies including high-throughput screening, fragment-based ligand design, affinity screening (affinity-selection mass spectrometry, differential scanning fluorimetry, DNA-encoded library screening), as well as increasingly sophisticated computational predictive approaches. Herein we describe how an integrated strategy for hit discovery, whereby multiple hit identification techniques are tactically applied, selected in the context of target suitability and resource priority, represents an optimal and often essential approach to maximise the likelihood of identifying quality starting points from which to develop the next generation of medicines.

Bodyweight influences the relationship between serum testosterone and bone mineral density in men with spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine the association between serum testosterone levels (T levels) and bone mineral density after spinal cord injury (SCI). SETTING: Medical research center. METHODS: Body composition assessments were measured in 53 men with chronic SCI. Serum T levels were measured after an overnight fast. Total and regional bone mineral density (BMD) and bone mineral content (BMC) were measured using dual-energy X-ray absorptiometry. Participants were classified into three groups based on their body weight [<65 kg, 65-80 kg, >80 kg] or serum T levels into low (400 ng/dl), mid-normal (401-544 ng/dl) and normal (>545 ng/dl) ranges. RESULTS: Serum T level was negatively related to body weight (r = -0.33, P = 0.016), fat mass (r = -0.46, P < 0.001) and percentage fat mass (r = -0.48, P < 0.001). There were no significant relationships between serum T levels and any of the bone health measurements. Body weight was related to total, regional (P < 0.01 for both) and knee BMD (P < 0.05). T level was only related to total and regional BMD in the group with body weight of 65-80 kg. CONCLUSION: Testosterone has no direct relationship with BMD except within a specific weight group. However, body weight or fat mass negatively influences circulating T levels in men with SCI. The relationship between serum T levels and BMD is mediated by body weight in men with SCI.

Tailoring neo/adjuvant systemic therapy in breast cancer: "The advent of a personalized approach"-The Breast-Gynecological and Immuno-Oncology International Cancer Conference (BGICC) consensus and recommendations.

BACKGROUND: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. METHODS: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. RESULTS AND CONCLUSIONS: The consensus recommendations addressed different escalation and de-escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

Effect of Different Electroconductive Root Canal Irrigations on the Accuracy of Different Apex Locators: An In Vitro Comparative Study.

Aim: An accurate working length (WL) estimation is fundamental to a successful endodontic therapy. The objective of this comparative in vitro research was to investigate the performance of iPex II and the Root ZX Mini electronic apex locators (EALs) in measuring root canal WL with different irrigant solutions and their relation to the electrical conductivity of irrigation solutions. Materials and Methods: Seventy sound permanent lower premolar teeth, each with a single root and developed apices, were used. Under an X15 stereomicroscope, the real working length was determined with the aid of a #10 file. After that, teeth were placed into an alginate model, and the iPex II and Root ZX Mini were used for the detection of electronic working length with various irrigants. Seventy teeth were randomly distributed into seven groups, 10 per each group (group I: dry canal; group II: distilled water; group III: ozonated water; group IV: 5% sodium hypochlorite (NaOCl); group V: 2% chlorhexidine, group VI: 17% ethylenediaminetetraacetic acid (EDTA) solution, and group VII: 17% EDTA gel). The difference in WL was calculated by deducting real working length from its electronic working length. The study also evaluates the electrical conductivity of the seven endodontic irrigant solutions. The two-way analysis of variance (ANOVA) test was used for statistical analysis. Results: Statistically, neither both types of EALs (P = 0.088) nor various irrigating solutions with varying electrical conductivities (P = 0.099) significantly affect the accuracy of EL estimation. Conclusions: There were no significant differences between the accuracy of the Root ZX Mini and the iPex II. The accuracy of both apex locators is unaffected in the presence of various irrigation solutions with varying electrical conductivities in this research.

Machine learning and remote sensing-based lithological mapping of the Duwi Shear-Belt area, Central Eastern Desert, Egypt.

Machine learning and remote sensing techniques are widely accepted as valuable, cost-effective tools in lithological discrimination and mineralogical investigations. The current study represents an attempt to use machine learning classification along with several remote sensing techniques being applied to Landsat-8/9 satellite data to discriminate the various outcropping lithological rock units at the Duwi Shear Belt (DSB) area in the Central Eastern Desert of Egypt. Multi-class machine learning classification, multiple conventional remote sensing mapping techniques, spectral separability analysis based on the Jeffries-Matusita (J-M) distance measure, fieldwork, and petrographic investigations were integrated to enhance the lithological discrimination of the exposed rock units at DSB area. The well-recognized machine learning classifier (Support Vector Machine-SVM) was adopted in this study, with training data determined carefully based on enhancing the lithological discrimination attained from various remote sensing techniques of False Color Composites (FCC), Principal Component Analysis (PCA), and Minimum Noise Fraction (MNF), along with the fieldwork data and the previously published geologic maps. High overall accuracy of the SVM classification was obtained, however, inspection of the individual rock unit classes' accuracies revealed lower accuracy for certain types of rock units which were also found associated with lower separability scores as well. Among the least separable rock units were; metagabbro rocks that showed high spectral similarity with the volcaniclastic metasediments rocks, and the metaultramafics of the ophiolitic mélange showed spectral attitude of high correlation to that of the Hammamat volcanosedimentary rocks. Target-oriented Color Ratio Composites (CRC) technique was implemented to better discriminate these hardly separable rock units. A final integrated geological map was obtained comprising the various discriminated Neoproterozoic basement rock units of the DSB area. The successfully mapped litho-units include; Meatiq Group (amphibolites, gneissic granitoids, and mylonitized granitoids), ophiolitic mélange (metaultramafics, metagabbro-amphibolites, and volcaniclastic metasediments), Dokhan volcanics, Hammamat sediments, and granites. An adequate description of these rock units was also given in light of the conducted intense fieldwork and petrographic investigations.

Bioprocessing of camptothecin from Alternaria brassicicola, an endophyte of Catharanthus roseus, with a strong antiproliferative activity and inhibition to Topoisomerases.

Suppression of fungal camptothecin (CPT) biosynthesis with the preservation and successive subculturing is the challenge that impedes fungi from the industrial application, so, screening for a novel fungal isolate with a conceivable stable producing potency of CPT was the main objective of this work. Catharanthus roseus with diverse contents of bioactive metabolites could have a plethora of novel endophytes with unique metabolic properties. Among the endophytes of C. roseus, Alternaria brassicicola EFBL-NV OR131587.1 was the highest CPT producer (96.5 µg/L). The structural identity of the putative CPT was verified by HPLC, FTIR, HNMR and LC-MS/MS, with a molecular mass 349 m/z, and molecular fragmentation patterns that typically identical to the authentic one. The purified A. brassicicola CPT has a strong antiproliferative activity towards UO-31 (0.75 µM) and MCF7 (3.2 µM), with selectivity index 30.8, and 7.1, respectively, in addition to resilient activity to inhibit Topo II (IC50 value 0.26 nM) than Topo 1 (IC50 value 3.2 nM). The purified CPT combat the wound healing of UO-31 cells by ~ 52%, stops their matrix formation, cell migration and metastasis. The purified CPT arrest the cellular division of the UO-31 at the S-phase, and inducing their cellular apoptosis by ~ 20.4 folds, compared to the control cells. Upon bioprocessing with the surface response methodology, the CPT yield by A. brassicicola was improved by ~ 3.3 folds, compared to control. The metabolic potency of synthesis of CPT by A. brassicicola was attenuated with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by the 6th month of storage and 6th generation. Practically, the CPT productivity of the attenuated A. brassicicola was restored by addition of 1% surface sterilized leaves of C. roseus, ensuring the eliciting of cryptic gene cluster of A. brassicicola CPT via the plant microbiome-A. brassicicola interactions. So, for the first time, a novel endophytic isolate A. brassicicola, from C. roseus, was explored to have a relatively stable CPT biosynthetic machinery, with an affordable feasibility to restore their CPT productivity using C. roseus microbiome, in addition to the unique affinity of the extracted CPT to inhibit Topoisomerase I and II.

Comparing students' performance in self-directed and directed self-learning in College of Medicine, University of Bisha.

Background: Student-centered learning strategy increases the likelihood of graduation of competent, self-dependent, and problem-solving physicians. The University of Bisha, College of Medicine (UBCOM) adopted self-directed learning (SDL) represented by problem-based learning (PBL), and directed self-learning (DSL) represented by team-based learning (TBL). Aim: To compare the students' performance in SDL and DSL among UBCOM students. Methodology: A total of 502 multiple choice questions (MCQs) from the mid-course and final exams were collected by the relevant subject experts from nine courses during the period from September 2020 till June 2023 that adopted PBL and TBL; 247 MCQs related to PBL and 255 related to TBL. Psychometric analysis was used to determine difficult, easy, and optimum questions (≤25%, ≥90%, and 26-89%, respectively). Point biserial as <0.19, 0.20-0.29, 0.30-0.39, and >0.40 which indicate poor, marginal, good, and excellent point biserial, respectively. Finally, the number of functional distractors was attempted by >5% of the candidates. Results: No significant differences were noted for the students' performance in MCQs related to PBL (representing self-directed, small group learning tool), and TBL (representing directed-self, large group learning tool) regarding difficulty index (DI), point biserial, and distractors functionality. Conclusion: It has been observed that there is no difference in students' performance whether PBL or TBL is used for learning Basic Medical Science courses. Small group learning such as PBL needs more resources in comparison to large group learning as in TBL, therefore any institute can decide on the adopted learning strategy depending on its resources and the number of students.

Validation of basal metabolic rate equations in persons with innervated and denervated chronic spinal cord injury.

Basal metabolic rate (BMR) measurement is time consuming and requires specialized equipment. Prediction equations allow clinicians and researchers to estimate BMR; however, their accuracy may vary across individuals with chronic spinal cord injury (SCI). The objective of this study was to investigate the validity of SCI-specific equations as well as able-bodied (AB) prediction equations in individuals with upper motor neuron (UMN), lower motor neuron (LMN), and females with SCI. Twenty-six men and women with chronic SCI (n = 12 innervated males, n = 6 innervated females, n = 8 denervated males) participated in this cross-sectional study. BMR values were measured by indirect calorimetry. Body composition (dual-energy X-ray absorptiometry and anthropometrics) assessment was conducted. AB-prediction equations [Cunningham, Nelson, Owen, Harris and Benedict, Mifflin, Schofield, Henry] and SCI-specific equations [Chun and Nightingale & Gorgey] were used to estimate and validate BMR. The accuracy of AB-specific FFM equations in predicting BMR was evaluated using Bland-Altman plots, paired t-tests, and error metrics. Measured BMR for innervated males, females, and denervated males was 1436 ± 213 kcal/day, 1290 ± 114, and 1597 ± 333 kcal/day, respectively. SCI-specific equations by Chun et al., Nightingale & Gorgey, and AB-specific FFM equations accurately predicted BMR for innervated males. For the denervated males, Model 4 equation by Nightingale & Gorgey was not different (p = 0.18), and Bland-Altman analyses showed negative mean bias but similar limits of agreement between measured and predicted BMR for the SCI-specific equations and AB-specific FFM equations. We demonstrated that SCI-specific equations accurately predicted BMR for innervated males but underpredicted it for denervated males. The Model 4 equation by Nightingale & Gorgey accurately estimated BMR in females with SCI. Findings from the current study will help to determine caloric needs in different sub-groups of SCI.

Efficacy of Lasers in Debonding Ceramic Brackets: Exploring the Rationale and Methods.

The development of ceramic brackets in orthodontics three decades ago emerged as a response to the increasing patient demand for less visible orthodontic appliances. While these brackets provide superior aesthetics, they are characterized by lower fracture toughness and higher bond strength in contrast to metal brackets. These properties present challenges during the debonding step, including the risk of enamel micro-fractures and cracks. Historically, various strategies have been developed to address challenges associated with debonding, reduce patient discomfort, and ensure that the bond failure site is confined to the bracket-adhesive interface. This included the use of specially designed debonding pliers, electrothermal debonding, ultrasonic technique, and chemical agents. Recently, there has been a shift towards utilizing different types of laser irradiation for this purpose. The burgeoning strategy, however, requires diligent scientific scrutiny to establish a standardized protocol with particular laser parameters and ultimately achieve the goal of enhancing the patient experience by reducing discomfort. This article offers a narrative review of laser-aided debonding of ceramic brackets, aimed at comparing different laser types, presenting their benefits and downsides, validating the efficiency of each method, and summarizing the published literature on this subject. It also provides insights for orthodontists on reducing patient discomfort that usually accompanies debonding ceramic brackets by delving into the science behind the use of lasers for this purpose.

Multiple roles for hypoxia inducible factor 1-alpha in airway epithelial cells during mucormycosis.

During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.

Brilacidin, a novel antifungal agent against Cryptococcus neoformans.

Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans. BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans. BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis. IMPORTANCE: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii. There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of C. neoformans, acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against C. neoformans. We propose BRI as a new antifungal agent against cryptococcosis.

Postoperative analgesic consumption for primary versus first repeat Cesarean delivery: a historical cohort study.

PURPOSE: It is unclear if postoperative pain experience and opioid consumption differ in patients undergoing primary vs repeat Cesarean delivery (CD) as prior studies have yielded conflicting results and none used the same patients as their own controls. We sought to compare opioid consumption and pain scores in patients undergoing both a primary and a first repeat CD, using the same patients as their own controls. METHODS: We conducted a single-centre historical cohort study of patients who underwent both a primary and a first repeat CD under neuraxial anesthesia between 1 January 2016 and 30 November 2022. The same standardized multimodal analgesic regimen was used for all patients. The primary outcome was opioid consumption in oral morphine equivalents (OME) at 48 hr after surgery. Secondary outcomes included area under the curve for pain scores at 24 and 48 hr, and opioid consumption at 24 hr. RESULTS: We included 409 patients. In unadjusted analysis, there were no significant differences between primary and repeat CD in median [interquartile range] opioid consumption at 48 hr (45 [15-89] mg vs 45 [15-83] mg OME) or in any of the secondary outcomes. In the multivariable model adjusting for age, body mass index, anxiety, depression, priority, surgery duration, gestational age, receipt of postoperative ketorolac, and neuraxial type, repeat CD was still not associated with increased opioid consumption compared with primary CD (adjusted rate ratio, 1.20; 95% confidence interval, 0.95 to 1.51). CONCLUSION: In this retrospective study, we found no differences in postoperative opioid consumption or reported pain scores in patients who underwent both a primary and a first repeat CD.

RéSUMé: OBJECTIF: Nous ne savons pas si l'expérience de la douleur postopératoire et la consommation d'opioïdes diffèrent chez la patientèle accouchant par césarienne pour la première fois ou pour la seconde fois. En effet, les études antérieures ont donné des résultats contradictoires et aucune n'a utilisé la même patientèle comme témoins. Nous avons cherché à comparer la consommation d'opioïdes et les scores de douleur chez les personnes parturientes exposées à la fois à un premier puis un deuxième accouchement par césarienne en recrutant les mêmes personnes en tant que leurs propres témoins. MéTHODE: Nous avons mené une étude de cohorte historique monocentrique auprès de personnes parturientes ayant subi à la fois une première et une seconde césarienne sous anesthésie neuraxiale entre le 1er janvier 2016 et le 30 novembre 2022. Le même régime analgésique multimodal standardisé a été utilisé pour toutes les personnes dans l'étude. Le critère d'évaluation principal était la consommation d'opioïdes en équivalents morphine oraux (EMO) 48 heures après la chirurgie. Les critères d'évaluation secondaires comprenaient la surface sous la courbe pour les scores de douleur à 24 et 48 heures, et la consommation d'opioïdes à 24 heures. RéSULTATS: Nous avons inclus 409 personnes. Dans l'analyse non ajustée, il n'y avait pas de différence significative entre le premier et le deuxième accouchement par césarienne en ce qui concerne la consommation médiane d'opioïdes [écart interquartile] à 48 heures (45 [15 à 89] mg vs 45 [15­83] mg EMO) ou dans l'un des critères d'évaluation secondaires. Dans le modèle multivarié ajusté en fonction de l'âge, l'indice de masse corporelle, l'anxiété, la dépression, la priorité, la durée de la chirurgie, l'âge gestationnel, l'administration de kétorolac postopératoire et le type d'anesthésie neuraxiale, une deuxième césarienne n'était toujours pas associée à une consommation accrue d'opioïdes par rapport à une première césarienne (rapport de taux ajusté, 1,20; intervalle de confiance à 95 %, 0,95 à 1,51). CONCLUSION: Dans cette étude rétrospective, nous n'avons trouvé aucune différence dans la consommation d'opioïdes postopératoires ou les scores de douleur rapportés chez la patientèle ayant accouché par césarienne pour la première ou pour la deuxième fois.

The Clinical Management of Electrical Stimulation Therapies in the Rehabilitation of Individuals with Spinal Cord Injuries.

Background: People with spinal cord injuries (SCIs) often have trouble remaining active because of paralysis. In the past, exercise recommendations focused on the non-paralyzed muscles in the arms, which provides limited benefits. However, recent studies show that electrical stimulation can help engage the paralyzed extremities, expanding the available muscle mass for exercise. Methods: The authors provide an evidence-based approach using expertise from diverse fields, supplemented by evidence from key studies toward the management of electrical stimulation therapies in individuals with SCIs. Literature searches were performed separately using the PubMed, Medline, and Google Scholar search engines. The keywords used for the searches included functional electrical stimulation cycling, hybrid cycling, neuromuscular electrical stimulation exercise, spinal cord injury, cardiovascular health, metabolic health, muscle strength, muscle mass, bone mass, upper limb treatment, diagnostic and prognostic use of functional electrical stimulation, tetraplegic hands, and hand deformities after SCI. The authors recently presented this information in a workshop at a major rehabilitation conference. Additional information beyond what was presented at the workshop was added for the writing of this paper. Results: Functional electrical stimulation (FES) cycling can improve aerobic fitness and reduce the risk of cardiovascular and metabolic diseases. The evidence indicates that while both FES leg cycling and neuromuscular electrical stimulation (NMES) resistance training can increase muscle strength and mass, NMES resistance training has been shown to be more effective for producing muscle hypertrophy in individual muscle groups. The response to the electrical stimulation of muscles can also help in the diagnosis and prognosis of hand dysfunction after tetraplegia. Conclusions: Electrical stimulation activities are safe and effective methods for exercise and testing for motor neuron lesions in individuals with SCIs and other paralytic or paretic conditions. They should be considered part of a comprehensive rehabilitation program in diagnosing, prognosing, and treating individuals with SCIs to improve function, physical activity, and overall health.

Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: In Vitro Studies with Computational Predictions.

In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, 5a-f, 6a-f, and 7a-f, to evaluate their biological applications. The data from in vitro biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases 5a-f, 6a-f, and 7a-f showed that the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases 5d, 5e, and 7a are active against lung (A549) cells, while the two Schiff bases 5e and 7a exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f were evaluated. Furthermore, we assessed the in silico absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.

Potential fungicidal and antiaflatoxigenic effects of cinnamon essential oils on Aspergillus flavus inhabiting the stored wheat grains.

Wheat is one of the essential crops for the human and animal nutrition, however, contamination with aflatoxigenic fungi, due to the improper storage conditions and high humidity, was the main global threats. So, preventing the growth of aflatoxigenic fungi in stored wheat grains, by using different essential oils was the main objective of this work. Aspergillus flavus EFBL-MU12 PP087400, EFBL-MU23 PP087401 and EFBL-MU36 PP087403 isolates were the most potent aflatoxins producers inhabiting wheat grains. The effect of storage conditions of wheat grains "humidity, temperature, incubation period, and pH" on growth of A. flavus, was assessed by the response surface methodology using Plackett-Burman design and FCCD. The highest yield of aflatoxins EFBL-MU12 B1 and B2 by A. flavus grown on wheat grains were 145.3 and 7.6 µg/kg, respectively, at incubation temperature 35°C, 16% moisture contents, initial pH 5.0, and incubated for 14 days. The tested oils had a powerful antifungal activity for the growth and aflatoxins production by A. flavus in a concentration-dependent manner. Among these oils, cinnamon oil had the highest fungicidal activity for A. flavus at 0.125%, with about 85-90 % reduction to the aflatoxins B1 and B2, conidial pigmentation and chitin contents on wheat grains. From the SEM analysis, cinnamon oils had the most deleterious effect on A. flavus with morphological aberrations to the conidial heads, vegetative mycelia, alteration in conidiophores identity, hyphae shrank, and winding. To emphasize the effect of the essential oils on the aflatoxins producing potency of A. flavus, the molecular expression of the aflatoxins biosynthetic genes was estimated by RT-qPCR. The molecular expression of nor-1, afLR, pKsA and afLJ genes was suppressed by 94-96%, due to cinnamon oil at 0.062% compared to the control. Conclusively, from the results, cinnamon oils followed by the peppermint oils displayed the most fungicidal activity for the growth and aflatoxins production by A. flavus grown on wheat grains.

Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B.

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.