Noncoding RNAs as therapeutic targets in autophagy-related diabetic cardiomyopathy.

Diabetic cardiomyopathy, a multifaceted complication of diabetes mellitus, remains a major challenge in clinical management due to its intricate pathophysiology. Emerging evidence underscores the pivotal role of autophagy dysregulation in the progression of diabetic cardiomyopathy, providing a novel avenue for therapeutic intervention. Noncoding RNAs (ncRNAs), a diverse class of regulatory molecules, have recently emerged as promising candidates for targeted therapeutic strategies. The exploration of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) reveal their intricate regulatory networks in modulating autophagy and influencing the pathophysiological processes associated with diabetic cardiomyopathy. The nuanced understanding of the molecular mechanisms underlying ncRNA-mediated autophagic regulation offers a rationale for the development of precise and effective therapeutic interventions. Harnessing the regulatory potential of ncRNAs presents a promising frontier for the development of targeted and personalized therapeutic strategies, aiming to ameliorate the burden of diabetic cardiomyopathy in affected individuals. As research in this field advances, the identification and validation of specific ncRNA targets hold immense potential for the translation of these findings into clinically viable interventions, ultimately improving outcomes for patients with diabetic cardiomyopathy. This review encapsulates the current understanding of the intricate interplay between autophagy and diabetic cardiomyopathy, with a focus on the potential of ncRNAs as therapeutic targets.

Broccoli: A Multi-Faceted Vegetable for Health: An In-Depth Review of Its Nutritional Attributes, Antimicrobial Abilities, and Anti-inflammatory Properties.

Broccoli, Brassica oleracea var. italica, has recently gained considerable attention due to its remarkable nutritional composition and numerous health benefits. In this review, the nutritional aspects of broccoli are examined, highlighting its rich nutrient content and essential bioactive compounds. The cruciferous vegetable broccoli is a rich source of several important nutrients, including fiber, vitamins (A, C, and K), minerals (calcium, potassium, and iron), and antioxidants. It has also been shown to contain bioactive compounds such as glucosinolates, sulforaphane, and indole-3-carbinol, all of which have been shown to have significant health-promoting effects. These chemicals are known to have potent antioxidant, anti-inflammatory, and anticancer effects. This review article aims to comprehensively examine the diverse spectrum of nutrients contained in broccoli and explore its medicinal potential to promote human health.

Synthesis, Crystal Structure, Antibacterial and In Vitro Anticancer Activity of Novel Macroacyclic Schiff Bases and Their Cu (II) Complexes Derived from S-Methyl and S-Benzyl Dithiocarbazate.

A series of novel macroacyclic Schiff base ligands and their Cu (II) complexes were synthesised via reacting dicarbonyls of varying chain lengths with S-methyl dithiocarbazate (SMDTC) and S-benzyl dithiocarbazate (SBDTC) followed by coordination with Cu (II) ions. X-ray crystal structures were obtained for compound 4, an SBDTC-diacetyl analogue, and Cu7, an SMDTC-hexanedione Cu (II) complex. Anticancer evaluation of the compounds showed that Cu1, an SMDTC-glyoxal complex, demonstrated the highest cytotoxic activity against MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 1.7 µM and 1.4 µM, respectively. There was no clear pattern observed between the effect of chain length and cytotoxic activity; however, SMDTC-derived analogues were more active than SBDTC-derived analogues against MDA-MB-231 cells. The antibacterial assay showed that K. rhizophila was the most susceptible bacteria to the compounds, followed by S. aureus. Compound 4 and the SMDTC-derived analogues 3, 5, Cu7 and Cu9 possessed the highest antibacterial activity. These active analogues were further assessed, whereby 3 possessed the highest antibacterial activity with an MIC of <24.4 µg/mL against K. rhizophila and S. aureus. Further antibacterial studies showed that at least compounds 4 and 5 were bactericidal. Thus, Cu1 and 3 were the most promising anticancer and antibacterial agents, respectively.

Artemisia sieberi Besser essential oil inhibits the growth and migration of breast cancer cells via induction of S-phase arrest, caspase-independent cell death and downregulation of ERK.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia sieberi Besser is a medicinal herb that has been traditionally used across the Middle East for the treatment of cancer. Further pharmacological studies on its extracts revealed that they possess cytotoxic activity against certain cancer cells, however, there were no studies conducted on the anticancer potential of Artemisia sieberi essential oil (ASEO). AIM OF THE STUDY: To evaluate the anticancer potential of ASEO, elucidate the oil's mode of action for the first time and investigate its chemical composition. MATERIALS AND METHODS: Artemisia sieberi was collected from Hail, Saudi Arabia, and its essential oil was obtained via hydrodistillation. The oil's activity against HCT116, HepG2, A549 and MCF-7 cells was assessed using SRB assay, while its anti-metastatic potential was assessed via a migration assay. Cell-cycle analysis and apoptosis assay were conducted via flow cytometry, while protein expression levels were investigated using Western blotting. The oil's chemical constituents were identified using GCMS. RESULTS: ASEO exerted its highest cytotoxic activity against MCF-7 with an IC50 value of 38.7 µg/ml. Further studies showed that the oil inhibited MCF-7 cells' migration, induced S-phase arrest and apoptosis. Western blot analysis showed no change in the expression level of caspase-3 after treatment, indicating the induction of caspase-independent apoptosis-like cell death in MCF-7. Treatment of MCF-7 with the oil resulted in downregulation of the protein expression levels of total ERK and its downstream target, LC3, indicating that any potential activation of the ERK signalling pathway during the cancer cells' growth would be inhibited. Finally, GCMS analysis identified the oil's major components as cis-crysanthenyl acetate (48.56%), davanone (10.28%), 1,8-cineole (6.81%) and caryophyllene diepoxide (5.34%), whereby it is suggested that these compounds might be responsible for the oil's bioactivity. CONCLUSION: ASEO possessed in vitro anticancer activity and modulated the ERK signalling pathway. This is the first study to explore the anticancer potential of ASEO in detail and reflects the significance of investigating essential oils from medicinal plants that have been traditionally used against cancer. This work might pave the way for further in vivo studies that could result in developing the oil into a natural effective anticancer treatment.

Antibacterial and Antifungal Alkaloids from Asian Angiosperms: Distribution, Mechanisms of Action, Structure-Activity, and Clinical Potentials.

The emergence of multidrug-resistant bacteria and fungi requires the development of antibiotics and antifungal agents. This review identified natural products isolated from Asian angiosperms with antibacterial and/or antifungal activities and analyzed their distribution, molecular weights, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1979 to 2022. One hundred and forty-one antibacterial and/or antifungal alkaloids were identified during this period, mainly from basal angiosperms. The most active alkaloids are mainly planar, amphiphilic, with a molecular mass between 200 and 400 g/mol, and a polar surface area of about 50 Å2, and target DNA and/or topoisomerase as well as the cytoplasmic membrane. 8-Acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2'-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine yielded MIC ≤ 1 µg/mL and are candidates for the development of lead molecules.

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of -8.5 kcal/mol, -10.8 kcal/mol and -9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski's rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.

Achillea fragrantissima (Forssk.) Sch.Bip. methanolic extract exerts potent antimicrobial activity and causes cancer cell death via induction of caspase-dependent apoptosis and S-phase arrest.

This study was done to evaluate the anticancer potential of Achillea fragrantissima (Forssk.) Sch.Bip. leaves methanolic extract in detail for the first time, in addition to investigating its antimicrobial activity. The antimicrobial assay revealed that the extract exerted high activity against P. vulgaris (MIC = 156.25 µg/ml) and C. albicans (MIC = 625 µg/ml), while moderate activity was observed against other microbes. The extract was also screened against HepG2, A549, HCT116 and MCF7 cancer cells and was found to be active across all cells with highest selectivity and cytotoxic activity being observed for A549 cells (IC50 = 1.21 µg/ml). Further mechanistic studies on A549 cells showed that the extract resulted in S-phase arrest and induced apoptosis via activation of caspase-3, p53 and Bax, in addition to downregulation of Bcl-2. HR-LCMS analysis indicated the presence of 3-hydroxycoumarin, quercetin 3,3'-dimethyl ether and skullcapflavone II which might be responsible for the extract's bioactivity.

Novel Semi-Synthetic Cu (II)-Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway.

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.

Cytotoxic Activity of Boesenbergia rotunda Extracts against Nasopharyngeal Carcinoma Cells (HK1). Cardamonin, a Boesenbergia rotunda Constituent, Inhibits Growth and Migration of HK1 Cells by Inducing Caspase-Dependent Apoptosis and G2/M-Phase Arrest.

Boesenbergia rotunda (L.) Mansf. is an edible herb that is commonly used in the cuisine of several Asian countries. Studies have shown that it possesses high bioactivity against a variety of cancer cells. In this study, we investigated the cytotoxic activity of Boesenbergia rotunda rhizomes and some of its constituents on nasopharyngeal carcinoma cells (HK1). MTT assay results showed that the methanolic and hexane extracts of Boesenbergia rotunda decreased HK1 cell viability with IC50 values of 136 µg/ml and 66 µg/ml, respectively. Cardamonin, a constituent of Boesenbergia rotunda, exhibited the highest cytotoxic activity with an IC50 value of 27 µg/ml. Further studies on cardamonin revealed that it inhibited the migration of HK1 cells, caused G2/M-phase arrest and induced apoptosis. Apoptosis was induced via activating caspase-8 and caspase-3, but independent of caspase-9. This indicated that cardamonin induced extrinsic apoptosis. Western blot analysis further showed that cardamonin caused extrinsic apoptosis, as the expression levels of intrinsic apoptosis-related proteins (Bcl-XL, Bcl-2 and Bax), were not affected. Finally, JC-1 staining of HK1 cells revealed an increase in the mitochondrial membrane potential after treatment, further proving that cardamonin did not induce apoptosis via the intrinsic pathway. These results reflect cardamonin's potential as an anticancer agent.

Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway.

Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2µM and 0.7µM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.

Crystal structure of benzyl (E)-2-(3,4-di-meth-oxy-benzyl-idene)hydrazine-1-carbodi-thio-ate.

The title compound, C17H18N2O2S2, synthesized via a condensation reaction between S-benzyl di-thio-carbazate and 3,4-di-meth-oxy-benzaldehyde, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an L-shape but differ in the orientation of the benzyl ring with respect to the 3,4-di-meth-oxy-benzyl-idine ring, this dihedral angle is 65.59 (8)° in mol-ecule A and 73.10 (8)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H⋯O hydrogen bonds, giving inversion dimers of dimers. These units are linked by C-H⋯π inter-actions, forming ribbons propagating in the [100] direction.

Synthesis, Characterization, and Bioactivity of Schiff Bases and Their Cd(2+), Zn(2+), Cu(2+), and Ni(2+) Complexes Derived from Chloroacetophenone Isomers with S-Benzyldithiocarbazate and the X-Ray Crystal Structure of S-Benzyl- ß -N-(4-chlorophenyl)methylenedithiocarbazate.

Two bidentate Schiff base ligands having nitrogen sulphur donor sequence were derived from the condensation of S-benzyldithiocarbazate (SBDTC) with 2-chloroacetophenone and 4-chloroacetophenone to give S-benzyl- ß -N-(2-chlorophenyl)methylenedithiocarbazate (NS2) and S-benzyl- ß -N-(4-chlorophenyl)methylenedithiocarbazate (NS4) isomers. Each of the ligands was then chelated with Cd(2+), Zn(2+), Cu(2+), and Ni(2+). The compounds were characterized via IR spectroscopy and melting point while the structure of NS4 was revealed via X-ray crystallography. Finally, the compounds were screened for antimicrobial activity to investigate the effect that is brought by the introduction of the chlorine atom to the benzene ring. X-ray crystallographic analysis showed that the structure of NS4 is planar with a phenyl ring that is nearly perpendicular to the rest of the molecules. The qualitative antimicrobial assay results showed that NS4 and its complexes lacked antifungal activity while Gram-positive bacteria were generally inhibited more strongly than Gram-negative bacteria. Furthermore, NS4 metal complexes were inhibited more strongly than the ligand while the opposite was seen with NS2 ligand and its complexes due to the partial solubility in dimethyl sulfoxide (DMSO). It was concluded that generally NS2 derivatives have higher bioactivity than that of NS4 derivatives and that the Cd complexes of both ligands have pronounced activity specifically on K. rhizophila.

Bis{(Z)-[(E)-2-(pyridin-2-yl-methyl-idene)hydrazin-1-yl-idene][(pyridin-2-yl)methyl-sulfan-yl]methane-thiol-ato}nickel(II).

The title compound, [Ni(C13H11N4S2)2], was obtained by the reaction of S-2-picolyldi-thio-carbazate and pyridine-2-carbaldehyde with nickel(II) acetate. The Ni(II) atom is located on a twofold rotation axis and is bonded to four N atoms at distances of 2.037 (8) and 2.109 (9) Å, and to two S atoms at a distance of 2.406 (3) Å, leading to a distorted octa-hedral coordination. The angle between the mean planes of the coordinating moieties of the two symmetry-related tridentate ligands is 83.3 (2)°. In the crystal, complex mol-ecules are linked by weak C-H⋯S hydrogen bonds, π-π inter-actions between the pyridine rings [centroid-centroid distance = 3.775 (9) Å] and C-H⋯π inter-actions. The hydrogen-bonding inter-actions lead to the formation of layers parallel to (010); π-π inter-actions link these layers into a three-dimensional network.

Benzyl N-[(Z)-(1-methyl-2-sulfanyl-propyl-idene)amino]-carbamodithio-ate.

The title compound, C(12)H(16)N(2)S(3), was obtained by the condensation reaction of S-benzyl dithio-carbazate and 3-mercaptobutan-2-one. The phenyl ring and thiol (SH) group are approximately perpendicular [S-C-C-C and N-C-C-S torsion angles = 67.8 (3) and 116.9 (2)°, respectively] to the rest of the mol-ecule. In the crystal, mol-ecules are linked by weak S-H⋯S and N-H⋯S hydrogen bonds, π-π inter-actions between the benzene rings [centroid-centroid distance = 3.823 (2) Å] and C-H⋯π inter-actions.