Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.

Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet

BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.

Modern approaches for detection of volatile organic compounds in metabolic studies focusing on pathogenic bacteria:Current state of the art

Pathogenic microorganisms produce numerous metabolites,including volatile organic compounds(VOCs).Monitoring these metabolites in biological matrices(e.g.,urine,blood,or breath)can reveal the presence of specific microorganisms,enabling the early diagnosis of infections and the timely implementation of tar-geted therapy.However,complex matrices only contain trace levels of VOCs,and their constituent com-ponents can hinder determination of these compounds.Therefore,modern analytical techniques enabling the non-invasive identification and precise quantification of microbial VOCs are needed.In this paper,we discuss bacterial VOC analysis under in vitro conditions,in animal models and disease diagnosis in humans,including techniques for offline and online analysis in clinical settings.We also consider the advantages and limitations of novel microextraction techniques used to prepare biological samples for VOC analysis,in addition to reviewing current clinical studies on bacterial volatilomes that address inter-species in-teractions,the kinetics of VOC metabolism,and species-and drug-resistance specificity.

Bioactivities,Mechanisms,Production,and Potential Application of Bile Acids in Preventing and Treating Infectious Diseases

Infectious diseases are a global public health problem,with emerging and re-emerging infectious diseases on the rise worldwide.Therefore,their prevention and treatment are still major challenges.Bile acids are common metabolites in both hosts and microorganisms that play a significant role in controlling the metabolism of lipids,glucose,and energy.Bile acids have historically been utilized as first-line,valuable therapeutic agents for related metabolic and hepatobiliary diseases.Notably,bile acids are the major active ingredients of cow bezoar and bear bile,which are commonly used traditional Chinese medicines(TCMs)with the therapeutic effects of clearing heat,detoxification,and relieving wind and spasm.In recent years,the promising performance of bile acids against infectious diseases has attracted attention from the scientific community.This paper reviews for the first time the biological activities,possible mechanisms,production routes,and potential applications of bile acids in the treatment and prevention of infectious diseases.Compared with previous reviews,we comprehensively summarize existing studies on the use of bile acids against infectious diseases caused by pathogenic microorganisms that are leading causes of global morbidity and mortality.In addition,to ensure a stable supply of bile acids at affordable prices,it is necessary to clarify the biosynthesis of bile acids in vivo,which will assist scientists in elucidating the accumulation of bile acids and discovering how to engineer various bile acids by means of chemosynthesis,biosynthesis,and chemoenzymatic synthesis.Finally,we explore the current challenges in the field and recommend a development strategy for bile-acid-based drugs and the sustainable production of bile acids.The presented studies suggest that bile acids are potential novel therapeutic agents for managing infectious diseases and can be artificially synthesized in a sustainable way.

Adverse drug reactions of first-line antitubercular drugs:A retrospective study on characteristics,management,factors,and impacts

Objective:To elucidate the characteristics,management strategies,risk factors,and clinical impacts associated with adverse drug reactions(ADRs)induced by first-line antitubercular drugs to enhance tuberculosis(TB)management.Methods:A retrospective cohort study was conducted by retrieving drug-susceptible TB records among adult patients who received TB treatment from 2018 to 2021 at 10 public health clinics in Sarawak,Malaysia.Only the initial TB treatment and occurrence of specific ADRs within the study period were considered.Regression analysis was performed to identify the risk factors associated with both overall ADRs and individual types of ADRs.Results:Among 2953 cases,705(23.9%)developed ADRs.Cutaneous reactions were the most prevalent(47.1%),followed by hepatotoxicity(32.8%)and gastrointestinal disturbances(29.8%).Six out of seven types of ADRs investigated occurred within the intensive phase,mostly manifesting at approximately 2 weeks of initiation.Hepatotoxicity resulted in the majority(85.3%)of treatment discontinuations,while vision problems led to treatment modifications in half of the cases.Risk factors for all ADRs included age≥60 years,females,illicit drug use,and comorbidities such as HIV-positive,diabetes,and chronic liver disease.Alcohol consumption was independently associated with hepatotoxicity.ADRs caused around one-third of interruptions exceeding 2 weeks(33.0%)and subsequently necessitated treatment restarts(34.5%).Conclusions:Understanding these various aspects contributes to improving the overall management of ADRs in TB treatment.Close ADR monitoring and reporting are essential to strengthen ADR management.

Methanolic extract of Ephedra alata inhibits breast cancer cells in vitro and in vivo

Objective:To determine the anticancer potential of the methanolic extract from Ephedra alata against breast cancer both in vitro and in vivo.Methods:The effects of the methanolic extract of Ephedra alata on the viability,migration as well as apoptosis of breast cancer 4T1 cells were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,Transwell assay,and annexin V-FITC staining assay,respectively.Histological examination was also carried out.Moreover,a murine breast cancer model was established to evaluate the inhibitory effect of the extract.Biochemical parameters including hepatic and non-hepatic enzymes,malondialdehyde,and glutathione were investigated.Results:The methanolic extract of Ephedra alata showed a strong anti-proliferative and anti-migratory activity against 4T1 cells in a dose-dependent manner.It also induced apoptosis in 4T1 cells.In an in vivo mouse model,the extract markedly inhibited tumor growth,reduced malondialdehyde,and hepatic and non-hepatic enzymes as well as increased glutathione level.Conclusions:The methanolic extract of Ephedra alata inhibits breast cancer in vitro and in vivo,which may be a promising anticancer agent.

Effect of coenzyme Q10 supplementation on post-vitrification mouse embryo development

Objective:To investigate the effects of coenzyme Q10(CoQ10)supplementation on post-vitrification embryo development and gross morphology.Methods:Balb/c mouse embryos were cultured in potassium simplex optimised medium(KSOM)with varying CoQ10 concentrations[0(control),20,40,and 60μM].The most effective CoQ10 concentration(40μM)was selected for subsequent post-vitrification morphology study.Embryos were randomly divided into four groups:Group A(non-vitrified without CoQ10),Group B(non-vitrified with CoQ10),Group C(vitrified without CoQ10),and Group D(vitrified with CoQ10),followed by vitrification at the 8-cell stage.Survival rates and development until the blastocyst stage were evaluated through morphological examinations using ASEBIR's system,distinguishing normal and abnormal embryos.Results:Supplementation of 40μM CoQ10 significantly increased blastocyst formation(95%)compared to the control group(92%),20μM(62%),and 60μM(56%)(P<0.001).Following vitrification,Group D exhibited a significant increase in blastocyst formation(92%)compared to Group C(82%)(P<0.05).Morphological assessments indicated superior embryo quality in Group B over Group D during the cleavage stage,morula,and blastocyst(P<0.05).Conclusions:CoQ10 supplementation exhibits promising potential to enhance preimplantation embryo development,increase blastocyst formation rates,and improve embryo quality post-vitrification.This offers a promising approach to mitigate oxidative stress on embryos,potentially improving overall assisted reproductive technology outcomes.

Timing impact on the initiation of pirfenidone therapy on idiopathic pulmonary fibrosis disease progression

In this editorial,we comment on the article by Lei et al,with a specific focus on the timing of the initiation of the antifibrotic agent pirfenidone(PFD)in the management of idiopathic pulmonary fibrosis(IPF)and its impact on lung function of IPF patients.PFD is an antifibrotic agent that is widely used in the management of IPF in both early and advanced stages.It inhibits various pathways and has antifibrotic,anti-inflammatory,and antioxidant properties.Despite dosage lowering,PFD slowed IPF progression and maintained functional capacity.The 6-min walk distance test indicated that patients tolerated adverse events well,and PFD significantly reduced the incidence of progression episodes and death.Even when a single disease-progression event occurred,continuing PFD treatment had benefits.

Adding chitosan nanoparticles of green tea extract in diluent and thawing temperatures ameliorate the post-thawed quality of Boer buck semen

Objective:To improve the quality of post-thawing Boer buck semen for artificial insemination by adding green tea extract chitosan nanoparticles to skimmed egg yolk diluent,and the proper thawing temperature.Methods:The ejaculate of Boer buck was added to skimmed egg yolk diluent without(the control group)and with adding 1μg of chitosan nanoparticles of green tea extract per mL of diluent(the treatment group).Then,the diluted semen was filled in French mini straws containing 60×106 live sperm per straw,frozen in a standard protocol,and stored as frozen semen at−196℃for a week.Six replicates from each group were diluted for 30 s at 37℃or 39℃sterile water to evaluate the semen quality.Results:Post-thawing(at 37℃or 39℃)of live sperm,progressive motility,and plasma membrane integrity were lower compared to those of the pre-freezing stage(P<0.05).Thawing at 37℃resulted in no significant difference in live sperm,progressive motility,and plasma membrane between the control group and the treatment group(P>0.05).The live sperm,progressive motility,and plasma membrane of the treatment group in the pre-freezing stage,and post-thawed at 39℃were higher compared to those of the control group(P<0.05).There was no significant difference in malondialdehyde(MDA)concentration,DNA fragmentation,and catalase concentration of thawing at 37℃compared to those of 39℃in the same group.The MDA concentration and DNA fragmentation in thawing at 37℃and 39℃of the treatment group were significantly lower than those of the control group(P<0.05).However,the catalase concentration in thawing at 37℃and 39℃of the treatment group was not significantly different than the control group(P>0.05).Conclusions:Higher quality post-thawing Boer buck semen is achieved by adding 1μg/mL of chitosan nanoparticles of green tea extract to the skimmed egg yolk diluent and thawing at 39℃.

Recognition and quality mapping of traditional herbal drugs:way forward towards artificial intelligence

The use of traditional herbal drugs derived from natural sources is on the rise due to their minimal side effects and numerous health benefits.However,a major limitation is the lack of standardized knowledge for identifying and mapping the quality of these herbal medicines.This article aims to provide practical insights into the application of artificial intelligence for quality-based commercialization of raw herbal drugs.It focuses on feature extraction methods,image processing techniques,and the preparation of herbal images for compatibility with machine learning models.The article discusses commonly used image processing tools such as normalization,slicing,cropping,and augmentation to prepare images for artificial intelligence-based models.It also provides an overview of global herbal image databases and the models employed for herbal plant/drug identification.Readers will gain a comprehensive understanding of the potential application of various machine learning models,including artificial neural networks and convolutional neural networks.The article delves into suitable validation parameters like true positive rates,accuracy,precision,and more for the development of artificial intelligence-based identification and authentication techniques for herbal drugs.This article offers valuable insights and a conclusive platform for the further exploration of artificial intelligence in the field of herbal drugs,paving the way for smarter identification and authentication methods.

Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

A texture-modified dessert with high nutritional value designed for people with dysphagia:effect of refrigeration and frozen storage

Dysphagia is commonly associated with malnutrition and an increased choking risk.To overcome these complications,food designed for people with dysphagia should have an appropriate texture and a high nutritional value.In this study,six formulations of a strawberry dessert enriched in protein(calcium caseinate)and fiber(wheat dextrin or inulin)were developed using different hydrocolloids(xanthan gum,carboxymethyl cellulose or modified starch)to provide desirable texture and stability.Nutritional value was calculated and total phenolic content and antioxidant activity of the samples were analyzed.Back-extrusion test,rheological measurements and sensory analysis were performed in refrigerated and frozen samples to characterize their textural and viscoelastic properties.The high content in protein(14.7 g/100 g)and fiber(7.9-8.7 g/100 g)made possible to use the claims“high protein”and“high fiber”.Phytochemicals supplied by strawberries contributed to the antioxidant properties of the dessert.Loss tangent ranged 0.28-0.35 for all the formulations,indicating a weak gel behavior,which could be considered safe to swallow.The formulations with dextrin in combination with carboxymethyl cellulose or xanthan gum seemed to be less susceptible to structural changes during frozen storage.This work provides insights for the development of a nutrient-dense dessert that meets the requirements of people with dysphagia.

Metabologenomics and network pharmacology to understand the molecular mechanism of cancer research

In this editorial I comment on the article“Network pharmacological and molecular docking study of the effect of Liu-Wei-Bu-Qi capsule on lung cancer”published in the recent issue of the World Journal of Clinical Cases 2023 November 6;11(31):7593-7609.Almost all living forms are able to manufacture particular chemicals-metabolites that enable them to differentiate themselves from one another and to overcome the unique obstacles they encounter in their natural habitats.Numerous methods for chemical warfare,communication,nutrition acquisition,and stress prevention are made possible by these specialized metabolites.Metabolomics is a popular technique for collecting direct mea-surements of metabolic activity from many biological systems.However,con-fusing metabolite identification is a typical issue,and biochemical interpretation is frequently constrained by imprecise and erroneous genome-based estimates of enzyme activity.Metabolite annotation and gene integration uses a biochemical reaction network to obtain a metabolite-gene association so called metabologe-nomics.This network uses an approach that emphasizes metabolite-gene consensus via biochemical processes.Combining metabolomics and genomics data is beneficial.Furthermore,computer networking proposes that using meta-bolomics data may improve annotations in sequenced species and provide testable hypotheses for specific biochemical processes.CONCLUSION The genome and metabolites of biological organisms are not fully characterized with current technologies.However,increasing high-throughput metabolomics and genomics data provide promising generation of paired data sets to understand the molecular mechanism of biochemical processes as well as determining targets for pharmaceutical drug design.Contemporary network infrastructures to integrate omics analysis can provide molecular mechanism of biochemical pathways.Furthermore,clinical data may be integrated to gene expression–metabolite expression by system genetics approach.Calculating pair-wise correlations and weighted correlation network analysis provide the basis of this integration[11-13].The occurrence of strong correlations between classified metabolites and co-expression transcripts implies either various roles of metabolites or linkages between metabolic pathways and the immune system.

A therapeutic potentiality and toxicity concern of nutrient plant Annona squamosa Linn.

Annona squamosa Linn.fruit is famous for its nutritional value with a long history of medicinal benefits due to the presence of many phytochemicals,including alkaloids,diterpenes,essential oil,phytopeptides,etc.Several studies envisaged that Annona squamosa possesses cytotoxic,diuretic,antiurolithiatic,antitumor,anti-psoriatic,antioxidant,and hepatoprotective properties.This plant is traditionally used for the treatment of wound infection,dysentery,seizure,tumors,fever,vomiting,parasitic infections,hypertension,thyroid,toothache,acne,heart disease,inflammation,diabetes,hair loss,dandruff,hemorrhage,maggot-infected sores,abortifacient,and cough.However,some chemical constituents isolated from the plant have shown specific toxic effects in human and animal models,such as acute oral toxic effects,genotoxic,neurotoxic,and ocular toxic.The plant has diverse pharmacological actions,the seeds of this plant possess a genotoxic effect but on the contrary,the bark of the plant shows genoprotective activity.A large number of ethnobotanical studies reported the seed of this plant is used to induce abortion in humans,but a scientific study carried out in pregnant rats reported aqueous seed extract of the plant did not interfere with reproductive performance.The presented review summarized the traditional uses,pharmacological,and toxicological activities of the isolated compounds from this plant.Additionally,some patents and commercial products related to Annona squamosa are also brought up in this article to explore its application which would attract the scientific community to search out its hidden side.

Sexual dimorphism of G protein-coupled receptor signaling in the brain

G protein-coupled receptors(GPCRs)represent the most substantial family of membrane receptors that are targeted by U.S.Food and Drug Administration-approved drugs.Much of the preclinical research to understand the pharmacology of many membrane receptors including GPCRs is derived from studies in male animal models(Karp and Reavey,2019).

Insights into the anorexic mechanism of Khat:an integrated in vivo,ex vivo,and in silico investigations

Background:Chewing Khat(Catha edulis)releases cathine and cathinone,which may reduce appetite via an unknown mechanism.This study investigated the peripheral and central effects of fresh leaves and buds of Catha edulis water extract(CEWE)on appetite biomarkers,gene expression,and body weight,using in vivo,ex vivo,and in silico models.Methods:Rats of both sexes were orally administered CEWE at different doses and durations in three different experiments.Liquid chromatography-mass spectroscopy(LC-MS)-MS was used to detect cathinone and cathine in the murine blood.The effect of Khat on serotonin receptors was studied in isolated rat fundus samples.Docking of the two Khat ligands was performed on G(The 5-hydroxytryptamine-type 2C receptor(5-HT2C)in an agonist-bound active conformation)and H(5-HT2C in an antagonist-bound inactive conformation)proteins to determine which ligands are most likely to act as agonists or antagonists.Results:Significant differences(P<0.05)in body weight were observed between the CEWE-treated groups and the controls over eight weeks.However,the plasma leptin and ghrelin levels did not change significantly(P>0.05).The expression of the ghrelin and leptin genes was also unaffected,but the expression of the 5-hydroxytryptamine(5-HT)gene decreased(P<0.05)with CEWE treatment.CEWE antagonizes 5-HT receptors in isolated rat fundus samples.Docking findings indicated that the khat ligands bound to 5-HT2C receptors.Cathine and cathinone levels in rat plasma were measured.Conclusion:Khat extract may suppress appetite by antagonizing the 5-HT receptors.Further research is required to understand its mechanism and potential applications.

Charcoal Nanoparticles as a Delivery System for Doxorubicin and Sorafenib in Treatment of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. The delivery of therapeutic compounds to the target site is a major challenge in the treatment of many diseases. Objective: This study aims to evaluate activated charcoal nanoparticles as a drug delivery system for anticancer agents (Sorafenib and Doxorubicin) in Hepatocellular Cancer Stem Cells. Method: The percent efficiency of entrapment (% EE) of the doxorubicin and sorafenib entrapped onto the activated charcoal was obtained by determining the free doxorubicin and sorafenib concentration in the supernatant-prepared solutions. Then the characterizations of nanoparticles were formed by determination of the particle size distribution, zeta potential, and polydispersity index (PDI). The anticancer activity of activated Charcoal, Doxorubicin-ACNP, sorafenib-ACNP, free doxorubicin, and free sorafenib solutions was measured based on cell viability percentage in HepG2 cell lines (ATCC-CCL 75). In vitro RBC’s toxicity of Doxorubicin/sorafenib loaded charcoal was estimated by hemolysis percentage. Results: The synthesized Doxorubicin-ACNP and Sorafenib-ACNP were evaluated and their physiochemical properties were also examined. Essentially, the percent Efficiency of Entrapment (EE %) was found to be 87.5% and 82.66% for Doxorubicin-ACNP and Sorafenib-ACNP, respectively. The loading capacity was 34.78% and 24.31% for Doxorubicin-ACNP and Sorafenib-ACNP. Using the Dynamic Light scattering [DLS] for the determination of the hydrodynamic size and surface zeta potential, a narrow sample size distribution was obtained of (18, 68, and 190 nm for charcoal, 105, 255, and 712 nm for doxorubicin, and 91, 295, and 955 nm for sorafenib), respectively. A surface charge of −13.2, −15.6 and −17 was obtained for charcoal, doxorubicin/charcoal, and sorafenib/charcoal nanoparticles. The cytotoxic activity of Doxorubicin-ACNP and Sorafenib-ACNP was evaluated in-vitro against HepG2 cell lines and it was observed that Drug loaded ACNP improved anticancer activity when compared to Doxorubicin or Sorafenib alone. Moreover, testing the toxicity potential of DOX-ACNP and Sorafenib-ACNP showed a significant reduction in the hemolysis of red blood cells when compared to Doxorubicin and Sorafenib alone. Conclusion: In conclusion, it is notable to state that this study is regarded as the first to investigate the use of Activated charcoal for the loading of Doxorubicin and Sorafenib for further use in the arena of hepatocellular carcinoma. Doxorubicin-ACNP and Sorafenib-ACNP showed noteworthy anticancer activity along with a reduced potential of RBCs hemolysis rendering it as an efficacious carrier with a low toxicity potential.

Aszonapyrone A Isolated from Neosartorya spinosa IFM 47025 Inhibits the NF-κB Signaling Pathway Activated by Expression of the Ependymoma-Causing Fusion Protein ZFTA-RELA

Ependymoma is a rare and chemotherapy-resistant brain tumor, which has resulted in a delay in the development of drugs to treat it. A subclass of supratentorial ependymomas (ST-EPN), designated ST-EPN-zinc finger-translocation-associated (ZFTA, ST-EPN-ZFTA), exhibits the expression of a fusion protein comprising ZFTA and v-rel reticuloendotheliosis viral oncogene homolog A (RELA), an effector transcription factor of the nuclear factor-kappa B (NF-κB) pathway (ZFTA-RELA). The expression of ZFTA-RELA results in the hyperactivation of the oncogenic NF-κB signaling pathway, which ultimately leads to the development of ST-EPN-ZFTA. To identify inhibitors of the NF-κB signaling pathway activated by the expression of ZFTA-RELA, we used a doxycycline-inducible ZFTA-RELA-expressing NF-κB reporter cell line and found that extracts of the fungus Neosartorya spinosa IFM 47025 exhibited NF-κB inhibitory activity. We identified eight compounds [aszonapyrone A (2), sartorypyrone A (3), epiheveadride (4), acetylaszonalenin (5), (R)-benzodiazepinedione (6), aszonalenin (7), sartorypyrone E (8) and (Z, Z)-N,N’-(1,2-bis[(4-methoxyphenyl)methylene]-1,2-ethanediyl)bis-formamide (9)] from N. spinosa IFM 47025 culture extract using a variety of chromatographic techniques. The structures of these compounds were identified through the analysis of various instrumental data (1D, 2D-NMR, MS, and optical rotation). The NF-κB responsive reporter assay indicated that compounds 2, 3, 5, 7, and 9 exhibited inhibitory activity. We further evaluated the inhibitory activity of these compounds against the expression of endogenous NF-κB responsive genes (CCND1, L1CAM, ICAM1, and TNF) and found that compound 2 showed significant inhibitory activity. Further studies are required to elucidate the mechanism of action of compound 2, which may serve as a lead compound for the development of a novel therapy for ST-EPN-ZFTA.

Evaluation of Azadirachta indica cultivated in Egypt against biofilm formation by Pseudomonas aeruginosa: Insights from molecular docking studies targeting LasR

Background:Azadirachta indica(A.indica),commonly known as neem,is a widely distributed medicinal plant in Asia and Africa and is well known to have a wide spectrum of biological activity.A.indica is considered a skin food that was traditionally used in different cultures to treat a wide range of skin disorders.A.indica was reported to possess antibacterial activity against Pseudomonas aeruginosa(P.aeruginosa)which is considered the most common biofilm model organism.This study aims to investigate the ability of A.indica cultivated in Egypt to inhibit/reduce the biofilm formation by P.aeruginosa.Methods:The microtiter plate assay was used to evaluate the anti-biofilm activity of neem,cultivated in Egypt,leaves against P.aeruginosa as well as the ability to reduce the activity of P.aeruginosa.To investigate the phytocompounds responsible for their bioactivity and to explore potential interactions between their bioactive components and one of the quorum-sensing regulatory proteins of P.aeruginosa involved in biofilm formation,liquid chromatography-mass spectrometric and molecular docking studies were done.Results:Results showed that methanol extract of leaves can reduce the formation of P.aeruginosa biofilm at lower concentrations than those reported in other regions with 1.25 mg/mL as the optimum concentration.The two-way analysis of variance revealed the significance of the extract effect and its concentration on the reduction of biofilm formation(P<0.05).Liquid chromatography-mass spectrometric study revealed the presence of fourteen compounds that belong to limonoids and flavonoids.Molecular docking analysis against LasR,the quorum-sensing regulatory protein,of P.aeruginosa supported these findings.Nimbolinin,a limonoid,has achieved the highest Libdock score of 138.769.Conclusion:It was concluded that A.indica,cultivated in Egypt,leaves can target LasR as a new mechanism of action for biofilm control by A.indica and therefore could be a good source of leads for anti-biofilm medicine.

Molecular phylogeny and taxonomy of Phlomoides(Lamiaceae subfamily Lamioideae)in China:Insights from molecular and morphological data

Phlomoides,with 150-170 species,is the second largest and perhaps most taxonomically challenging genus within the subfamily Lamioideae(Lamiaceae).With about 60 species,China is one of three major biodiversity centers of Phlomoides.Although some Phlomoides species from China have been included in previous molecular phylogenetic studies,a robust and broad phylogeny of this lineage has yet to be completed.Moreover,given the myriad new additions to the genus,the existing infrageneric classification needs to be evaluated and revised.Here,we combine molecular and morphological data to investigate relationships within Phlomoides,with a focus on Chinese species.We observed that plastid DNA sequences can resolve relationships within Phlomoides better than nuclear ribosomal internal and external transcribed spacer regions(nrITS and nrETS).Molecular phylogenetic analyses confirm the monophyly of Phlomoides,but most previously defined infrageneric groups are not monophyletic.In addition,morphological analysis demonstrates the significant taxonomic value of eight characters to the genus.Based on our molecular phylogenetic analyses and morphological data,we establish a novel section Notochaete within Phlomoides,and propose three new combinations as well as three new synonyms.This study presents the first molecular phylogenetic analyses of Phlomoides in which taxa representative of the entire genus are included,and highlights the phylogenetic and taxonomic value of several morphological characters from species of Phlomoides from China.Our study suggests that a taxonomic revision and reclassification for the entire genus is necessary in the future.