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Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment. [ABSTRACT FROM AUTHOR]

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition. [ABSTRACT FROM AUTHOR]

The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6–0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic "prodrugs" in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) and its derivatives have garnered significant attention due to their extensive pharmacological activity. UA is a pentacyclic triterpenoid found in a variety of plants, such as apples, rosemary, thyme, etc., and it possesses a range of pharmacological properties. Researchers have synthesized various derivatives of UA through structural modifications to enhance its potential pharmacological properties. Various in vitro and in vivo studies have indicated that UA and its derivatives possess diverse biological activities, such as anticancer, antifungal, antidiabetic, antioxidant, antibacterial, anti-inflammatory and antiviral properties. This review article provides a review of the biological activities of UA and its derivatives to show their valuable therapeutic properties useful in the treatment of different diseases, mainly focusing on the relevant structure-activity relationships (SARs), the underlying molecular targets/pathways, and modes of action. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of −7.7 kcal/mol and −7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of −78.08 kcal/mol and −82.05 kcal/mol for MMP12-BDC_24037121 and −48.79 kcal/mol and −49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL. [ABSTRACT FROM AUTHOR]

A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 μg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole (2h) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis. Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets. [ABSTRACT FROM AUTHOR]

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five. [ABSTRACT FROM AUTHOR]

As a conformationally restricted amino acid, hydroxy-l-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened synthetic hydroxy-l-proline derivatives using electrophysiological and radiolabeled uptake methods against amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We have discovered a novel class of alkoxy hydroxy-pyrrolidine carboxylic acids (AHPCs) that act as selective high-affinity inhibitors of the SLC1 family neutral amino acid transporters SLC1A4 and SLC1A5. AHPCs were computationally docked into a homology model and assessed with respect to predicted molecular orientation and functional activity. The series of hydroxyproline analogs identified here represent promising new agents to pharmacologically modulate SLC1A4 and SLC1A5 amino acid exchangers which are implicated in numerous pathophysiological processes such as cancer and neurological diseases. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023. [ABSTRACT FROM AUTHOR]

Targeting translation factor proteins holds promise for developing innovative anti-tuberculosis drugs. During protein translation, many factors cause ribosomes to stall at messenger RNA (mRNA). To maintain protein homeostasis, bacteria have evolved various ribosome rescue mechanisms, including the predominant trans-translation process, to release stalled ribosomes and remove aberrant mRNAs. The rescue systems require the participation of translation elongation factor proteins (EFs) and are essential for bacterial physiology and reproduction. However, they disappear during eukaryotic evolution, which makes the essential proteins and translation elongation factors promising antimicrobial drug targets. Here, we review the structural and molecular mechanisms of the translation elongation factors EF-Tu, EF-Ts, and EF-G, which play essential roles in the normal translation and ribosome rescue mechanisms of Mycobacterium tuberculosis (Mtb). We also briefly describe the structure-based, computer-assisted study of anti-tuberculosis drugs. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like Urtica dioica (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation. [ABSTRACT FROM AUTHOR]

Epigallocatechin gallate (EGCG) is a catechin, which is a type of flavonoid found in high concentrations in green tea. EGCG has been studied extensively for its potential health benefits, particularly in cancer. EGCG has been found to exhibit anti-proliferative, anti-angiogenic, and pro-apoptotic effects in numerous cancer cell lines and animal models. EGCG has demonstrated the ability to interrupt various signaling pathways associated with cellular proliferation and division in different cancer types. EGCG anticancer activity is mediated by interfering with various cancer hallmarks. This article summarize and highlight the effects of EGCG on cancer hallmarks and focused on the impacts of EGCG on these cancer-related hallmarks. The studies discussed in this review enrich the understanding of EGCG's potential as a therapeutic tool against cancer, offering a substantial foundation for scientists and medical experts to advance scientific and clinical investigations regarding EGCG's possibility as a potential anticancer treatment. [ABSTRACT FROM AUTHOR]

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 μM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were −45.93 and −71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics. [ABSTRACT FROM AUTHOR]

A new chloroquine-derived photoaffinity probe has been prepared by a convergent synthesis from derivative of 4,7-dichloroquinoline and N1,N1-diethyl-N4-methylpentane. The features of this probe are a unique 3-azido photolabel, the pyridine ring of the quinoline, and the presence of a secondary amine at the 4-position of the quinoline. These features, particularly the 4-amino methylation, prevent triazole formation through combination of the 3-azide and the 4-amine. This undergoes facile cleavage with exposure to a medium-pressure mercury lamp with a 254 nm excitation wavelength. Trapping of the nitrene byproduct is accomplished with its reaction with N-phenylmaleimide as its cycloazidation product. The structure of a ring-opened DBU amine has been structurally characterized. [ABSTRACT FROM AUTHOR]

Repurposing is a universal mechanism for innovation, from the evolution of feathers to the invention of Velcro tape. Repurposing is particularly attractive for drug development, given that it costs more than a billion dollars and takes longer than ten years to make a new drug from scratch. The COVID-19 pandemic has triggered a large number of drug repurposing activities. At the same time, it has highlighted potential pitfalls, in particular when concessions are made to the target product profile. Here, we discuss the pros and cons of drug repurposing for infectious diseases and analyze different ways of repurposing. We distinguish between opportunistic and rational approaches, i.e., just saving time and money by screening compounds that are already approved versus repurposing based on a particular target that is common to different pathogens. The latter can be further distinguished into divergent and convergent: points of attack that are divergent share common ancestry (e.g., prokaryotic targets in the apicoplast of malaria parasites), whereas those that are convergent arise from a shared lifestyle (e.g., the susceptibility of bacteria, parasites, and tumor cells to antifolates due to their high rate of DNA synthesis). We illustrate how such different scenarios can be capitalized on by using examples of drugs that have been repurposed to, from, or within the field of anti-infective chemotherapy. [ABSTRACT FROM AUTHOR]

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Aromatase is an enzyme that plays a crucial role in the biosynthesis of estrogens, which are hormones that contribute to the growth of certain types of breast cancer. In particular, aromatase catalyzes the conversion of androgens (male hormones) into estrogens (female hormones) in various tissues, including the adrenal glands, ovaries, and adipose tissue. Given the role of estrogen in promoting the growth of hormone-receptor-positive breast cancers, aromatase has become an important molecular target for the development of anticancer agents. Aromatase inhibitors can be classified into two main groups based on their chemical structure: steroidal and non-steroidal inhibitors. This work presents a review of the literature from the last ten years regarding the search for new aromatase inhibitors. We present the directions of search, taking into account the impact of structure modifications on anticancer activity. [ABSTRACT FROM AUTHOR]

The development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our understanding of type 2 diabetes mellitus (T2DM). The virtual screening, based on a three-dimensional (3D) protein structure, is a potential technique to accelerate the development of molecular target drugs. Among the targets implicated in insulin resistance, the genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays significant variations in T2DM, and its gene product is known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on a 3D structure of the IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect the blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein–protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14. [ABSTRACT FROM AUTHOR]

The present investigation reports the efficient multistep synthesis of 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (7a–f) in good yields. All the 1-(1,3-dioxoisoindolin-2-yl)-3-aryl urea analogs (7a–f) were characterized by spectroscopic techniques. Five among the six compounds were tested against 56 cancer cell lines at 10 µM as per the standard protocol. 1-(4-Bromophenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (7c) exhibited moderate but significant anticancer activity against EKVX, CAKI-1, UACC-62, MCF7, LOX IMVI, and ACHN with percentage growth inhibitions (PGIs) of 75.46, 78.52, 80.81, 83.48, 84.52, and 89.61, respectively. Compound 7c was found to exhibit better anticancer activity than thalidomide against non-small cell lung, CNS, melanoma, renal, prostate, and breast cancer cell lines. It was also found to exhibit superior anticancer activity against melanoma cancer compared to imatinib. Among the tested compounds, the 4-bromosubstitution (7c) on the phenyl ring demonstrated good anticancer activity. Docking scores ranging from −6.363 to −7.565 kcal/mol were observed in the docking studies against the molecular target EGFR. The ligand 7c displayed an efficient binding against the EGFR with a docking score of −7.558 kcal/mol and displayed an H-bond interaction with Lys745 and the carbonyl functional group. Compound 7c demonstrated a moderate inhibition of EGFR with an IC50 of 42.91 ± 0.80 nM, in comparison to erlotinib (IC50 = 26.85 ± 0.72 nM), the standard drug. The antioxidant potential was also calculated for the compounds (7a–f), which exhibited good to low activity. 1-(2-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (7f) and 1-(4-Methoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)urea (7d) demonstrated significant antioxidant activity with IC50 values of 15.99 ± 0.10 and 16.05 ± 0.15 µM, respectively. The 2- and 4-methoxysubstitutions on the N-phenyl ring showed good antioxidant activity among the series of compounds (7a–f). An in silico ADMET prediction studies showed the compounds' adherence to Lipinski's rule of five: they were free from toxicities, including mutagenicity, cytotoxicity, and immunotoxicity, but not for hepatotoxicity. The toxicity prediction demonstrated LD50 values between 1000 and 5000 mg/Kg, putting the compounds either in class IV or class V toxicity classes. Our findings might create opportunities for more advancements in cancer therapeutics. [ABSTRACT FROM AUTHOR]

N-glycanase 1 (NGLY1) is an essential enzyme involved in the deglycosylation of misfolded glycoproteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which could hydrolyze N-glycan from N-glycoprotein or N-glycopeptide in the cytosol. Recent studies indicated that NGLY1 inhibition is a potential novel drug target for antiviral therapy. In this study, structure-based virtual analysis was applied to screen candidate NGLY1 inhibitors from 2960 natural compounds. Three natural compounds, Poliumoside, Soyasaponin Bb, and Saikosaponin B2 showed significantly inhibitory activity of NGLY1, isolated from traditional heat-clearing and detoxifying Chinese herbs. Furthermore, the core structural motif of the three NGLY1 inhibitors was a disaccharide structure with glucose and rhamnose, which might exert its action by binding to important active sites of NGLY1, such as Lys238 and Trp244. In traditional Chinese medicine, many compounds containing this disaccharide structure probably targeted NGLY1. This study unveiled the leading compound of NGLY1 inhibitors with its core structure, which could guide future drug development. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of −7.7 kcal/mol and −7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of −78.08 kcal/mol and −82.05 kcal/mol for MMP12-BDC_24037121 and −48.79 kcal/mol and −49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL.

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC50 and the selectivity index SI. The most active derivative, 4c, showed an IC50 activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential. [ABSTRACT FROM AUTHOR]

Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone. [ABSTRACT FROM AUTHOR]

Over 30 compounds, including para-, meta-, and ortho-phenylenediboronic acids, ortho-substituted phenylboronic acids, benzenetriboronic acids, di- and triboronated thiophenes, and pyridine derivatives were investigated as potential β-lactamase inhibitors. The highest activity against KPC-type carbapenemases was found for ortho-phenylenediboronic acid 3a, which at the concentration of 8/4 mg/L reduced carbapenems' MICs up to 16/8-fold, respectively. Checkerboard assays revealed strong synergy between carbapenems and 3a with the fractional inhibitory concentrations indices of 0.1–0.32. The nitrocefin hydrolysis test and the whole cell assay with E. coli DH5α transformant carrying blaKPC-3 proved KPC enzyme being its molecular target. para-Phenylenediboronic acids efficiently potentiated carbapenems against KPC-producers and ceftazidime against AmpC-producers, whereas meta-phenylenediboronic acids enhanced only ceftazidime activity against the latter ones. Finally, the statistical analysis confirmed that ortho-phenylenediboronic acids act synergistically with carbapenems significantly stronger than other groups. Since the obtained phenylenediboronic compounds are not toxic to MRC-5 human fibroblasts at the tested concentrations, they can be considered promising scaffolds for the future development of novel KPC/AmpC inhibitors. The complexation of KPC-2 with the most representative isomeric phenylenediboronic acids 1a, 2a, and 3a was modeled by quantum mechanics/molecular mechanics calculations. Compound 3a reached the most effective configuration enabling covalent binding to the catalytic Ser70 residue. [ABSTRACT FROM AUTHOR]

Multicomponent reactions have emerged as an important approach for the synthesis of diverse and complicated chemical compounds. They have various advantages over two-component reactions, including the convenience of one-pot procedures and the ability to modify the structure of agents. Here, we employed in vitro and in silico studies to explore the anticancer potential of novel aminobenzylnaphthols derived from the Betti reaction (MMZ compounds). MTT assay was used to explore the cytotoxic activity of the compounds in pancreatic (BxPC-3 cells) and colorectal (HT-29) cancer cell lines or normal human lung fibroblasts (WI-38 cells). Proapoptotic properties of two derivatives MMZ-45AA and MMZ-140C were explored using AO/EB and annexin V-FITC/PI staining. In silico studies including ADMET profiling, molecular target prediction, docking, and dynamics were employed. The compounds exhibited cytotoxic properties and showed proapoptotic properties in respective IC50 concentrations. As indicated by in silico investigations, anticancer activity of MMZs can be attributed to the inhibition of ADORA1, CDK2, and TRIM24. Furthermore, compounds exhibited favorable ADMET properties. MMZs constitute an interesting scaffold for the potential development of new anticancer agents. [ABSTRACT FROM AUTHOR]

The biological target identification process, a pivotal phase in the drug discovery workflow, becomes particularly challenging when mutations affect proteins' mechanisms of action. COVID-19 Spike glycoprotein mutations are known to modify the affinity toward the human angiotensin-converting enzyme ACE2 and several antibodies, compromising their neutralizing effect. Predicting new possible mutations would be an efficient way to develop specific and efficacious drugs, vaccines, and antibodies. In this work, we developed and applied a computational procedure, combining constrained logic programming and careful structural analysis based on the Structural Activity Relationship (SAR) approach, to predict and determine the structure and behavior of new future mutants. "Mutations rules" that would track statistical and functional types of substitutions for each residue or combination of residues were extracted from the GISAID database and used to define constraints for our software, having control of the process step by step. A careful molecular dynamics analysis of the predicted mutated structures was carried out after an energy evaluation of the intermolecular and intramolecular interactions using the HINT (Hydrophatic INTeraction) force field. Our approach successfully predicted, among others, known Spike mutants. [ABSTRACT FROM AUTHOR]

Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b–4c showing three substitution patterns A–C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4′-carboxylate 2b, 4′-ester 2c and N1-carbamate-4′-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing. [ABSTRACT FROM AUTHOR]

In the current study, we described the synthesis of ten new 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine analogs (4a–j), as well as their characterization, anticancer activity, molecular docking studies, ADME, and toxicity prediction. The title compounds (4a–j) were prepared in three steps, starting from substituted anilines in a satisfactory yield, followed by their characterization via spectroscopic techniques. The National Cancer Institute (NCI US) protocol was followed to test the compounds' (4a–j) anticancer activity against nine panels of 58 cancer cell lines at a concentration of 10−5 M, and growth percent (GP) as well as percent growth inhibition (PGI) were calculated. Some of the compounds demonstrated significant anticancer activity against a few cancer cell lines. The CNS cancer cell line SNB-75, which showed a PGI of 41.25 percent, was discovered to be the most sensitive cancer cell line to the tested compound 4e. The mean GP of compound 4i was found to be the most promising among the series of compounds. The five cancer cell lines that were found to be the most susceptible to compound 4i were SNB-75, UO-31, CCRF-CEM, EKVX, and OVCAR-5; these five cell lines showed PGIs of 38.94, 30.14, 26.92, 26.61, and 23.12 percent, respectively, at 10−5 M. The inhibition of tubulin is one of the primary molecular targets of many anticancer agents; hence, the compounds (4a–j) were further subjected to molecular docking studies looking at the tubulin–combretastatin A-4 binding site (PDB ID: 5LYJ) of tubulin. The binding affinities were found to be efficient, ranging from −6.502 to −8.341 kcal/mol, with two major electrostatic interactions observed: H-bond and halogen bond. Ligand 4i had a binding affinity of −8.149 kcal/mol with the tubulin–combretastatin A-4 binding site and displayed a H-bond interaction with the residue Asn258. The ADME and toxicity prediction studies for each compound were carried out using SwissADME and ProTox-II software. None of the compounds' ADME predictions showed that they violated Lipinski's rule of five. All of the compounds were also predicted to have LD50 values between 440 and 500 mg/kg, putting them all in class IV toxicity, according to the toxicity prediction. The current discovery could potentially open up the opportunity for further developments in cancer. [ABSTRACT FROM AUTHOR]

We investigated the immediate molecular consequences of traumatic brain injuries (TBIs) using a novel proteomics approach. We simulated TBIs using an innovative laboratory apparatus that employed a 5.1 kg dummy head that held neuronal cells and generated a ≤4000 g-force acceleration upon impact. A Proteome Integral Solubility Alteration (PISA) assay was then employed to monitor protein solubility changes in a system-wide manner. Dynamic impacts led to both a reduction in neuron viability and massive solubility changes in the proteome. The affected proteins mapped not only to the expected pathways, such as those of cell adhesion, collagen, and laminin structures, as well as the response to stress, but also to other dense protein networks, such as immune response, complement, and coagulation cascades. The cellular effects were found to be mainly due to the shockwave rather than the g-force acceleration. Soft materials could reduce the impact's severity only until they were fully compressed. This study shows a way of developing a proteome-based meter for measuring irreversible shockwave-induced cell damage and provides a resource for identifying protein biomarkers of TBIs and potential drug targets for the development of products aimed at primary prevention and intervention. [ABSTRACT FROM AUTHOR]

An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors. [ABSTRACT FROM AUTHOR]

Although loop epitopes at protein-protein binding interfaces often play key roles in mediating oligomer formation and interaction specificity, their binding sites are underexplored as drug targets owing to their high flexibility, relatively few hot spots, and solvent accessibility. Prior attempts to develop molecules that mimic loop epitopes to disrupt protein oligomers have had limited success. In this study, we used structure-based approaches to design and optimize cyclic-constrained peptides based on loop epitopes at the human phosphoglycerate dehydrogenase (PHGDH) dimer interface, which is an obligate homo-dimer with activity strongly dependent on the oligomeric state. The experimental validations showed that these cyclic peptides inhibit PHGDH activity by directly binding to the dimer interface and disrupting the obligate homo-oligomer formation. Our results demonstrate that loop epitope derived cyclic peptides with rationally designed affinity-enhancing substitutions can modulate obligate protein homo-oligomers, which can be used to design peptide inhibitors for other seemingly intractable oligomeric proteins. [ABSTRACT FROM AUTHOR]

The essential oils (OEs) of the leaves, stems, and spikes of P. marginatum were obtained by hydrodistillation, steam distillation, and simultaneous extraction. The chemical constituents were identified and quantified by GC/MS and GC-FID. The preliminary biological activity was determined by assessing the toxicity of the samples to Artemia salina Leach larvae and calculating the mortality rate and lethal concentration (LC50). The antioxidant activity of the EOs was determined by the DPPH radical scavenging method. Molecular modeling was performed using molecular docking and molecular dynamics, with acetylcholinesterase being the molecular target. The OES yields ranged from 1.49% to 1.83%. The EOs and aromatic constituents of P. marginatum are characterized by the high contents of (E)-isoosmorhizole (19.4–32.9%), 2-methoxy-4,5-methylenedioxypropiophenone (9.0–19.9%), isoosmorhizole (1.6–24.5%), and 2-methoxy-4,5-methylenedioxypropiophenone isomer (1.6–14.3%). The antioxidant potential was significant in the OE of the leaves and stems of P. marginatum extracted by SD in November (84.9 ± 4.0 mg TE·mL−1) and the OEs of the leaves extracted by HD in March (126.8 ± 12.3 mg TE·mL−1). Regarding the preliminary toxicity, the OEs of Pm-SD-L-St-Nov and Pm-HD-L-St-Nov had mortality higher than 80% in concentrations of 25 µg·mL−1. This in silico study on essential oils elucidated the potential mechanism of interaction of the main compounds, which may serve as a basis for advances in this line of research. [ABSTRACT FROM AUTHOR]

Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from Bacillus cereus (PC-PLCBc). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLCBc have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, N,N′-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-b]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients. [ABSTRACT FROM AUTHOR]

Steroidal (glycol)alkaloids S(G)As are secondary metabolites made of a nitrogen-containing steroidal skeleton linked to a (poly)saccharide, naturally occurring in the members of the Solanaceae and Liliaceae plant families. The genus Solanum is familiar to all of us as a food source (tomato, potato, eggplant), but a few populations have also made it part of their ethnobotany for their medicinal properties. The recent development of the isolation, purification and analysis techniques have shed light on the structural diversity among the SGAs family, thus attracting scientists to investigate their various pharmacological properties. This review aims to overview the recent literature (2012–2022) on the pharmacological benefits displayed by the SGAs family. Over 17 different potential therapeutic applications (antibiotic, antiviral, anti-inflammatory, etc.) were reported over the past ten years, and this unique review analyzes each pharmacological effect independently without discrimination of either the SGA's chemical identity or their sources. A strong emphasis is placed on the discovery of their biological targets and the subsequent cellular mechanisms, discussing in vitro to in vivo biological data. The therapeutic value and the challenges of the solanum steroidal glycoalkaloid family is debated to provide new insights for future research towards clinical development. [ABSTRACT FROM AUTHOR]

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies. [ABSTRACT FROM AUTHOR]

The secondary metabolites of clerodane diterpenoids have been found in several plant species from various families and in other organisms. In this review, we included articles on clerodanes and neo-clerodanes with cytotoxic or anti-inflammatory activity from 2015 to February 2023. A search was conducted in the following databases: PubMed, Google Scholar and Science Direct, using the keywords clerodanes or neo-clerodanes with cytotoxicity or anti-inflammatory activity. In this work, we present studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belonging to 9 families. These plants are mostly from the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. In summary, clerodane diterpenes have activity against different cell cancer lines. Specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some of which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. Furthermore, some diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way. [ABSTRACT FROM AUTHOR]

Oncogenic fusion proteins, arising from chromosomal rearrangements, have emerged as prominent drivers of tumorigenesis and crucial therapeutic targets in cancer research. In recent years, the potential of small molecular inhibitors in selectively targeting fusion proteins has exhibited significant prospects, offering a novel approach to combat malignancies harboring these aberrant molecular entities. This review provides a comprehensive overview of the current state of small molecular inhibitors as therapeutic agents for oncogenic fusion proteins. We discuss the rationale for targeting fusion proteins, elucidate the mechanism of action of inhibitors, assess the challenges associated with their utilization, and provide a summary of the clinical progress achieved thus far. The objective is to provide the medicinal community with current and pertinent information and to expedite the drug discovery programs in this area. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) is a promising drug target for inhibiting the coronavirus due to its conserved properties and lack of homologous genes in humans. However, previous studies on Mpro's kinetic parameters have been confusing, hindering the selection of accurate inhibitors. Therefore, obtaining a clear view of Mpro's kinetic parameters is necessary. In our study, we investigated the kinetic behaviors of Mpro from SARS-CoV-2 and SARS-CoV using both FRET-based cleavage assay and the LC-MS method, respectively. Our findings indicate that the FRET-based cleavage assay could be used for preliminary screening of Mpro inhibitors, while the LC-MS method should be applied to select the effective inhibitors with higher reliability. Furthermore, we constructed the active site mutants (H41A and C145A) and measured the kinetic parameters to gain a deeper understanding of the atomic-level enzyme efficiency reduction compared to the wild type. Overall, our study provides valuable insights for inhibitor screening and design by offering a comprehensive understanding of Mpro's kinetic behaviors. [ABSTRACT FROM AUTHOR]

A pipeline for metabolomics, based on UPLC-ESI-MS, was tested on two malignant breast cancer cell lines of the sub-types ER(+), PR(+), and HER2(3+) (MCF-7 and BCC), and one non-malignant epithelial cancer cell line (MCF-10A). This allowed us to quantify 33 internal metabolites, 10 of which showed a concentration profile associated with malignancy. Whole-transcriptome RNA-seq was also carried out for the three mentioned cell lines. An integrated analysis of metabolomics and transcriptomics was carried out using a genome-scale metabolic model. Metabolomics revealed the depletion of several metabolites that have homocysteine as a precursor, which was consistent with the lower activity of the methionine cycle caused by lower expression of the AHCY gene in cancer cell lines. Increased intracellular serine pools in cancer cell lines appeared to result from the over-expression of PHGDH and PSPH, which are involved in intracellular serine biosynthesis. An increased concentration of pyroglutamic acid in malignant cells was linked to the overexpression of the gene CHAC1. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia mutated and Rad3-related (ATR), a vital member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, plays a critical role in the DNA damage response (DDR). Tumor cells with a loss of DDR function or defects in the ataxia telangiectasia mutated (ATM) gene are generally more dependent on ATR for survival, suggesting that ATR is an attractive anticancer drug target based on its synthetic lethality. Herein, we present a potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 μM). It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR inhibitor based on the principle of synthetic lethality and deserves further in-depth study. [ABSTRACT FROM AUTHOR]

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA. [ABSTRACT FROM AUTHOR]

Plant parasitic nematodes (PPNs) are highly destructive and difficult to control, while conventional chemical nematicides are highly toxic and cause serious environmental pollution. Additionally, resistance to existing pesticides is becoming increasingly common. Biological control is the most promising method for the controlling of PPNs. Therefore, the screening of nematicidal microbial resources and the identification of natural products are of great significance and urgency for the environmentally friendly control of PPNs. In this study, the DT10 strain was isolated from wild moss samples and identified as Streptomyces sp. by morphological and molecular analysis. Using Caenorhabditis elegans as a model, the extract of DT10 was screened for nematicidal activity, which elicited 100% lethality. The active compound was isolated from the extracts of strain DT10 using silica gel column chromatography and semipreparative high-performance liquid chromatography (HPLC). The compound was identified as spectinabilin (chemical formula C28H31O6N) using liquid chromatography mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). Spectinabilin exhibited a good nematicidal activity on C. elegans L1 worms, with a half-maximal inhibitory concentration (IC50) of 2.948 μg/mL at 24 h. The locomotive ability of C. elegans L4 worms was significantly reduced when treated with 40 μg/mL spectinabilin. Further analysis of spectinabilin against known nematicidal drug target genes in C. elegans showed that it acts via target(s) different from those of some currently used nematicidal drugs such as avermectin and phosphine thiazole. This is the first report on the nematicidal activity of spectinabilin on C. elegans and the southern root-knot nematode Meloidogyne incognita. These findings may pave the way for further research and application of spectinabilin as a potential biological nematicide. [ABSTRACT FROM AUTHOR]

1,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and development. To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. In this review, we mainly focus on s-triazines targeting topoisomerases, tyrosine kinases, phosphoinositide 3-kinases, NADP+-dependent isocitrate dehydrogenases, and cyclin-dependent kinases in diverse signaling pathways, which have been extensively studied. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix–loop–helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR. [ABSTRACT FROM AUTHOR]

Gold(I) metal complexes are finding increasing applications as therapeutic agents against a variety of diseases. As their potential use as effective metallodrugs is continuously confirmed, the issue of their administration, distribution and delivery to desired biological targets emerges. Graphene and its derivatives possess attractive properties in terms of high affinity and low toxicity, suggesting that they can efficaciously be used as drug nanocarriers. In the present study, we computationally address the adsorption of a gold(I) N-heterocyclic monocarbene, namely, IMeAuCl (where IMe = 1,3-dimethylimidazol-2-ylidene), on graphene. The Au(I) N-heterocyclic carbene family has indeed shown promising anticancer activity and the N-heterocyclic ring could easily interact with planar graphene nanostructures. By means of high-level electronic structure approaches, we investigated the strength and nature of the involved interaction using small graphene prototypes, which allow us to benchmark the best-performing DFT functionals as well as assess the role of the different contributions to total interaction energies. Moreover, realistic adsorption enthalpies and free energy values are obtained by exploiting the optimal DFT method to describe the drug adsorption on larger graphene models. Such values (ΔHads = −18.4 kcal/mol and ΔGads= −7.20 kcal/mol for the largest C150H30 model) indicate a very favorable adsorption, mainly arising from the dispersion component of the interaction, with the electrostatic attraction also playing a non-negligible role. [ABSTRACT FROM AUTHOR]

The outer membrane of Gram-negative bacteria is closely related to the pathogenicity and drug resistance of bacteria. Outer membrane proteins (OMPs) are a class of proteins with important biological functions on the outer membrane. The β-barrel assembly machinery (BAM) complex plays a key role in OMP biogenesis, which ensures that the OMP is inserted into the outer membrane in a correct folding manner and performs nutrient uptake, antibiotic resistance, cell adhesion, cell signaling, and maintenance of membrane stability and other functions. The BAM complex is highly conserved among Gram-negative bacteria. The abnormality of the BAM complex will lead to the obstruction of OMP folding, affect the function of the outer membrane, and eventually lead to bacterial death. In view of the important role of the BAM complex in OMP biogenesis, the BAM complex has become an attractive target for the development of new antibacterial drugs against Gram-negative bacteria. Here, we summarize the structure and function of the BAM complex and review the latest research progress of antibacterial drugs targeting BAM in order to provide a new perspective for the development of antibiotics. [ABSTRACT FROM AUTHOR]

Bone and cartilage disorders are the leading causes of musculoskeletal disability. There is no absolute cure for all bone and cartilage disorders. The exploration of natural compounds for the potential therapeutic use against bone and cartilage disorders is proving promising. Among these natural chemicals, naringin, a flavanone glycoside, is a potential candidate due to its multifaceted pharmacological activities in bone and cartilage tissues. Emerging studies indicate that naringin may promote osteogenic differentiation, inhibit osteoclast formation, and exhibit protective effects against osteoporosis in vivo and in vitro. Many signaling pathways, such as BMP-2, Wnt/β-catenin, and VEGF/VEGFR, participate in the biological actions of naringin in mediating the pathological development of osteoporosis. In addition, the anti-inflammatory, anti-oxidative stress, and anti-apoptosis abilities of naringin also demonstrate its beneficial effects against bone and cartilage disorders, including intervertebral disc degeneration, osteoarthritis, rheumatoid arthritis, bone and cartilage tumors, and tibial dyschondroplasia. Naringin exhibits protective effects against bone and cartilage disorders. However, more efforts are still needed due to, at least in part, the uncertainty of drug targets. Further biological and pharmacological evaluations of naringin and its applications in bone tissue engineering, particularly its therapeutic effects against osteoporosis, might result in developing potential drug candidates. [ABSTRACT FROM AUTHOR]

Geraniol (GNL), a natural monoterpene, is found in many essential oils of fruits, vegetables, and herbs, including lavender, citronella, lemongrass, and other medicinal and aromatic plants. GNL is commonly used by the cosmetic and food industries and has shown a wide spectrum of pharmacological activities including anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities. It represents a potential anti-inflammatory agent and a promising cancer chemopreventive agent, as it has been found to be effective against a broad range of cancers, including colon, prostate, breast, lung, skin, kidney, liver, and pancreatic cancer. Moreover, GNL scavenges free radicals and preserves the activity of antioxidant enzymes. In addition, GNL induces apoptosis and cell cycle arrest, modulates multiple molecular targets, including p53 and STAT3, activates caspases, and modulates inflammation via transcriptional regulation. In the present study, different modes of action are described for GNL's activity against cancer and inflammatory diseases. This compound protects various antioxidant enzymes, such as catalase, glutathione-S-transferase, and glutathione peroxidase. Experiments using allergic encephalomyelitis, diabetes, asthma, and carcinogenesis models showed that GNL treatment had beneficial effects with low toxicity. GNL has been shown to be effective in animal models and tumor cell lines, but there have not been any clinical studies carried out for it. The aim of the present review is to provide updated data on the potential effects of GNL on cancer and inflammation, and to enhance our understanding of molecular targets, involved pathways, and the possible use of GNL for clinical studies and therapeutic purposes in the treatment of cancer and inflammation-related diseases. [ABSTRACT FROM AUTHOR]