Induction of antimicrobial, antioxidant metabolites production by co-cultivation of two red-sea-sponge-associated Aspergillus sp. CO2 and Bacillus sp. COBZ21.

The growing spread of infectious diseases has become a potential global health threat to human beings. According to WHO reports, in this study, we investigated the impact of co-cultivating the isolated endophytic fungus Aspergillus sp. CO2 and Bacillus sp. COBZ21 as a method to stimulate the production of natural bioactive substances. (GC/MS)-based metabolomics profiling of two sponge-associated microbes, Aspergillus sp. CO2 and Bacillus sp. COBZ21, revealed that the co-culture of these two isolates induced the accumulation of metabolites that were not traced in their axenic cultures. By detection of different activities of extracts of Bacillus sp. COBZ21 and Aspergillus sp. CO2 and coculture between Bacillus sp. COBZ21 and Aspergillus sp. CO2. It was noted that the coculture strategy was the reason for a notable increase in some different activities, such as the antimicrobial activity, which showed potent activity against Escherichia coli ATCC 25,922, Staphylococcus aureus NRRLB-767, and Candida albicans ATCC 10,231. The antibiofilm activity showed significant biofilm inhibitory activity toward Bacillus subtilis ATCC 6633, Pseudomonas aeruginosa ATCC 10,145, and Staph aureus NRRLB-767, with activity up to 53.66, 71.17, and 47.89%, while it showed low activity against E. coli ATCC 25,922, while the antioxidant activity based on the DPPH assay showed maximum activity (75.25%). GC-MS investigations revealed the presence of variable chemical constituents belonging to different chemical categories, which reflected their chemical diversity. The main components are (+-) cis-Deethylburnamine (2.66%), Bis(3,6,9,12-tetraoxapentaethylene) crowno-N,N,N',N'-tetra methylpphanediamine (2.48%), and 11-phenyl-2,4,6,8-tetra(2-thienyl)-11-aza-5,13-dithiaeteracyclo[7.3.0.1(2,8)0.0(3,7)] trideca-3,6-diene-10,12,13-trione (3.13%), respectively, for Bacillus sp. axenic culture, Aspergillus sp. CO2, Aspergillus sp. CO2, and Bacillus sp. COBZ21 coculture. By studying the ADME-related physicochemical properties of coculture extract, the compound showed log Po/w values above 5 (8.82). The solubility of the substance was moderate. In order to provide a comprehensive definition of medicinal chemistry and leadlikness, it is important to note that the latter did not meet the criteria outlined in the rule of three (RO3). The toxicity prediction of the coculture extract was performed using the ProTox II web server, which showed that the selected compound has no pronounced toxicity.

Characterization, modeling, and anticancer activity of L.arginase production from marine Bacillus licheniformis OF2.

BACKGROUND: L-arginase, is a powerful anticancer that hydrolyzes L-arginine to L-ornithine and urea. This enzyme is widely distributed and expressed in organisms like plants, fungi, however very scarce from bacteria. Our study is based on isolating, purifying, and screening the marine bacteria that can produce arginase. RESULTS: The highest arginase producing bacteria will be identified by using microbiological and molecular biology methods as Bacillus licheniformis OF2. Characterization of arginase is the objective of this study. The activity of enzyme was screened, and estimated beside partial sequencing of arginase gene was analyzed. In silico homology modeling was applied to generate the protein's 3D structure, and COACH and COFACTOR were applied to determine the protein's binding sites and biological annotations based on the I-TASSER structure prediction. The purified enzyme was undergone an in vitro anticancer test. CONCLUSIONS: L-arginase demonstrated more strong anti-cancer cells with an IC50 of 21.4 ug/ml in a dose-dependent manner. L-arginase underwent another investigation for its impact on the caspase 7 and BCL2 family of proteins (BCL2, Bax, and Bax/Bcl2). Through cell arrest in the G1/S phase, L-arginase signals the apoptotic cascade, which is supported by a flow cytometry analysis of cell cycle phases.

Biogenic selenium nanoparticles and selenium/chitosan-Nanoconjugate biosynthesized by Streptomyces parvulus MAR4 with antimicrobial and anticancer potential.

BACKGROUND: As antibiotics and chemotherapeutics are no longer as efficient as they once were, multidrug resistant (MDR) pathogens and cancer are presently considered as two of the most dangerous threats to human life. In this study, Selenium nanoparticles (SeNPs) biosynthesized by Streptomyces parvulus MAR4, nano-chitosan (NCh), and their nanoconjugate (Se/Ch-nanoconjugate) were suggested to be efficacious antimicrobial and anticancer agents. RESULTS: SeNPs biosynthesized by Streptomyces parvulus MAR4 and NCh were successfully achieved and conjugated. The biosynthesized SeNPs were spherical with a mean diameter of 94.2 nm and high stability. Yet, Se/Ch-nanoconjugate was semispherical with a 74.9 nm mean diameter and much higher stability. The SeNPs, NCh, and Se/Ch-nanoconjugate showed significant antimicrobial activity against various microbial pathogens with strong inhibitory effect on their tested metabolic key enzymes [phosphoglucose isomerase (PGI), pyruvate dehydrogenase (PDH), glucose-6-phosphate dehydrogenase (G6PDH) and nitrate reductase (NR)]; Se/Ch-nanoconjugate was the most powerful agent. Furthermore, SeNPs revealed strong cytotoxicity against HepG2 (IC50 = 13.04 µg/ml) and moderate toxicity against Caki-1 (HTB-46) tumor cell lines (IC50 = 21.35 µg/ml) but low cytotoxicity against WI-38 normal cell line (IC50 = 85.69 µg/ml). Nevertheless, Se/Ch-nanoconjugate displayed substantial cytotoxicity against HepG2 and Caki-1 (HTB-46) with IC50 values of 11.82 and 7.83 µg/ml, respectively. Consequently, Se/Ch-nanoconjugate may be more easily absorbed by both tumor cell lines. However, it exhibited very low cytotoxicity on WI-38 with IC50 of 153.3 µg/ml. Therefore, Se/Ch-nanoconjugate presented the most anticancer activity. CONCLUSION: The biosynthesized SeNPs and Se/Ch-nanoconjugate are convincingly recommended to be used in biomedical applications as versatile and potent antimicrobial and anticancer agents ensuring notable levels of biosafety, environmental compatibility, and efficacy.

Normal CEA Levels After Neoadjuvant Chemotherapy and Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion Predict Improved Survival from Colorectal Peritoneal Metastases.

BACKGROUND: Normal carcinoembryonic antigen (CEA) levels (≤ 2.5 ng/ml) after resection of localized colorectal cancer or liver metastases are associated with improved survival, however, these trends are understudied for colorectal peritoneal metastases (CRPM). PATIENTS AND METHODS: We conducted a retrospective single-institution study of patients with CRPM undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) with and without neoadjuvant chemotherapy (NACT). CEA was measured before and after NACT and within 3 months after CRS/HIPEC. RESULTS: A total of 253 patients (mean age 55.3 years) with CRPM undergoing CRS/HIPEC had complete CEA data and 191 also underwent NACT with complete data. The median peritoneal carcinomatosis index score (PCI) of the overall cohort was 12 and 82.7% of patients had complete cytoreduction (CC0). In total, 64 (33.5%) patients had normal CEA levels after NACT with a median overall survival (OS) of 45.2 months compared with those with an elevated CEA (26.4 months, p = 0.004). Patients with normal CEA after NACT had a lower PCI found at the time of surgery than those with elevated CEA (10 versus 14, p < 0.001), 68 (26.9%) patients with an elevated preoperative CEA level experienced normalization after CRS/HIPEC, and 118 (46.6%) patients had elevated CEA after CRS/HIPEC. Patients who experienced normalization demonstrated similar OS to patients that had normal CEA levels pre- and post-surgery and improved OS compared with those with elevated postop CEA (median 41.9 versus 47 months versus 17.1 months, respectively, p < 0.001). CONCLUSIONS: Normal CEA levels after NACT and/or CRS/HIPEC are associated with improved survival for patients with CRPM. Patients that normalize CEA levels after surgery have similar survival to those with normal preoperative levels.

Increasing the sensitivity and accuracy of detecting exosomes as biomarkers for cancer monitoring using optical nanobiosensors.

The advancement of nanoscience and material design in recent times has facilitated the creation of point-of-care devices for cancer diagnosis and biomolecule sensing. Exosomes (EXOs) facilitate the transfer of bioactive molecules between cancer cells and diverse cells in the local and distant microenvironments, thereby contributing to cancer progression and metastasis. Specifically, EXOs derived from cancer are likely to function as biomarkers for early cancer detection due to the genetic or signaling alterations they transport as payload within the cancer cells of origin. It has been verified that EXOs circulate steadily in bodily secretions and contain a variety of information that indicates the progression of the tumor. However, acquiring molecular information and interactions regarding EXOs has presented significant technical challenges due to their nanoscale nature and high heterogeneity. Colorimetry, surface plasmon resonance (SPR), fluorescence, and Raman scattering are examples of optical techniques utilized to quantify cancer exosomal biomarkers, including lipids, proteins, RNA, and DNA. Many optically active nanoparticles (NPs), predominantly carbon-based, inorganic, organic, and composite-based nanomaterials, have been employed in biosensing technology. The exceptional physical properties exhibited by nanomaterials, including carbon NPs, noble metal NPs, and magnetic NPs, have facilitated significant progress in the development of optical nanobiosensors intended for the detection of EXOs originating from tumors. Following a summary of the biogenesis, biological functions, and biomarker value of known EXOs, this article provides an update on the detection methodologies currently under investigation. In conclusion, we propose some potential enhancements to optical biosensors utilized in detecting EXO, utilizing various NP materials such as silicon NPs, graphene oxide (GO), metal NPs, and quantum dots (QDs).

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

A machine learning approach for predicting textbook outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Peritoneal carcinomatosis is considered a late-stage manifestation of neoplastic diseases. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be an effective treatment for these patients. However, the procedure is associated with significant morbidity. Our aim was to develop a machine learning model to predict the probability of achieving textbook outcome (TO) after CRS-HIPEC using only preoperatively known variables. METHODS: Adult patients with peritoneal carcinomatosis and who underwent CRS-HIPEC were included from a large, single-center, prospectively maintained dataset (2001-2020). TO was defined as a hospital length of stay ≤14 days and no postoperative adverse events including any complications, reoperation, readmission, and mortality within 90 days. Four models (logistic regression, neural network, random forest, and XGBoost) were trained, validated, and a user-friendly risk calculator was then developed. RESULTS: A total of 1954 CRS-HIPEC procedures for peritoneal carcinomatosis were included. Overall, 13% (n = 258) achieved TO following CRS-HIPEC procedure. XGBoost and logistic regression had the highest area under the curve (AUC) (0.76) after model optimization, followed by random forest (AUC 0.75) and neural network (AUC 0.74). The top preoperative variables associated with achieving a TO were lower peritoneal cancer index scores, not undergoing proctectomy, splenectomy, or partial colectomy and being asymptomatic from peritoneal metastases prior to surgery. CONCLUSION: This is a data-driven study to predict the probability of achieving TO after CRS-HIPEC. The proposed pipeline has the potential to not only identify patients for whom surgery is not associated with prohibitive risk, but also aid surgeons in communicating this risk to patients.

Neuromuscular Ultrasound in Polyneuropathies.

Neuromuscular ultrasound is a painless, radiation-free, high-resolution imaging technique for assessing the peripheral nervous system. It can accurately depict changes in the nerves and muscles of individuals with neuromuscular conditions, and it is therefore a robust diagnostic tool for the assessment of individuals with polyneuropathies. This review will outline the typical ultrasonographic changes found in a wide variety of polyneuropathies. In general, demyelinating conditions result in greater nerve enlargement than axonal conditions, and acquired conditions result in more patchy nerve enlargement compared to diffuse nerve enlargement in hereditary conditions. This review is data-driven, but more nuanced anecdotal findings are also described. The overall goal of this paper is to provide clinicians with an accessible review of the ultrasonographic approaches and findings in a wide variety of polyneuropathies.

Evaluation of Serum Neurofilament Light Chain and Nerve Ultrasound in Diabetic Neuropathy.

OBJECTIVE: To assess the role of serum neurofilament light chain (NfL) levels in individuals with diabetic polyneuropathy (DPN) compared with controls, as well as to highlight the different sonographic changes in DPN and determine if NfL correlates with sonographic, clinical, and functional parameters. METHODS: Diabetic individuals with signs or symptoms consistent with peripheral nerve involvement were recruited. They were evaluated by examination, functional neuropathy severity scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was performed of the bilateral median, ulnar, tibial, fibular, sural, and vagus nerves, and cervical roots 5 and 6. Results were compared with age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with diabetes with a mean and standard deviation of 6.95 ± 2.95 pg/mL in the diabetic group and 2.83 ± 0.77 pg/mL in controls (P < .001). Nerve cross-sectional area and serum NfL levels correlated significantly with clinical and functional parameters and with each other (P < .05). CONCLUSION: Individuals with DPN have significantly higher NfL levels than healthy controls, and NfL levels correlate with ultrasonographic parameters. These findings may be useful for the diagnosis, prognosis, and disease monitoring of those with DPN, though further exploration is needed.

Enhancing functional buffalo yogurt: Improving physicochemical properties, biological activities, and shelf life using Marjoram and Geranium essential oils.

The use of essential oils (EOs) has attracted interest in the food industry due to their wide range of beneficial properties. In this study, a new functional yogurt was developed using 2 essential oils [Marjoram (M) and Geranium (G)], at 3 different concentrations (0.2%, 0.4%, and 0.6% vol/vol). The physicochemical properties (syneresis, viscosity, pH, and chemical composition), bioactivities (antioxidant activity, anticancer and antibacterial effects, total phenolic content (TPC), and total flavonoid content (TFC)), and sensory characteristics of the developed yogurt were evaluated. The findings indicated that the yogurts fortified with 0.6% M or G exhibited higher viscosity and lower syneresis compared with other treatments. The yogurt supplemented with 0.6% M displayed significant antibacterial activity against Listeria monocytogenes, Staphylococcus aureus, Salmonella typhimurium, and Escherichia coli. In addition, the yogurt enriched with Geranium and Marjoram oils at a concentration of 0.6% had notably significant (P < 0.05) higher TFC levels compared with the control sample and other concentrations. In the same context, in terms of TPC, yogurt supplemented with 0.6% Marjoram oil displayed significantly (P < 0.05) elevated levels in comparison to the other samples tested. Yogurt enriched with Marjoram oil exhibited noteworthy antioxidant activity, followed by Geranium oil compared with the control samples. The yogurt supplemented with 0.6% M demonstrated strong radical scavenging activity, while the yogurt fortified with 0.6% G showed higher anticancer activity against HepG2 human liver carcinoma cells and oxidative stress enzyme activities. Among the various concentrations of EOs tested, the yogurts fortified with 0.6% M or G EOs exhibited the most favorable outcomes, followed by 0.4% M or G. To summarize, G and M EOs can be used as a potential nutritious ingredient and as a natural preservative for milk and related products.

Silver and gold nanoparticles: Eco-friendly synthesis, antibiofilm, antiviral, and anticancer bioactivities.

For the first time in this study, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were green synthesized by the cost-effective and eco-friendly procedure using Cotton seed meal and Fodder yeast extracts. The biosynthesized NPs were characterized by UV-Vis spectroscopy, dynamic light scattering analysis (DLS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and fourier-transform infrared (FTIR) spectroscopy. Furthermore, the biosynthesized NPs were tested in vitro against biofilm formation by some pathogenic negative bacteria (Escherichia coli, Proteus mirabilis, Klebsiella sp., Salmonella sp., and Pseudomonas aeruginosa) and negative bacteria (staphylococcus aureus) as well as against human denovirus serotype 5 (HAdV-5) and anticancer activity using HepG2 hepatocarcinoma cells. UV-Vis absorption spectra of reaction mixture of AgNPs and AuNPs exhibited maximum absorbance at 440 nm and 540 nm, respectively. This finding was confirmed by DLS measurements that the highest intensity of the AgNPs and AuNPs were 84 nm and 73.9 nm, respectively. FTIR measurements identified some functional groups detected in Cotton seed meal and Fodder yeast extracts that could be responsible for reduction of silver and gold ions to metallic silver and gold. The morphologies and particle size of AgNPs and AuNPs were confirmed by the TEM and SAED pattern analysis. Biosynthesized AgNPs and AuNPs showed good inhibitory effects against biofilms produced by Escherichia coli, Proteus mirabilis, Klebsiella sp., Salmonella sp., Pseudomonas aeruginosa, and Staphylococcus aureus. In addition, they showed anticancer activities against hepatocellular carcinoma (HepG-2) and antiviral activity against human adenovirus serotype 5 infection in vitro. Finally, the results of this study is expected to be extremely helpful to nano-biotechnology, pharmaceutical, and food packing applications through developing antimicrobial and/or an anticancer drugs from ecofriendly and inexpensive nanoparticles with multi-potentiality.

Production and evaluation of novel functional cream cottage cheese fortified with bovine colostrum and probiotic bacteria.

Nutrient-dense colostrum can be employed as a functional food ingredient. This work aimed to produce novel functional probiotic Cream cottage cheese (FPC) using probiotic (ABT) culture and bovine colostrum powder (BCP) at levels of 1, 2, and 3%. Physicochemical and functional properties (antioxidant activity, fatty acid profile, and antibacterial activity) were analyzed. The outcome revealed that hardness, cohesiveness, and gumminess were increased while springiness and chewiness were decreased for the treated cheeses. In FPC, medium-chain fatty acids were the predominant forms, followed by short- and long-chain fatty acids, polyunsaturated (PUFA), and small amounts of monounsaturated (MUFA). The antioxidant activity of all the cheese samples was significantly (P < 0.05) increased by increasing the quantity of colostrum powder and lengthening storage time. Color parameters were influenced by enrichment with BCP, whether in fresh or stored samples. With the addition of BCP, the growth of lactic acid bacteria and Bifidobacteria was enhanced, whereas that of pathogenic bacteria, mold and yeast, and coliform groups was inhibited. Cheeses fortified with 2% BCP had significantly higher score values than those in the other treatments. Therefore, it could be concluded that cottage cheese fortified with 2% BCP has high nutritional value and health benefits. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05910-0.

Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases.

BACKGROUND: Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival. METHODS: This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors. RESULTS: A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival. CONCLUSIONS: Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms (Pseudomyxoma Peritonei).

BACKGROUND: Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. METHODS: Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). RESULTS: Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). CONCLUSIONS: Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.

Exploration of Neurofilament Light Chain and Nerve Ultrasound in Leprotic Neuropathy.

OBJECTIVES: To explore neurofilament light chain (NfL) levels in leprotic neuropathy compared to controls, and to determine if the changes correlate with ultrasonographic nerve findings. METHODS: Individuals with leprosy with signs or symptoms suggestive of peripheral nerve involvement were recruited. They were evaluated by clinical examination, functional scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was conducted in bilateral median, ulnar, tibial, fibular, sural, and vagus nerves as well as cervical roots 5 and 6. Results were compared to age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with leprosy with a mean and standard deviation of 7.50 + 2.83 compared with 3.42 + 1.18 in controls (P < .001). Ultrasound showed focal enlargement of the nerves, particularly at entrapment sites. Additionally, there were noticeable changes in neural Doppler signal, echogenicity, and epineural thickness among the measured nerve sites. NfL levels in those with leprosy correlated closely with nerve cross-sectional area at all sites (P < .05). Functional and clinical assessment scores correlated with NfL and sonographic cross-sectional area as well (P ≤ .05). CONCLUSIONS: NfL is elevated in leprotic neuropathy. Ultrasound showed specific morphological changes in individuals with leprosy, and nerve enlargement correlated with NfL levels. Thus, both modalities may be useful for the diagnosis, prognosis, and disease monitoring in those with leprotic neuropathy, and further investigations are warranted.

Effectiveness of mixing poultry litter compost with rice husk biochar in mitigating ammonia volatilization and carbon dioxide emission.

Nitrogen-rich materials such as poultry litter (PL) contributes to substantial N and C loss in the form of ammonia (NH3) and carbon dioxide (CO2) during composting. Biochar can act as a sorbent of ammonia (NH3) and CO2 emission released during co-composting. Thus, co-composting poultry litter with rice husk biochar as a bulking agent is a good technique to mitigate NH3 volatilization and CO2 emission. A study was conducted to evaluate the effects of composting the mixtures of poultry litter with rice husk biochar at different ratios on NH3 and CO2 emissions. Four mixtures of poultry litter and rice husk biochar at different rate were composted at 0:1, 0.5:1, 1.3:1 and 2.3:1 ratio of rice husk biochar (RHB): poultry litter (PL) on a dry weight basis to achieve a suitable C/N ratio of 15, 20, 25, and 30, respectively. The results show that composting poultry litter with rice husk biochar can accelerate the breakdown of organic matter, thereby shortening the thermophilic phase compared to composting using poultry litter alone. There was a significant reduction in the cumulative NH3 emissions, which accounted for 78.38%, 94.60%, and 97.30%, for each C/N ratio of 20, 25, and 30. The total nitrogen (TN) retained relative was 75.96%, 85.61%, 90.24%, and 87.89% for each C/N ratio of 15, 20, 25, and 30 at the completion of composting. Total carbon dioxide lost was 5.64%, 6.62%, 8.91%, and 14.54%, for each C/N ratio of 15, 20, 21, and 30. In addition, the total carbon (TC) retained were 66.60%, 72.56%, 77.39%, and 85.29% for 15, 20, 25, and 30 C/N ratios and shows significant difference as compared with the initial reading of TC of the compost mixtures. In conclusion, mixing and composting rice husk biochar in poultry litter with C/N ratio of 25 helps in reducing the NH3 volatilization and CO2 emissions, while reducing the overall operational costs of waste disposal by shortening the composting time alongside nitrogen conservation and carbon sequestration. In formulating the compost mixture with rice husk biochar, the contribution of C and N from the biochar can be neglected in the determination of C/N ratio to predict the rate of mineralization in the compost because biochar has characteristic of being quite inert and recalcitrant in nature.

Bioactive fraction from Plumeria obtusa L. attenuates LPS-induced acute lung injury in mice and inflammation in RAW 264.7 macrophages: LC/QToF-MS and molecular docking.

In this study, the anti-inflammatory effects of the methanolic extract (TE) of Plumeria obtusa L. (aerial parts) and its fractions were evaluated in vitro, and active fraction was evaluated in vivo. Among tested extracts, dichloromethane fraction (DCM-F) exhibited the strongest inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) in RAW 264.7 macrophages. The effect of DCM-F on LPS-induced acute lung injury (ALI) in mice was studied. The animals were divided into five groups (n = 7) randomly; Gp I: negative control, GP II: positive control (LPS group), GP III: standard (dexamethasone, 2 mg/kg b.wt), GP IV and V: DCM-F (100 mg/kg), and DEM-F (200 mg/kg), respectively. DCM-F at a dose of 200 mg/kg suppressed the ability of LPS to increase the levels of nitric oxide synthase (iNOS), NO, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), as measured by ELISA. In addition, the expression of cyclooxygenase-2 (COX-2) was reduced (determined by immunohistochemistry) and the level of malondialdehyde (MDA) was decreased while that of catalase was restored to the normal values. Furthermore, the histopathological scores of inflammation induced by LPS were reduced. Twenty-two compounds were tentatively identified in DCM-F using LC/ESI-QToF with iridoids, phenolic derivatives and flavonoids as major constituents. Identified compounds were subjected to two different molecular docking processes against iNOS and prostaglandin E synthase-1 target receptors. Notably, protoplumericin A and 13-O-coumaroyl plumeride were the most promising members compared to the co-crystallized inhibitor in each case. These findings suggested that DCM-F attenuates the LPS-induced ALI in experimental animals through its anti-inflammatory and antioxidant potential.

Cholinesterase Inhibitors from an Endophytic Fungus Aspergillus niveus Fv-er401: Metabolomics, Isolation and Molecular Docking.

Alzheimer's disease poses a global health concern with unmet demand requiring creative approaches to discover new medications. In this study, we investigated the chemical composition and the anticholinesterase activity of Aspergillus niveus Fv-er401 isolated from Foeniculum vulgare (Apiaceae) roots. Fifty-eight metabolites were identified using UHPLC-MS/MS analysis of the crude extract. The fungal extract showed acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects with IC50 53.44 ± 1.57 and 48.46 ± 0.41 µg/mL, respectively. Two known metabolites were isolated, terrequinone A and citrinin, showing moderate AChE and BuChE inhibitory activity using the Ellman's method (IC50 = 11.10 ± 0.38 µg/mL and 5.06 ± 0.15 µg/mL, respectively for AChE, and IC50 15.63 ± 1.27 µg/mL and 8.02 ± 0.08 µg/mL, respectively for BuChE). As evidenced by molecular docking, the isolated compounds and other structurally related metabolites identified by molecular networking had the required structural features for AChE and BuChE inhibition. Where varioxiranol G (-9.76 and -10.36 kcal/mol), penicitrinol B (-9.50 and -8.02 kcal/mol), dicitrinol A (-8.53 and -7.98 kcal/mol) and asterriquinone CT5 (-8.02 and -8.25 kcal/mol) showed better binding scores as AChE and BuChE inhibitors than the co-crystallized inhibitor (between -7.89 and 7.82 kcal/mol) making them promising candidates for the development of new drugs to treat Alzheimer's.

Prunetin in a GPR30-dependent manner mitigates renal ischemia/reperfusion injury in rats via interrupting indoxyl sulfate/TLR4/TRIF, RIPK1/RIPK3/MLKL, and RIPK3/PGAM5/DRP-1 crosstalk.

The potential health benefits of phytochemicals in preventing and treating diseases have gained increasing attention. Here, we proved that the methylated isoflavone prunetin possesses a reno-therapeutic effect against renal ischemia/reperfusion (I/R) insult by activating G protein-coupled receptor 30 (GPR30). After choosing the therapeutic dose of prunetin against renal I/R injury in the pilot study, male Sprague Dawley rats were allocated into 5 groups; viz., sham-operated (SO), SO injected with 1 mg/kg prunetin intraperitoneally for three successive days, untreated I/R, I/R treated with prunetin, and I/R treated with G-15, the selective GPR30 blocker, followed by prunetin. Treatment with prunetin reversed the I/R renal injury effect and majorly restored normal renal function and architecture. Mechanistically, prunetin restored the I/R-induced depletion of renal GPR30, an impact that was canceled by the pre-administration of G-15. Additionally, post-administration of prunetin normalized the boosted inflammatory markers indoxyl sulfate, TLR4, and TRIF and abrogated renal cell demise by suppressing necroptotic signaling, verified by the inactivation of p-RIPK1, p-RIPK3, and p-MLKL while normalizing the inhibited caspase-8. Besides, prunetin reversed the I/R-mediated mitochondrial fission by inhibiting the protein expression of PGMA5 and p-DRP-1. All these favorable impacts of prunetin were nullified by G-15. To sum up, prunetin exhibited a significant reno-therapeutic effect evidenced by the enhancement of renal morphology and function, the suppression of the inflammatory cascade indoxyl sulfate/TLR4/TRIF, which turns off the activated/phosphorylated necroptotic trajectory RIPK1/RIPK3/MLKL, while enhancing caspase-8. Additionally, prunetin opposed the mitochondrial fission pathway RIPK3/PGMA5/DRP-1, effects that are mediated via the activation of GPR30.

Bioactive secondary metabolites from marine Actinomyces sp. AW6 with an evaluation of ADME-related physicochemical properties.

This study was designed to evaluate the antimicrobial, antioxidant, and cytotoxic potentials of the marine actinomycetes spp. isolated from the Red Sea water, Hurghada, Egypt. Out of 80 actinomycetes isolates, one isolate AW6 was selected based on its antioxidant activity (IC50 about 5.24 µg/mL which scavenged 91% of formed DPPH free radicals) and antimicrobial potential against E. coli, S. aureus, B. subtilis, and P. aeruginosa, A. niger, and C. albicans. The strain was identified based on phenotypic and genotypic analysis, and deposited in the GenBank with accession number OK090864.1. Cultivation of the selected strain on rice, chromatographic purification, and structural elucidation led to the isolation of two compounds C1: umbelliferone, and C2: 1-methoxy-3-methyl-8-hydroxy-anthraquinone. The antimicrobial activity of the obtained compounds showed that C1 and C2 have low antibacterial activity toward S. aureus and E. coli with no pronounced activity toward P. aeruginosa, C. albicans, and A. niger. Additionally, the antioxidant activity of C1 and C2 revealed that C2 has a good antioxidant activity, with DPPH scavenging activity reaching (55.25%), followed by C1 (30.20%). Moreover, both compounds displayed anti-Gyr-B enzyme activity with IC50 value of (3.79 ± 0.21 µM) for C1, and (IC50 = 13 ± 0.71 µM) for C2. The ADME-related physicochemical properties of the obtained compound were predicted using SwissADME web tools and the ProToxii webserver was used to estimate in silico toxicity.