Potential Candidate Research Articles

Discovery of the therapeutic potential of PPARδ agonist bearing 1,3,4- thiadiazole in inflammatory disorders

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11’s potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

Synthesis and Evaluation of Novel 1-Methyl-1H-pyrazol-5-amine Derivatives with Disulfide Moieties as Potential Antimicrobial Agents.

Sulfur-containing compounds have diverse biological functions and are crucial in crop protection chemistry. In this study, a series of novel 1-methyl-1H-pyrazol-5-amine derivatives incorporating disulfide moieties were synthesized and evaluated for their antimicrobial properties. In vitro bioassays demonstrated that compound 7f displayed potent antifungal activity against Valsa mali, with an EC50 value of 0.64 mg/L, outperforming allicin (EC50 = 26.0 mg/L) but lower than tebuconazole (EC50 = 0.33 mg/L). In vivo experiments confirmed that compound 7f could effectively inhibit V. mali infection on apples at a concentration of 100 mg/L, similar to the positive control tebuconazole. Mechanistic studies revealed that compound 7f could induce hyphal shrinkage and collapse, trigger intracellular reactive oxygen species accumulation, modulate antioxidant enzyme activities, initiate lipid peroxidation, and ultimately cause irreversible oxidative damage to the cells of V. mali. Additionally, compound 7b exhibited notable antibacterial activity, particularly against Pseudomonas syringae pv. actinidiae, with a MIC90 value of 1.56 mg/L, surpassing the positive controls allicin, bismerthiazol, and streptomycin sulfate. These findings suggest that 1-methyl-1H-pyrazol-5-amine derivatives containing disulfide moieties hold promise as potent candidates for the development of novel antimicrobial agents.

Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation

BackgroundTargeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.MethodsPhenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression.ResultsWe identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment.ConclusionsOur findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

The Role of Essential Oils on Sleep Quality and Other Sleep-related Issues: Evidence from Clinical Trials.

Essential oils (EOs) are a volatile mixture of bioactive compounds extracted from aromatic plants. The composition of EOs varies, which majorly depends on the extraction methods and plant parts. Aromatherapy using EOs has been reported for its several beneficial effects in humans. Aromatherapy is considered a complementary and/ or adjuvant therapeutic approach for treating several illnesses, especially to improve mental health and well-being. The incidence of sleep disorders, specifically insomnia, is nowadays increased, possibly due to urbanization and lifestyle. The studies showed that EOs-based treatments using lavender EO, bergamot EO, cinnamon EO, and rosemary EO (alone or in combinations) could improve sleep quality, duration, and deprivation in healthy subjects and patients, those who suffer from sleep-related issues. The current manuscript details the outcomes of EO-based treatments on the sleep quality of humans and the possible mechanisms associated with the health-promoting properties of EOs. Also, the toxicity and adverse effects of EOs have been discussed. The study indicated that EOs are potent adjuvant therapeutic candidates to manage mood-associated complications in humans. Moreover, the aromatherapeutic field requires detailed studies on toxicity and dose determination, which could provide safe and effective therapeutic results.

Design, synthesis, molecular docking, and evaluation of sulfonyl quinazoline analogues as promising liver cancer drugs

Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for cancer treatments by interfering with apoptotic proteins related to cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC50 values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced apoptosis in HepG-2 cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compoundsB34 andB35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.

Plug-and-play nucleic acid-mediated multimerization of biparatopic nanobodies for molecular imaging

In cancer molecular imaging, selecting binders with high specificity and affinity for biomarkers is paramount for achieving high-contrast imaging within clinical time frames. Nanobodies have emerged as potent candidates, surpassing antibodies in pre-clinical imaging due to their convenient production, rapid renal clearance, and deeper tissue penetration. Multimerization of nanobodies is a popular strategy to enhance their affinity and pharmacokinetics, however, traditional methods are laborious and may yield heterogeneous products. In this study, we employed a Holliday junction-like (HJ) nucleic acid-based scaffold to create homogeneous nanostructures with precise multivalent and multiparatopic nanobody displays. The plug-and-play assembly allowed the screening of several nanobody multimer configurations for the detection of the breast cancer biomarker, human epidermal growth factor receptor 2 (HER2). In vitro studies demonstrated significant improvements in binding avidity, particularly with the biparatopic construct exhibiting high sensitivity, surpassing that of traditional antibody-based cell binding. Furthermore, our HJ platform allowed for adaptation from fluorescence-based to nuclear imaging, as demonstrated in xenografted mice, thereby allowing for future in vivo applications. This work highlights the potential of nucleic acid-mediated multimerization to markedly enhance nanobody binding, by exploring synergistic combinations and offering versatility for both in vitro diagnostics and cancer molecular imaging with prospects for future theranostic applications.

In silico Identification of MHC Displayed Tumor Associated Peptides in Ovarian Cancer for Multi-Epitope Vaccine Construct.

Recognizing the potential of the immune system, immunotherapies have brought about a revolution in the treatment of cancer. Low tumour mutational burden and strong immunosuppression in the peritoneal tumor microenvironment (TME) lead to poor outcomes of immune checkpoint inhibition (ICI) and CART cell therapy in ovarian cancer. Alternative immunotherapeutic strategies are of utmost importance to achieve sound clinical success. The development of peptide vaccines based on tumor-associated antigens (TAAs) for ovarian cancer cells can be a potential target to provoke an anti-tumor immune response and subsequent clearance of tumour cells. The purpose of this in-silico study was to find potential epitopes for a multi-epitope vaccine construct using the immunopeptidomics landscape of ovarian carcinoma. The four TAAs (MUC16, IDO1, FOLR1, and DDX5) were selected as potential epitopes for B-cells, helper T-lymphocytes (HTLs), and cytotoxic T-lymphocytes (CTLs) predicted on the basis of antigenic, allergenic, and toxic properties. These epitopes were combined with suitable linkers and an adjuvant to form a multi-epitope construct. Four HTLs, 13 CTLs, and 6 potential B-cell epitopes were predicted from the TAAs. The designed multi-epitope construct was potentially immunogenic, non-toxic, and nonallergenic. Physicochemical properties and higher-order structural analyses of the final construct revealed a potential vaccine candidate. The designed vaccine construct has the potential to trigger both humoral and cellular immune responses and may be employed as a therapeutic immunization candidate for ovarian malignancies. However, further in vitro and animal experimentation is required to establish the efficacy of the vaccine candidate.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.

Bioprospecting the Anticancer Efficacy of <i>Garcinia anomala</i> from North-East India in Ovarian Cancer Cells – An <i>In Vitro</i> Study

Background: Ovarian cancer is a type of gynaecological cancer with a worldwide prevalence affecting women aged above 50. Despite several advances made in chemotherapy and surgery, the average time of clinical exemption is approximately two years, and the 5-year survival rate is 45%. But even after survival, they have long-term side effects. So, there is an urgent need for natural anticancer drugs. In this context, Garcinia spp. is one such plant that is explored for its anticancer properties. However, the endemic species Garcinia anomala from North-East India has not been studied for anticancer efficacy. Thereby present study aimed to understand the anticancer efficacy of hexane and methanol extracts of Garcinia anomola short mamilla plant available in the North-East region of India with a major emphasis on antioxidant potential. Further, the best extract with higher antioxidant activity was used to evaluate the anticancer potential through modulation of redox status. Methods: Total phenolic content in extract samples was determined by the Folin-Ciocalteu method. The 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity assay was used to assess the antioxidant activities of extracts. For in vitro evaluation of the anticancer potential of the extract, ovarian teratocarcinoma PA1 cells were used as a model to study the dose-dependent effect of the extract. Various assays, such as wound healing assay and transcriptional analysis of genes, such as Bcl-2, PCNA, and TP53, were performed. For the redox parameter, DCFDA (2’,7’-Dichlorofluoroscin Diacetate) assay was used. Results: The results showed that Garcinia anomola methanol extract (EB) exhibited higher antioxidant activity in comparison to the hexane extract (EA). A cytotoxicity assay was performed to find the effective IC50. From this assay, the effective dose concentration confirmed for EA was 40 µg/mL, EB was 20 µg/mL, and the time point selected was 24 hrs. As the IC50 for EB was less than EA, EB was chosen for further assays. From the wound healing assay, the migration rate obtained was 0.967±0.041 µm/hr. The methanol extract was found to affect key cell cycle checkpoint genes at the transcript level. Conclusion: These results indicate that the anticancer potential is mediated through the modulation of antioxidant status. Thus, Garcinia anomala short mamilla extract from northeast India has good efficacy as an anticancer agent, which can be considered as a future potent drug candidate for ovarian cancer.

Engineered lipid nanoparticles enable therapeutic gene silencing of GTSE1 for the treatment of liver fibrosis

Liver fibrosis is characterized by abnormal accumulation of extracellular matrix proteins, disrupting normal liver function. Despite its significant health impact, effective treatments remain limited. Here, we present the development of engineered lipid nanoparticles (LNPs) for targeted RNA therapeutic delivery in the liver. We investigated the therapeutic potential of modulating the G2 and S-phase expressed 1 (GTSE1) protein for treating liver fibrosis. Through screening, we identified P138Y LNP as a potent candidate with superior delivery efficiency and lower toxicity. Using these engineered LNPs, we successfully delivered siGTSE1 to hepatocytes, significantly reducing collagen accumulation and restoring liver function in a fibrosis animal model. Additionally, GTSE1 downregulation altered miRNA expression and upregulated hepatocyte nuclear factor 4 alpha (HNF4α). These findings suggest that therapeutic gene silencing of GTSE1 is a promising strategy for treating liver fibrosis by regenerating liver phenotypes and functions.

Fully human monoclonal antibodies against Ebola virus possess complete protection in a hamster model

ABSTRACT Ebola disease is a lethal viral hemorrhagic fever caused by ebolaviruses within the Filoviridae family with mortality rates of up to 90%. Monoclonal antibody (mAb) based therapies have shown great potential for the treatment of EVD. However, the potential emerging ebolavirus isolates and the negative effect of decoy protein on the therapeutic efficacy of antibodies highlight the necessity of developing novel antibodies to counter the threat of Ebola. Here, 11 fully human mAbs were isolated from transgenic mice immunized with GP protein and recombinant vesicular stomatitis virus-bearing GP (rVSV-EBOV GP). These mAbs were divided into five groups according to their germline genes and exhibited differential binding activities and neutralization capabilities. In particular, mAbs 8G6, 2A4, and 5H4 were cross-reactive and bound at least three ebolavirus glycoproteins. mAb 4C1 not only exhibited neutralizing activity but no cross-reaction with sGP. mAb 7D8 exhibited the strongest neutralizing capacity. Further analysis on the critical residues for the bindings of 4C1 and 8G6 to GPs was conducted using antibodies complementarity-determining regions (CDRs) alanine scanning. It has been shown that light chain CDR3 played a crucial role in binding and neutralization and that any mutation in CDRs could not improve the binding of 4C1 to sGP. Importantly, mAbs 7D8, 8G6, and 4C1 provided complete protections against EBOV infection in a hamster lethal challenge model when administered 12 h post-infection. These results support mAbs 7D8, 8G6, and 4C1 as potent antibody candidates for further investigations and pave the way for further developments of therapies and vaccines.

Lipo-pam™ adjuvanted herpes zoster vaccine induces potent gE-specific cellular and humoral immune responses

Herpes zoster (HZ), also known as shingles, is caused by the reactivation of latent varicella-zoster virus (VZV). Decreased VZV-specific T-cell immune responses significantly contribute to the development of HZ. Shingrix is a recombinant zoster vaccine that is currently used to prevent HZ. However, Shingrix has high reactogenicity and pain at the injection site due to QS21, one of the adjuvant components. In this study, we developed a new herpes zoster vaccine formulation called CVI-VZV-001, containing gE protein and a novel liposome-based adjuvant Lipo-pam™, which consists of two TLR agonists. We evaluated the immunogenicity of CVI-VZV-001 in mouse and rabbit models. CVI-VZV-001 elicited robust gE-specific T-cell immune responses and gE-specific antibody production. Specifically, CVI-VZV-001 induced polyfunctional CD4+ T cell populations that secrete multiple cytokines. Furthermore, CVI-VZV-001 sustained the gE-specific immune responses for up to six months after immunization. To ensure CVI-VZV-001’s safety for further development, we conducted a good laboratory practice (GLP) toxicity test, which confirmed that CVI-VZV-001 is safe for use. At present, CVI-VZV-001 is undergoing phase I clinical trials. This study suggests that CVI-VZV-001 can be a potent candidate for the HZ vaccine with high immunogenicity and safety.

Synthesis and Antibacterial Activities of Linezolid Analogues with C5‐thioether/N,S‐acetal Amide

AbstractThe modification on the C5‐side chain in Linezolid analogues development is sporadic owing to the fact that trivial alternation on this position always leads to significant loss of antibacterial activity and in many cases to complete inactivity. The present work focused on constructing the potent yet relatively unexplored C5‐side chain of Linezolid, therefore various C5‐thioethers were synthesized and evaluated for their antibacterial activities. The most potent candidates, hydroxyl thioether (R)‐5 a, (R)‐10 a, and (R)‐5 r which featuring a linear N,S‐acetal amide motif at the C5 side chain, shown strong antibacterial activities with no observable cytotoxicity.

Application of Drug Repurposing Approach for Therapeutic Intervention of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract (GIT) characterized by chronic relapsing intestinal inflammation, abdominal pain, cramping, loss of appetite, fatigue, diarrhoea, and weight loss. Although the etiology of IBD remains unclear, it is believed to be an interaction between genes, and environmental factors, such as an imbalance of the intestinal microbiota, changing food habits, an ultra-hygiene environment, and an inappropriate immune system. The development of novel effective therapies is stymied by a lack of understanding of the aetiology of IBD. The current therapy involves the use of aminosalicylates, immunosuppressants, and corticosteroids that can effectively manage symptoms, induce and sustain remission, prevent complications, modify the course of the disease, provide diverse treatment options, showcase advancements in biologic therapies, and enhance the overall quality of life. However, the efficacy of current therapy is overshadowed by a plethora of adverse effects, such as loss of weight, mood swings, skin issues, loss of bone density, higher vulnerability to infections, and elevated blood pressure. Biologicals, like anti-tumour necrosis factor agents, can stimulate an autoimmune response in certain individuals that may diminish the effectiveness of the medication over time, necessitating a switch to alternative treatments. The response of IBD patients to current drug therapy is quite varied, which can lead to disease flares that underlines the urgent need to explore alternative treatment option to address the unmet need of developing new treatment strategies for IBD with high efficacy and fewer adverse effects. Drug repurposing is a novel strategy where existing drugs that have already been validated safe in patients for the management of certain diseases are redeployed to treat other, unindicated diseases. The present narrative review focuses on potential drug candidates that could be repurposed for the management of IBD using on-target and off-target strategies. It covers their preclinical, clinical assessment, mechanism of action, and safety profiles, and forecasts their appropriateness in the management of IBD. The review presents useful insights into the most promising candidates for repurposing, like anti-inflammatory and anti-apoptotic troxerutin, which has been found to improve the DSS-induced colitis in rats, an antiosteoarthritic drug diacetylrhein that has been found to have remarkable ameliorating effects on DSS-induced colitis via anti-oxidant and anti- inflammatory properties and by influencing both apoptosis and pyroptosis. Topiramate, an antiepileptic and anticonvulsant drug, has remarkably decreased overall pathophysiological and histopathological events in the experimental model of IBD in rodents by its cytokine inhibitory action.

Current Development of Data Resources and Bioinformatics Tools for Anticoronavirus Peptide.

Since December 2019, the emergence of severe acute respiratory syndrome coronavirus 2, which gave rise to coronavirus disease 2019 (COVID-19), has considerably impacted global health. The identification of effective anticoronavirus peptides (ACVPs) and the establishment of robust data storage methods are critical in the fight against COVID-19. Traditional wet-lab peptide discovery approaches are timeconsuming and labor-intensive. With advancements in computer technology and bioinformatics, machine learning has gained prominence in the extraction of functional peptides from extensive datasets. In this study, we comprehensively review data resources and predictors related to ACVPs published over the past two decades. In addition, we analyze the influence of various factors on model performance. We have reviewed nine ACVP-containing databases, which integrate detailed information on protein fragments effective against coronaviruses, providing crucial references for the development of antiviral drugs and vaccines. Additionally, we have assessed 15 peptide predictors for antiviral or specifically anticoronavirus activity. These predictors employ computational models to swiftly screen potential antiviral candidates, offering an efficient pathway for drug development. Our study provides conclusive results and insights into the performance of different computational methods, and sheds light on the future trajectory of bioinformatics tools for ACVPs. This work offers a representative overview of contributions to the field, with an emphasis on the crucial role of ACVPs in combating COVID-19.

Comprehensive Review on the Genus Haloxylon: Pharmacological and Phytochemical Properties.

This review aimed to review the biological, pharmacological, and phytochemical aspects of the genus Haloxylon. Plants of the genus Haloxylon have been used for a long time in traditional medicine, and they are distributed in the western Mediterranean region to the Middle East, Iran, Mongolia, Burma, and southwest China. The studied parts of Haloxylon species include aerial parts, leaves, branches, seeds, roots, rhizosphere, soil, and whole plants, used to treat several diseases, including sexual disorders, hepatobiliary disorders, eye disorders, skin diseases and hemorrhoids, diarrhea, and effective in the treatment of various ailments such as snake bite, stomach ache, diabetes, wounds, earache and sciatica pain, windbreak dune fixation, feeding of livestock and firewood. Till now, no review on the genus Haloxylon has been conducted. This review aimed to provide updated information on the genus Haloxylon, including traditional medicinal uses, valorization and exploitation of medicinal plants, phytochemistry, botanical characterization, pharmacological and toxicological research focusing on the medicinal properties of several Haloxylon species, especially their antioxidant, antibacterial, anti-inflammatory, cytotoxic and antifungal activities, as well as the effect of each bioactive molecule isolated from these species and their pharmacological use, including the preclinical evaluation of new drugs. The present work was conducted using various scientific databases, including Science Direct, Scopus, PubMed, Google Scholar, etc. Correct plant names were verified from plantlist.org. The results of this search were interpreted, analyzed, and documented based on the obtained bibliographic information. Among all species of the Chenopodiaceae family, 6 species of the Haloxylon genus have approved antioxidant activity, 5 species have antibacterial activity, 3 species have anti-inflammatory activity, 2 species have cytotoxic activity, and 3 species have antifungal activity. The majority of the chemical constituents of this plant include flavonoids, alkaloids, phenols, saponins, glycosides, and tannins. Among them, the main bioactive constituents would be present in the alkaloid fraction. The study of more than 9 Haloxylon plants has identified more than 46 compounds. Pharmacological research proved that crude extracts and some pure compounds obtained from Haloxylon had activities for the treatment of different diseases. The objective of the present study was focused on antioxidant, antibacterial, anti-inflammatory, cytotoxic and antifungal diseases. From the study of the phytochemistry of the Haloxylon family, it was concluded that all studied plants had active compounds. Among them, 11 isolated molecules have medicinal activities with antioxidant properties, 10 molecules showed antibacterial effects, more than 6 molecules have anti-inflammatory properties, more than 9 isolated molecules have medicinal activities against cytotoxic diseases, and more than 28 molecules have antifungal effects. Therefore, the safety of Haloxylon herbal medicine should be considered a top priority in the early stages of development and clinical trials. Several previously conducted studies have validated multiple traditional uses of Haloxylon species. Further research is needed on Haloxylon plants before they can be fully utilized in the clinic as a potent drug candidate, as researchers are mainly focusing on alkaloids, diterpenoids, and triterpenoids, whereas there are many other types of compounds that may possess novel biological activities.

A Six-gene Prognostic Model Based on Neutrophil Extracellular Traps (NETs)-related Gene Signature for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common malignant cancers. Neutrophil extracellular traps (NETs) have been discovered to play a crucial role in the pathogenesis of LUAD. We aimed to establish an innovative prognostic model for LUAD based on the distinct expression patterns of NETs-related genes. The TCGA LUAD dataset was utilized as the training set, while GSE31210, GSE37745, and GSE50081 were undertaken as the verification sets. The patients were grouped into clusters based on the expression signature of NETs-related genes. Differentially expressed genes between clusters were identified through the utilization of the random forest and LASSO algorithms. The NETs score model for LUAD prognosis was developed by multiplying the expression levels of specific genes with their corresponding LASSO coefficients and then summing them. The validity of the model was confirmed by analysis of the survival curves and ROC curves. Additionally, immune infiltration, GSEA, mutation analysis, and drug analysis were conducted. Silencing ABCC2 in A549 cells was achieved to investigate its effect. We identified six novel NETs-related genes, namely UPK1B, SFTA3, GGTLC1, SCGB3A1, ABCC2, and NTS, and developed a NETs score signature, which exhibited a significant correlation with the clinicopathological and immune traits of the LUAD patients. High-risk patients showed inhibition of immune-related processes. Mutation patterns exhibited variability among the different groups. AZD3759, lapatinib, and dasatinib have been identified as potential candidates for LUAD treatment. Moreover, the downregulation of ABCC2 resulted in the induction of apoptosis and suppression of migration and invasion in A549 cells. Altogether, this study has identified a novel NET-score signature based on six novel NET-related genes to predict the prognosis of LUAD and ABCC2 and has also explored a new method for personalized chemo-/immuno-therapy of LUAD.

Predicting immune response targets in orthoflaviviruses through sequence homology and computational analysis.

Flaviviruses cause severe encephalitic or hemorrhagic diseases in humans. Its members, Kyasanur forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (ALKV), cause hemorrhagic fever and are prevalent in India and Saudi Arabia, respectively, while the tick-borne encephalitis virus (TBEV) causes a dangerous encephalitic infection in Europe and Asia. However, little information is available about the targets of immune responses for these deadly viruses. Here, we predict potential antigenic peptide epitopes of viral envelope protein for inducing a cell-mediated and humoral immune response. Using the Immune Epitope Database and Analysis Resource (IEDB-AR), we identified 13 MHC-I and two MHC-II dominant conserved epitopes in KFDV and ALKV and six MHC-I and three MHC-II epitopes in TBEV envelope proteins. Parallelly, we also predicted B-cell linear and discontinuous envelope protein epitopes for these viruses. Interestingly, the epitopes are conserved in all three viral envelope proteins. Further, the discontinuous epitopes are structurally compared with the available DENV, ZIKV, WNV, TBEV, and LIV envelope protein antibody structures. Overall structural comparison analyses highlight (i) lateral ridge epitope in the ED-III domain of E protein, and (ii) envelope dimer epitope (EDE) could be targeted for developing potent vaccine candidates as well as therapeutic antibody production. Moreover, existing structural and biochemical functions of the same epitopes in homologous viruses are predicted to have a reduced antibody-dependent enhancement (ADE) effect on flaviviral infection.

Compounds derived from 5-fluoropyridine and benzo[b]thiophene: killing Mycobacterium tuberculosis and reducing its virulence.

The rise of drug-resistant Mycobacterium tuberculosis (Mtb) has extended the duration of tuberculosis (TB) treatment and reduced the likelihood of cure. One strategy to combat this issue is the development of inhibitors targeting the virulence factors of bacterial pathogens. Mtb' catalase (KatG) is crucial for its detoxification mechanisms and also serves as a significant virulence factor for the bacterium. In this study, twelve derivatives synthesized from 5-fluoropyridine and benzo[b]thiophene demonstrated antimycobacterial efficacy with minimum inhibitory concentrations (MICs) varying between 0.5 and 32 µg/mL. Compound 2, 2-(benzo[b]thiophene-2-ylmethylene) hydrazine-1-carbothioamide, emerged as the most potent candidate. It effectively inhibited Mtb KatG. Molecular docking revealed that compound 2 binds to the active site of Mtb-KatG with docking score of 114. The rabbit skin tuberculosis model was employed to assess the virulence of Mtb. Animal study results indicated that the granulomas induced by Mtb after treatment with compound 2 were reduced in size, exhibited a lower bacterial load, and the bacteria were no longer aggregated, in contrast to those caused by untreated Mtb. Hence, compound 2 can be regarded as a molecule capable of neutralizing the virulence factors of Mtb. This research offers insights into the design of anti-Mtb molecules with novel mechanisms of action.

Machine-learning-assisted high-throughput identification of potent and stable neutralizing antibodies against all four dengue virus serotypes

Several computational methods have been developed to identify neutralizing antibodies (NAbs) covering four dengue virus serotypes (DENV-1 to DENV-4); however, limitations of the dataset and the resulting performance remain. Here, we developed a new computational framework to predict potent and stable NAbs against DENV-1 to DENV-4 using only antibody (CDR-H3) and epitope sequences as input. Specifically, our proposed computational framework employed sequence-based ML and molecular dynamic simulation (MD) methods to achieve more accurate identification. First, we built a novel dataset (n = 1108) by compiling the interactions of CDR-H3 and epitope sequences with the half maximum inhibitory concentration (IC50) values, which represent neutralizing activities. Second, we achieved an accurately predictive ML model that showed high AUC values of 0.879 and 0.885 by tenfold cross-validation and independent tests, respectively. Finally, our computational framework could be applied to filter approximately 2.5 million unseen antibodies into two final candidates that showed strong and stable binding to all four serotypes. In addition, the most potent and stable candidate (1B3B9_V21) was evaluated for its development potential as a therapeutic agent by molecular docking and MD simulations. This study provides an antibody computational approach to facilitate the high-throughput identification of NAbs and accelerate the development of therapeutic antibodies.