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We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type. Interestingly, the acetylcholine and nicotine-evoked activation was not modified in human α7 mutated receptors, but the net charge was enhanced for clothianidin and imidacloprid, respectively. Flupyradifurone responses strongly increased under the Q79K mutation. The molecular docking investigations demonstrated that the orientations and interactions of the ligands considered were in accordance with those observed experimentally. Specifically, the charged fragments of acetylcholine and nicotine, used as reference ligands, and their neonicotinoid homologs were found to be surrounded by aromatic residues, with key interactions with Trp171 and Y210. Furthermore, the molecular docking investigations predicted the water-mediated interaction between the carbonyl oxygen of acetylcholine and the Nsp 2 nitrogen of the pyridine ring for nicotine (as well as for the majority of the corresponding neonicotinoid fragments) and main chain NH of L141. The docking scores, extending over a significant range of 6 kcal/mol, showed that most neonicotinoids were poorly stabilized in the α7 nAChR compared to acetylcholine, except sulfoxaflor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The present study intended to divulge the potential role of garlic-derived organosulfur compounds (OSCs) in targeting PCSK-9 and averting its interaction with the EGF-A portion of LDL-R via in-vitro and in-silico analysis. Our in-silico screening data showed that 3-(Propylsulfinyl)-L-alanine (PSA), S -Ethyl-L-cysteine (SEC), alliin, and S -Allyl-L-cysteine (SAC) exhibited higher binding energy (-7.05, -7.00, -6.65, and -6.31 Kcal/mol, respectively) against PCSK-9, among other selected OSCs. Further, the protein-protein interaction study of PCSK-9-OSCs-complex with EGF-A demonstrated a similar binding pattern with E-total values ranging from -430.01 to -405.6 Kcal/mol. These results were further validated via in-vitro analysis which showed that SEC, SAC, and diallyl trisulphide (DAT) exhibited the lowest IC 50 values of 4.70, 5.26, and 5.29 µg/mL, respectively. In conclusion, the presented data illustrated that SEC, SAC, and DAT were the best inhibitors of PCSK-9 activity and may have the potential to improve the LDL-R function and lower the circulatory LDL-C level.

Aphis gossypii Glover is one of the most agriculturally important phloem-feeding economic pests, causing tremendous loss in crop yield annually. The hormesis is an important cause of A. gossypii resistance formation, population resurgence, and re-outbreak. However, whether the hormesises induced by different insecticides interact mutually remain largely unclear. In the study, four-generation A. gossypii experiment found that the 24-h sublethal-dose (LC 20 ) sulfoxaflor treatment on G0 significantly increased the net reproductive rate (R0) and fecundity of G1 and G2 generation A. gossypii, but it did not significantly affect the fecundity of G3 and G4 individuals. Transcriptomic analyses revealed that the insecticide-induced significant up-regulation of pathways ribosome, energy metabolism, and the DNA replication and reparation might be responsible for the enhancement of fecundity in G1 and G2 A. gossypii. Notably, G0 exposure to LC 20 sulfoxaflor followed by G1 exposure to LC 30 deltamethrin resulted in a stronger reproductive stimulation than sulfoxaflor or deltamethrin exposure alone. Our findings provide valuable reference for optimizing sulfoxaflor application in integrated pest management strategies., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI 50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTS ● decolorization, DPPH ● decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S -allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p -coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic.

Background: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia., Methods: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks., Results: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight., Conclusions: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted., Trial Registration: Clinicaltrials.gov identifier: NCT03055338., Competing Interests: Declaration of competing interest Mukai, Lupinacci, Snow-adami, Voss, Smith, and Egan are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA (MSD) and own stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Marder has acted as a consultant for MSD., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To assess the efficacy of Phyllanthus emblica extract in alleviating halitosis and reducing the inflammatory response to halitosis-related bacteria., Methodology: This investigation, using Phyllanthus emblica fruit extract (PE), involved four aspects. First, we evaluated the effect on growth and aggregation of halitosis-related bacteria, including Fusobacterium nucleatum, Porphyromonas gingivalis, and Solobacterium moorei, using a microdilution assay and scanning electron microscopy. Second, volatile sulfur compound (VSC) levels were measured on individuals with halitosis in randomized short-term (26 participants) and double-blind randomized long-term trials (18 participants in each group) after rinsing with PE for 3, 6, and 12 h, and 28 days. Third, we analyzed pro-inflammatory cytokine expression in TR146 cells using quantitative real-time PCR and enzyme-linked immunosorbent assays. Lastly, we assessed pro-inflammatory cytokine secretion and Toll-like receptor (TLR) 2 mRNA expression via the same experimental methods in a three-dimensional oral mucosal epithelial model (3D OMEM)., Results: PE extract dose-dependently inhibited the growth of F. nucleatum (50% inhibition concentration [IC50]=0.079%), P. gingivalis (IC50=0.65%), and S. moorei (IC50=0.07%) and effectively prevented bacterial aggregation. Furthermore, VSC contents decreased significantly at 3, 6, and 12 h after rinsing with 5% PE compared with those in the control. Long-term use of mouthwash containing 5% PE for 28 days led to a significant decrease in VSC contents. PE attenuated the F. nucleatum- or P. gingivalis-stimulated mRNA expression and protein release of interleukin (IL)-6 and IL-8 in TR146 cells. It also suppressed IL-8 and prostaglandin E2 secretion and TLR2 mRNA expression in F. nucleatum-induced OMEMs., Conclusion: Our findings support the use of PE in oral care products to alleviate halitosis and it may reduce inflammation.

Sulfur-containing natural products possess a variety of biological functions including antitumor, antibacterial, anti-inflammatory and antiviral activities. In this study, four previously undescribed sulfur-containing compounds asperteretals L and M, terreins A and B, together with 17 known compounds were obtained from a culture of marine fungus A. terreus supplemented with inorganic sulfur source Na 2 SO 4 . Their planar structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD experiments. The in vitro cytotoxicities of compounds 1-21 against HCT-116 and Caco-2 were evaluated by SRB assay. Asperteretal M (2) exhibited activity against HCT-116 with the IC 50 value at 30μM. The antiproliferative effect of asperteretal M was confirmed by colony formation assay and cell death staining. Furthermore, the preliminary study on the anti-colon cancer mechanism of asperteretal M was performed by RNA-seq analysis. Western blotting validated that asperteretal M significantly decreased the expression of cell-cycle regulatory proteins CDK1, CDK4, and PCNA in a concentration-dependent manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The green peach aphid, Myzus persicae (Sulzer), is one of the most economically important crop pests worldwide. Insecticide resistance in this pest was first detected over 60 years ago, with resistance in M. persicae now spanning over 80 active ingredients. Sulfoxaflor is a relatively new insecticide that is primarily used to control sap-feeding insects. In 2018 resistance to sulfoxaflor was discovered in field populations of M. persicae in Australia. This study aimed to determine the current distribution and phenotypic levels of sulfoxaflor resistance in Australian clones of M. persicae and to investigate how these patterns relate to clonal type., Results: For the first time, we show there is low-level resistance (8-26-fold) distributed across Australia, with resistance being detected in aphids collected from approximately 20% of all M. persicae collected and screened. Furthermore, this study shows sulfoxaflor resistance is found in two M. persicae haplotypes, providing evidence that there have been multiple independent evolutionary events which have given rise to sulfoxaflor resistance in this species., Conclusion: These findings have important implications for the chemical control of M. persicae in Australia, especially when considering the broader genetic background of these aphids which are known to harbour a number of other insecticide resistance mechanisms. We recommend continuous monitoring of sulfoxaflor resistance in field populations of M. persicae (in Australia and elsewhere) and further research into the underlying genetic mechanisms conferring resistance to sulfoxaflor in both clonal haplotypes. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

"Sulmona Red Garlic" is a well-known Italian traditional product. Bulbs, used for culinary purposes, have been largely investigated for their medicinal properties whereas aerial bulbils are usually removed as waste material. Here, for the first time, chemical composition and biological properties of the hydroalcoholic extract from aerial bulbils were investigated. Complementary information on metabolite composition were obtained using both NMR based untargeted and HPLC-DAD targeted methodologies. The NMR analysis revealed the presence of sugars, organic acids, amino acids, organosulphur compounds (methiin, alliin, allicin and cycloalliin), and other secondary metabolites. In particular, methiin and alliin were identified for the first time in the NMR spectra of aerial bulbil garlic extracts. Polyphenol content was determined by HPLC-DAD analysis: catechin, chlorogenic acid, and gallic acid turned out to be the most abundant phenolics. Hydroalcoholic extract blocked cell proliferation of colon cancer cell line HCT116 with an IC 50 of 352.07 µg/mL, while it was non-toxic to myoblast cell line C2C12. In addition, it caused seedling germination reduction of two edible and herbaceous dicotyledon species, namely Cichorium intybus and C. endivia. Moreover, the same extract reduced the gene expression of TNF-α (tumor necrosis factor), HIF1-α (hypoxia-inducible factor), VEGFA (vascular endothelial growth factor), and transient receptor potential (TRP) M8 (TRPM8) indicating the ability to contrast cancer development through the angiogenic pathway. Final, in silico experiments were also carried out supporting the biological effects of organosulphur compounds, particularly alliin, which may directly interact with TRPM8. The results here reported suggest the potential use of garlic aerial bulbils often considered a waste product as a source in phytotherapeutic remedies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aberrant innate immunity in the brain has been implicated in the pathogenesis of several central nervous system (CNS) disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and depression. Except for extraparenchymal CNS-associated macrophages, which predominantly afford protection against peripheral invading pathogens, it has been reported that microglia, a population of macrophage-like cells governing CNS immune defense in nearly all neurological diseases, are the main CNS resident immune cells. Although microglia have been recognized as the most important source of reactive oxygen species (ROS) in the CNS, ROS also may underlie microglial functions, especially M1 polarization, by modulating redox-sensitive signaling pathways. Recently, endogenous antioxidant systems, including glutathione, hydrogen sulfide, superoxide dismutase, and methionine sulfoxide reductase A, were found to be involved in regulating microglia-mediated neuroinflammation. A series of natural sulfur-containing compounds, including S-adenosyl methionine, S-methyl-L-cysteine, sulforaphane, DMS, and S-alk(enyl)-l-cysteine sulfoxide, modulating endogenous antioxidant systems have been discovered. We have summarized the current knowledge on the involvement of endogenous antioxidant systems in regulating microglial inflammatory activation and the effects of sulfur-containing compounds on endogenous antioxidant systems. Finally, we discuss the possibilities associated with compounds targeting the endogenous antioxidant system to treat neuroinflammation-associated diseases., Competing Interests: Declaration of competing interest We declare the manuscript entitled “Targeting the Endogenous Antioxidant System using Natural Sulfur-containing Compounds: A Novel Pharmacological Strategy to Regulate Brain Innate Immunity” and this submission have been approved by all co-authors. All the authors listed declare no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We studied the properties of N6-chloroadenosine phosphates (ATP, ADP, and AMP chloramines) as compounds with potentially increased antiplatelet efficacy determined by their binding to the plasma membrane of platelets. Chloramine derivatives of ATP, ADP, and AMP do not differ in their optical absorption characteristics: their absorption spectra are in the range of 220-340 nm with a maximum at 264 nm. Chloramines of adenosine phosphates are characterized by high reactivity with respect to thiol compounds. In particular, the rate constants of the reaction of N6-chloroadenosine-5'-diphosphate with N-acetylcysteine, reduced glutathione, dithiothreitol, and cysteine reach 59,000, 250,000, 340,000, and 1,250,000 M -1 ×sec -1 , respectively, and only 1.10±0.02 M -1 ×sec -1 with methionine. It has been found that N6-chloradenosine-5'-triphosphate is a strong inhibitor of platelet functions: it effectively suppresses ADP-induced cell aggregation (IC 50 in the whole blood is 5 μM) and inhibits aggregation of preactivated platelets and induces dissociation of their aggregates., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

A healthy vascular endothelium plays an essential role in modulating vascular tone by producing and releasing vasoactive factors such as nitric oxide (NO). Endothelial dysfunction (ED), the loss of the endothelium physiological functions, results in the inability to properly regulate vascular tone, leading to hypertension and other cardiovascular risk factors. Alongside NO, the gasotransmitter hydrogen sulfide (H 2 S) has emerged as a key molecule with vasodilatory and antioxidant activities. Since a reduction in H 2 S bioavailability is related to ED pathogenesis, natural H 2 S donors are very attractive. In particular, we focused on the sulfur-containing amino acid S -allyl cysteine (SAC), a bioactive metabolite, of which black garlic is particularly rich, with antioxidant activity and, among others, anti-diabetic and anti-hypertensive properties. In this study, we analyzed the protective effect of SAC against ED by evaluating reactive oxygen species level, H 2 S release, eNOS phosphorylation, and NO production (by fluorescence imaging and western blot analysis) in Bovine Aortic Endothelial cells (BAE-1). Furthermore, we chemically characterized a Black Garlic Extract (BGE) for its content in SAC and other sulfur-containing amino acids. BGE was used to carry out an analysis on H 2 S release on BAE-1 cells. Our results show that both SAC and BGE significantly increase H 2 S release. Moreover, SAC reduces ROS production and enhances eNOS phosphorylation and the consequent NO release in our cellular model. In this scenario, a natural extract enriched in SAC could represent a novel therapeutic approach to prevent the onset of ED-related diseases.

Chronic cigarette smoke condensate (CSC) exposure is one of the preventable risk factors in the CS-induced lung cancer. However, understanding the mechanism of cellular transformation induced by CS in the lung remains limited. We investigated the effect of long term exposure of CSC in human normal lung epithelial Beas-2b cells, and chemopreventive mechanism of organosulphur garlic compounds, diallyl sulphide (DAS) and diallyl disulphide (DADS) using Next Generation Sequencing (NGS) transcriptomic analysis. CSC regulated 1077 genes and of these 36 genes are modulated by DAS while 101 genes by DADS. DAS modulated genes like IL1RL1 (interleukin-1 receptor like-1), HSPA-6 (heat shock protein family A, member 6) while DADS demonstrating ADTRP (Androgen-Dependent TFPI Regulating Protein), ANGPT4 (Angiopoietin 4), GFI1 (Growth Factor-Independent 1 Transcriptional Repressor), TBX2 (T-Box Transcription Factor 2), with some common genes like NEURL-1 (Neuralized E3-Ubiquitin Protein Ligase 1), suggesting differential effects between these two garlic compounds. They regulate genes by influencing pathways including HIF-1alpha, STAT-3 and matrix metalloproteases, contributing to the chemoprotective ability of organosulfur garlic compounds against CSC-induced cellular transformation. Taken together, we demonstrated CSC induced global gene expression changes pertaining to cellular transformation which potentially can be delayed with dietary chemopreventive phytochemicals like DS and DADS influencing alterations at the transcriptomic level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Yohimbine is a small indole alkaloid derived from the bark of the yohimbe tree with documented biological activity, including anti-inflammatory, erectile dysfunction relieving, and fat-burning properties. Hydrogen sulfide (H 2 S) and sulfane sulfur-containing compounds are regarded as important molecules in redox regulation and are involved in many physiological processes. Recently, their role in the pathophysiology of obesity and obesity-induced liver injury was also reported. The aim of the present study was to verify whether the mechanism of biological activity of yohimbine is related to reactive sulfur species formed during cysteine catabolism. We tested the effect of yohimbine at doses of 2 and 5 mg/kg/day administered for 30 days on aerobic and anaerobic catabolism of cysteine and oxidative processes in the liver of high-fat diet (HFD)-induced obese rats. Our study revealed that HFD resulted in a decrease in cysteine and sulfane sulfur levels in the liver, while sulfates were elevated. In the liver of obese rats, rhodanese expression was diminished while lipid peroxidation increased. Yohimbine did not influence sulfane sulfur and thiol levels in the liver of obese rats, however, this alkaloid at a dose of 5 mg decreased sulfates to the control level and induced expression of rhodanese. Moreover, it diminished hepatic lipid peroxidation. It can be concluded that HFD attenuates anaerobic and enhances aerobic cysteine catabolism and induces lipid peroxidation in the rat liver. Yohimbine at a dose of 5 mg/kg can alleviate oxidative stress and reduce elevated concentrations of sulfate probably by the induction of TST expression.

The purpose of this study was to analyze the effects of cadmium toxicity on rat embryogenesis when exposed to other heavy metal citrates. Despite the variety of scientific publications discussing the influence of cadmium on mammalian postnatal development, the effect of this metal on embryogenesis has not yet been sufficiently studied. In this experimental study, cadmium chloride was administered to experimental pregnant female Wistar rats at a daily dose of 1.0 mg/kg. Rats were allocated at random into groups receiving either cadmium chloride alone or additional zinc citrate, cerium citrate, or nanocomposite (based on iodine, sulfur, and selenium citrate). The control group received distilled water at an equivalent volume. In each group, operational intervention occurred at the 13th and 20th day of gestation to assess numbers of live fetuses, corpora lutea, pre-implantation losses, post-implantation losses, and total implantation losses. When cadmium chloride alone was administered, a pronounced embryotoxic effect was observed, manifested as a significant decrease in the number of live fetuses. Experimental groups which received cadmium chloride with zinc citrate, cerium citrate, or nanocomposite had an increased number of live fetuses and corpora lutea, as well as a decreased number of implantation losses, compared to the group which only received cadmium chloride. Each combination of cerium, zinc, and selenium nanocomposite citrates demonstrated a compensatory effect on all measures of embryogenesis impacted by cadmium embryotoxicity. Thus, administration of the citrates of cerium, zinc, and selenium nanocomposite reduces cadmium embryotoxicity and its accumulation in the body.

Asthma is a chronic inflammatory disease in the airways with a multifactorial origin but with inflammation and oxidative stress as related pathogenic mechanisms. Garlic ( Allium sativum ) is a nutraceutical with different biological properties due to sulfur-containing natural compounds. Studies have shown that several compounds in garlic may have beneficial effects on cardiovascular diseases, including those related to the lungs. Therefore, it is possible to take advantage of the compounds from garlic as nutraceuticals for treating lung diseases. The objective of this article is to review the biological properties of the sulfur compounds present in garlic for the treatment of asthma, as well as the cellular mechanisms involved. Here, we discuss the potential therapeutic effects of garlic compounds in the modulation of inflammation and oxidative stress, as well as its antibiotic and antiviral activities for identifying and testing potential treatment options for asthma management.

Natural sulfur compounds are emerging as therapeutic options for the management of hypertension and prehypertension. They are mainly represented by polysulfides from Alliaceae (i.e., garlic) and isothiocyanates from Brassicaceae (or crucifers). The beneficial cardiovascular effects of these compounds, especially garlic polysulfides, are well known and widely reported both in preclinical and clinical studies. However, only a few authors have linked the ability of natural sulfur compounds to induce vasorelaxation and subsequent antihypertensive effects with their ability to release hydrogen sulfide (H 2 S) in biological tissue. H 2 S is an endogenous gasotransmitter involved in vascular tone regulation. Some cardiovascular diseases, such as hypertension, are associated with lower plasma H 2 S levels. Consequently, exogenous sources of H 2 S (H 2 S donors) have been designed and synthesized or identified among secondary plant metabolites as potential therapeutic options. In addition to antioxidant effects due to its chemical properties as a reducing agent, H 2 S induces vasorelaxation by interacting with a range of molecular targets. The mechanisms of action accounting for H 2 S-induced vasodilation include opening of vascular potassium channels (such as ATP-sensitive (K ATP ) and voltage-operated (Kv7) channels), inhibition of 5-phosphodiesterase (5-PDE), and activation of vascular endothelial growth factor receptor-2 (VEGFR-2). These effects may be attributed to H 2 S-induced S-persulfidation (or S-sulfhydration), which is a posttranslational modification of cysteine residues of many types of proteins resulting in structural and functional alterations (activation/inhibition). Thus, H 2 S donors, such as natural sulfur compounds, are promising antihypertensive agents with novel mechanisms of action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: As a popular dietary supplement containing sulfur compound, methylsulfonylmethane (MSM) has been widely used as an alternative oral medicine to relieve joint pain, reduce inflammation and promote collagen protein synthesis. However, it is rarely used in developing bioactive scaffolds in bone tissue engineering., Methods: Three-dimensional (3D) hydroxyapatite/poly (lactide- co -glycolide) (HA/PLGA) porous scaffolds with different doping levels of MSM were prepared using the phase separation method. MSM loading efficiency, in vitro drug release as well as the biological activity of MSM-loaded scaffolds were investigated by incubating mouse pre-osteoblasts (MC3T3-E1) in the uniform and interconnected porous scaffolds., Results: Sustained release of MSM from the scaffolds was observed, and the total MSM release from 1% and 10% MSM/HA/PLGA scaffolds within 16 days was up to 64.9% and 68.2%, respectively. Cell viability, proliferation, and alkaline phosphatase (ALP) activity were significantly promoted by incorporating 0.1% of MSM in the scaffolds. In vivo bone formation ability was significantly enhanced for 1% MSM/HA/PLGA scaffolds indicated by the repair of rabbit radius defects which might be affected by a stimulated release of MSM by enzyme systems in vivo., Discussion: Finding from this study revealed that the incorporation of MSM would be effective in improving the osteogenesis activity of the HA/PLGA porous scaffolds., Competing Interests: There are no conflicts of interest to declare., (© 2022 Guo et al.)

Due to their known health-enhancing properties, Laminaria japonica polysaccharides (LJP) may alleviate obesity via unknown mechanisms. This study aimed to investigate beneficial LJP effects and mechanism(s) of action using an animal obesity model (ICR mice fed a high-fat diet). First, LJP were confirmed to consist of sulfated polysaccharides via infrared spectroscopy. Next, LJP administration to mice was found to induce weight loss, reduce liver fat accumulation, and support healthy obesity-related blood serum indicator levels. Notably, LJP treatment significantly reduced TC and LDL levels and significantly increased HDL, LPL, UCP-2, and PPAR-α levels. Furthermore, examinations of tissues of LJP-treated mice revealed significantly reduced intestinal tissue inflammation as compared to corresponding results obtained for untreated obese controls. Additionally, LJP treatment relieved colonic shortening and reduced colonic levels of inflammatory factors TNF-α and IL-6. Further exploration of LJP treatment effects on mouse gut microbiota conducted via fecal 16S rRNA gene sequence-based gut microbiome profiling analysis revealed that LJP treatment increased the Bacteroidetes/Firmicutes ratio and increased gut abundances of probiotics Bacteroides acidifaciens, s&#95;Lactobacillus intestinalis, and s&#95;Lactobacillus murinus. In conclusion, these results collectively suggest that LJP use as a food supplement may alleviate obesity and related gut microbiota dysbiosis and intestinal inflammatory disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Sulfoxaflor is a new insecticide which acts on the nicotinic acetylcholine receptor (nAChRs) in a similar way to neonicotinoids. However, sufloxaflor (SFX) is thought to act in a different manner and is thus proposed as an alternative in crop protection. The goal of this study is to evaluate the toxicity of SFX and its sublethal effect on the honeybee Apis mellifera after acute exposure. In toxicological assay studies, the LD50 value and sublethal dose (corresponding to the NOEL: no observed effect level) were 96 and 15 ng/bee, respectively. Using the proboscis extension response paradigm, we found that an SFX dose of 15 ng/bee significantly impairs learning and memory retrieval when applied 12 h before conditioning or 24 h after olfactory conditioning. SFX had no effect on honeybee olfactory performance when exposure happened after the conditioning. Relative quantitative PCR experiments performed on the six nicotinic acetylcholine receptor subunits demonstrated that they are differently expressed in the honeybee brain after SFX exposure, whether before or after conditioning. We found that intoxicated bees with learning defects showed a strong expression of the Amelβ1 subunit. They displayed overexpression of Amelα9 and Amelβ2, and down-regulation of Amelα1, Amelα3 and Amelα7 subunits. These results demonstrated for the first time that a sublethal dose of SFX could affect honeybee learning and memory performance and modulate the expression of specific nAChR subunits in the brain., Competing Interests: The authors have declared that no competing interests exist.

Tumor-associated macrophages (TAMs), especially the M2-like phenotype, promote tumor progression, making them candidate targets for anti-tumor therapy. We previously discovered a cyclic sulfur compound, Onionin A (ONA), which suppresses tumor progression by inhibiting the M2-polarization of TAMs. In the present study, we sought to find new candidate compounds possessing a stronger effect compared to ONA by exploring compounds with structures similar to those of ONA among several cyclic sulfur compounds. A total of 81 cyclic sulfur compounds were screened, and their effects on macrophage polarization toward an M2-like phenotype were tested using human monocyte-derived macrophages (HMDMs). The anti-tumor effects of the identified candidate compounds were examined in a tumor-bearing mouse model. Three candidate compounds inhibited both IL-10- and tumor culture supernatant (TCS)-induced M2-polarization of HMDMs. These compounds also suppressed STAT3 activation in HMDMs stimulated by IL-10 and TCS, whereas these compounds had no effect on STAT3 activation in tumor cells. Furthermore, these compounds inhibited tumor cell proliferation under co-culture conditions with HMDMs, indicating that the three candidate compounds suppress tumor proliferation by regulating cell-cell interactions between tumor cells and macrophages. In addition, two of these candidate compounds had inhibitory effects on tumor growth and lung metastasis in the LM8 tumor-bearing mouse model. Our study identified new candidate cyclic sulfur compounds for anti-tumor therapy targeting the M2-polarization of TAMs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objective: The antinociceptive effects of garlic have shown promise in treating different chronic diseases in humans, such as knee osteoarthritis, rheumatoid arthritis and peripheral arterial occlusive disease stage II. The most common garlic products are garlic powder (dried garlic), steam distilled garlic oils, garlic oil macerate and aged garlic extract. These commercial products contain organosulphur compounds (OSCs) that have been extensively evaluated in preclinical models and some clinical assays to treat different diseases against pain. In this review, we describe the importance of some bioactive compounds found in garlic and their role in treating pain., Materials & Methods: A systematic search of the literature in Dimensions, PubMed, Scopus, and Web of Science was performed. Terms and preselected keywords relating to garlic, its derivatives and organusulphure compounds in acute, chronic and neuropathic pain, were used to perform a systematic literature search. Two independent reviewers screened the papers for inclusion and assessed the methodological quality., Results & Discussion: The antinociceptive activity of garlic and its OSC is related to its antioxidant and anti-inflammatory properties, which may be explained by the ability to block the synthesis of PGs, pro-inflammatory cytokines and interferon-γ, by the reduction COX-2 activity and increasing the levels of anti-inflammatory cytokines. Besides, garlic extract is an activator of TRPA1 and TRPV1, where the principal responsible for this activation are OSC., Conclusion: The relationship between these pathways allows a better understanding how garlic and its derivates could be carrying out its pharmacological action over the management of acute and chronic pain and provide a base by further investigations., Significance: Antinociceptive effect of garlic and its OSCs has been extensively evaluated in preclinical models and clinical assays to treat different diseases, contributing to the modulation of inflammation as an essential factor in reducing pain. The current review emphasizes the potential therapeutic effect of garlic and its derivatives in treatment of pain and related mechanisms of action. Moreover, it provides information about the potential clinical use in patients with painful conditions., (© 2022 European Pain Federation - EFIC®.)

Sulfur-containing compounds, such as cyclic compounds with a vinyl sulfane structure, exhibit a wide range of biological activities including anticancer activity. Therefore, the development of efficient strategies to synthesize such compounds is a remarkable achievement. We have developed a unique approach for the rapid and modular preparation of nature-inspired cyclic and acyclic sulfur-containing compounds using thioacrolein, a naturally occurring chemically unstable intermediate. We constructed thiopyranone derivatives through the regioselective sequential double Diels-Alder reaction of thioacrolein produced by allicin, a major component in garlic, and two molecules of silyl enol ether as the diene partner. The cytotoxicity toward cancer stem cells of the thiopyranones was equal to or higher than that of ( Z )-ajoene (positive control) derived from garlic, and the thiopyranones had higher chemical stability than ( Z )-ajoene.

Background: Dusky cotton bug (DCB), Oxycarenus hyalinipennis (Costa) (Hemiptera: Lygaeidae), is a key insect pest of cotton. It causes huge losses to cotton and many other economically important crops. Sulfoxaflor is a newly introduced systemic insecticide that is effective against many sap-feeding insect pests such as aphids, whiteflies and true bugs. The present study was designed to characterize the inheritance of sulfoxaflor resistance in DCB. Moreover, the role of synergists in reducing sulfoxaflor resistance in DCB was also assessed., Results: A field population of DCB has developed 1132.0-fold resistance to sulfoxaflor after 11 selected generations in the laboratory. Nonsignificant difference of reciprocal crosses was observed depending on the LC 50 (median lethal concentration) values (95% confidence intervals overlapped), suggesting an autosomal mode of sulfoxaflor resistance inheritance. The degree of dominance of 0.7 for F 1 (Sulfo-Sel Pop ♀ × Lab-Pop♂) and 0.6 for F 1 '(Sulfo-Sel Pop ♂ × Lab-Pop♀), respectively, suggested that sulfoxaflor resistance was incompletely dominant. According to the monogenic model, the number of genes involved to induce sulfoxaflor resistance revealed that sulfoxaflor resistance was polygenic in nature. The realized heritability (h 2 ) value for sulfoxaflor resistance was 0.2. The synergists experiment indicated that esterases were involved in the sulfoxaflor resistance mechanism in DCB., Conclusions: The current results indicate that there is autosomal, incompletely dominant and polygenic inheritance of sulfoxaflor resistance in DCB. Our results would be helpful in delaying sulfoxaflor resistance against DCB in the field. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Sulfated galactans (SG) isolated from red alga Gracilaria fisheri have been reported to inhibit the growth of cholangiocarcinoma (CCA) cells, which was similar to the epidermal growth factor receptor (EGFR)-targeted drug, cetuximab. Herein, we studied the anti-cancer potency of SG compared to cetuximab. Biological studies demonstrated SG and cetuximab had similar inhibition mechanisms in CCA cells by down-regulating EGFR/ERK pathway, and the combined treatment induced a greater inhibition effect. The molecular docking study revealed that SG binds to the dimerization domain of EGFR, and this was confirmed by dimerization assay, which showed that SG inhibited ligand-induced EGFR dimer formation. Synchrotron FTIR microspectroscopy was employed to examine alterations in cellular macromolecules after drug treatment. The SR-FTIR-MS elicited similar spectral signatures of SG and cetuximab, pointing towards the bands of RNA/DNA, lipids, and amide I vibrations, which were inconsistent with the changes of signaling proteins in CCA cells after drug treatment. Thus, this study demonstrates the underlined anti-cancer mechanism of SG by interfering with EGFR dimerization. In addition, we reveal that FTIR signature spectra offer a useful tool for screening anti-cancer drugs' effect.

10-Alkylthiocolchicines have been obtained and characterized by spectroscopic methods and their biological activities as: cytotoxic, anti-inflammatory and analgesic activities have been tested. Cytotoxic activity against SKOV-3 ovarian cell line for 10-alkylthiocolchicine analogues was reported and tested compounds showed to be more active than commonly used doxorubicin. Some of tested C-10 alkylthiolated colchicines have been found to exhibit cytotoxicity at levels comparable to that of the natural product-colchicine. 10-Methylthiocolchicine has IC 50  = 8 nM and 10-ethylthiocolchicine has IC 50  = 47 nM in comparison to colchicine IC 50  = 37 nM. Moreover for 10-alkylthioderivatives apoptosis test, cyclin B1 and cell cycle tests were performed. 10-n-Butylthiocolchicine was tested for anti-inflammatory and analgesic activities it showed to produce analgesic rather than anti-inflammatory effect.

The review focuses on sulfated steroids that have been isolated from seaweeds, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. Sulfur-containing steroids and triterpenoids are sourced from sedentary marine coelenterates, plants, marine sediments, crude oil, and other geological deposits. The review presents the pharmacological profile of sulfated steroids, sulfur-containing steroids, and triterpenoids, which is based on data obtained using the PASS program. In addition, several semi-synthetic and synthetic epithio steroids, which represent a rare group of bioactive lipids that have not yet been found in nature, but possess a high level of antitumor activity, were included in this review for the comparative pharmacological characterization of this class of compounds. About 140 steroids and triterpenoids are presented in this review, which demonstrate a wide range of biological activities. Therefore, out of 71 sulfated steroids, thirteen show strong antitumor activity with a confidence level of more than 90%, out of 50 sulfur-containing steroids, only four show strong antitumor activity with a confidence level of more than 93%, and out of eighteen epithio steroids, thirteen steroids show strong antitumor activity with a confidence level of 91% to 97.4%.

Intensive efforts have been undertaken in the fields of prevention, diagnosis, and therapy of lung cancer. Fucoidans exhibit a wide range of biological activities, which are dependent on the degree of sulfation, sulfation pattern, glycosidic branches, and molecular weight of fucoidan. The determination of oversulfation of fucoidan and its effect on anti-lung cancer activity and related signaling cascades is challenging. In this investigation, we used a previously developed fucoidan (SCA), which served as a native fucoidan, to generate two oversulfated fucoidan derivatives (SCA-S1 and SCA-S2). SCA, SCA-S1, and SCA-S2 showed differences in compositions and had the characteristic structural features of fucoidan by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) analyses. The anticancer properties of SCA, SCA-S1, and SCA-S2 against human lung carcinoma A-549 cells were analyzed in terms of cytotoxicity, cell cycle, Bcl-2 expression, mitochondrial membrane potential (MMP), expression of caspase-3, cytochrome c release, Annexin V/propidium iodide (PI) staining, DNA fragmentation, and the underlying signaling cascades. Our findings indicate that the oversulfation of fucoidan promotes apoptosis of lung cancer cells and the mechanism may involve the Akt/mTOR/S6 pathway. Further in vivo research is needed to establish the precise mechanism whereby oversulfated fucoidan mitigates the progression of lung cancer.

Insecticides remain valuable tools for the control of insect pests that significantly impact human health and agriculture. A deeper understanding of insecticide targets is important in maintaining this control over pests. Our study systematically investigates the nicotinic acetylcholine receptor (nAChR) gene family, in order to identify the receptor subunits critical to the insect response to insecticides from three distinct chemical classes (neonicotinoids, spinosyns and sulfoximines). Applying the CRISPR/Cas9 gene editing technology in D. melanogaster, we were able to generate and maintain homozygous mutants for eight nAChR subunit genes. A ninth gene (Dβ1) was investigated using somatic CRISPR in neural cells to overcome the low viability of the homozygous germline knockout mutant. These findings highlight the specificity of the spinosyn class insecticide, spinosad, to receptors containing the Dα6 subunit. By way of contrast, neonicotinoids are likely to target multiple receptor subtypes, beyond those receptor subunit combinations previously identified. Significant differences in the impacts of specific nAChR subunit deletions on the resistance level of flies to neonicotinoids imidacloprid and nitenpyram indicate that the receptor subtypes they target do not completely overlap. While an R81T mutation in β1 subunits has revealed residues co-ordinating binding of sulfoximines and neonicotinoids differ, the resistance profiles of a deletion of Dβ1 examined here provide new insights into the mode of action of sulfoxaflor (sulfoximine) and identify Dβ1 as a key component of nAChRs targeted by both these insecticide classes. A comparison of resistance phenotypes found in this study to resistance reported in insect pests reveals a strong conservation of subunit targets across many different insect species and that mutations have been identified in most of the receptor subunits that our findings would predict to have the potential to confer resistance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the synthesis of 6 novel sulfahydantoin derivatives by the key reaction of chlorosulfonyl isocyanate to form α-amino acid derived sulfamides, and their cyclization into sulfahydantoins. The synthesis is rapid and provides the target compounds in 8 steps. We investigated their potential as β-lactamase inhibitors using two common Class A β-lactamases, TEM-1 and the prevalent extended-spectrum TEM-15. Two compounds, 3 and 6, show substantial inhibition of the β-lactamases with IC 50 values between 130 and 510 μM and inferred K i values between 32 and 55 μM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors. Glycosmis pentaphylla is used by traditional medical practitioners worldwide to treat various diseases. We isolated and identified a chemical component with potential anti-hepatocellular carcinoma (HCC) effects. Methylgerambullin is a sulfur containing amine and has significant antihepatoma activity in vitro and in vivo. Methylgerambullin was significantly cytotoxic to HCC cells and induces apoptosis in HCC cells. In addition, methylgerambullin is able to inhibit the growth of transplanted tumors in nude mice without significant toxicity. Regarding the anti-cancer mechanism of methylgerambullin, treatment with methylgerambullin increased the expression of caspase-3, caspase-9 and Bax in vitro and in vivo and reduce the expression of B-cell lymphoma-2 (Bcl-2). Simultaneously, methylgerambullin can also affect ERS-related proteins, inhibit Protein Kinase B (Akt) activity, cause dephosphorylation of downstream Bad, and inhibit the expression of the Signal Transducer and Activator of Transcription 3 (STAT3) protein to inhibit HCC cells proliferation. Overall, these results suggest that methylgerambullin can inhibit HCC cells proliferation by inducing mitochondrial apoptosis, activating ERS signaling pathways and inhibiting the Akt and STAT3 pathways., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Current therapeutic approaches to osteoporosis display some potential adverse effects and a limited efficacy on non-vertebral fracture reduction. Some sulfonylamidines targeting the scaffold proteins prohibitins-1 and 2 (PHB1/2) have been showed to inhibit the formation of osteoclasts in charge of bone resorption. Herein, we report the development of a second generation of anti-osteoclastic PHB ligands. The most potent compound, IN45, showed 88% inhibition at the low concentration of 5 μM, indicates that it might serve as a basis for the development of new antiosteoporotic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: The quest for strong, safe and cost-effective natural antiproliferative agents that could reduce cancer has been the focus now a days. In this regard, the organosulfur compounds from garlic (Allium sativum L.), like Diallyl Sulfide (DAS) and Diallyl Disulfide (DADS), have been shown to exhibit potent antiproliferative and anticancer properties in many studies. However, the potential of these compounds against viral oncoproteins in cervical cancer has not been fully elucidated yet., Objective: The objective of this study was to analyze the antiproliferative and apoptotic properties of DADS and DAS in HPV16+ human cervical cancer Caski cell line., Methods: Caski (cervical cancer cells) were cultured and followed by the treatment of various concentrations of organosulphur compounds (DADS and DAS), cell viability was measured by MTT assay. The apoptotic assay was performed by DAPI and Hoechst3342 staining. Reactive Oxygen Species (ROS) was estimated by DCFDA staining protocol. The distributions of cell cycle and apoptosis (FITC-Annexin V assay) were analyzed by flow cytometry. Finally, gene expression analysis was performed via quantitative real time PCR., Results: Our results showed that DAS and DADS exerted a significant antiproliferative effect on Caski cells by reducing the cell viability and inducing a dose-related increment in intracellular ROS production along with apoptosis in Caski cells. DAS and DADS also induced cell cycle arrest in G0/G1 phase, which was supported by the downregulation of cyclin D1 and CDK4 and upregulation of CDK inhibitors p21WAF1/CIP1 and p27KIP1 in Caski cells. Additionally, DAS and DADS lead to the downregulation of viral oncogene E6 and E7 and restoration of p53 function., Conclusion: Thus, this study confirms the efficacy of both the organosulfur compounds DADS and DAS against cervical cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In recent years, interest in sulfoximine chemistry has been greatly increased. For example, at least three sulfoximine containing drugs BAY 1143572, BAY 1251152 and AZD6738 have entered the clinic. Despite the increasing interest in sulfoximines and their chemistry, the routine application of this structure in drug discovery is still hampered due to limited experience in physicochemical and in vitro parameters of sulfoximines. Therefore, we reviewed all relevant articles from 2013 to the present in terms of potency and pharmacokinetic properties in order to support the addition of the sulfoximine component to the toolbox of medicinal chemists., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Masson SAS.)

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living systems. Se-containing compounds have been found to reduce carcinogenesis of animal models, and dietary supplemental Se might decrease cancer risk. Se is mainly taken up by plant roots in the form of selenate via high-affinity sulfate transporters. Consequently, owing to the chemical similarity between Se and sulfur (S), the availability of S plays a key role in Se accumulation owing to competition effects in absorption, translocation, and assimilation. Moreover, naturally occurring S-containing compounds have proven to exhibit anticancer potential, in addition to other bioactivities. Therefore, it is important to understand the interaction between Se and S, which depends on Se/S ratio in the plant or/and in the growth medium. Brassicaceae (also known as cabbage or mustard family) is an important family of flowering plants that are grown worldwide and have a vital role in agriculture and populations' health. In this review we discuss the distribution and further interactions between S and Se in Brassicaceae and provide several examples of Se or Se/S biofortifications' experiments in brassica vegetables that induced the chemopreventive effects of these crops by enhancing the production of Se- or/and S-containing natural compounds. Extensive further research is required to understand Se/S uptake, translocation, and assimilation and to investigate their potential role in producing anticancer drugs.

Colorectal cancer was the third most commonly diagnosed malignant tumor and the fourth leading cause of cancer deaths worldwide in 2012. A human colorectal cancer cell line, RCM-1, was established from a colon cancer tissue diagnosed as a well-differentiated rectum adenocarcinoma. RCM-1 cells spontaneously form 'domes' (formerly designated 'ducts') resembling villiform structures. Two sulphur-containing compounds from Cucumis melo var. conomon (Katsura-uri, or Japanese pickling melon), referred to as 3-methylthiopropionic acid ethyl ester (MTPE) and methylthioacetic acid ethyl ester (MTAE), can induce the differentiation of the unorganized cell mass of an RCM-1 human colorectal cancer cell culture into a dome. However, the underlying molecular mechanisms of such dome formation have not been previously reported. Here, we performed a structure-activity relationship analysis, which indicated that methylthioacetic acid (MTA) was the lowest molecular weight compound with the most potent dome-inducing activity among 37 MTPE and MTAE analogues, and the methylthio group was essential for this activity. According to our microarray analysis, MTA resulted in down-regulation of 537 genes and up-regulation of 117 genes. Furthermore, MTA caused down-regulation of many genes involved in cell-cycle control, with the cyclin E2 (CCNE2) and cell division cycle 25A (CDC25A) genes being the most significantly reduced. Pharmacological analysis showed that the administration of two cell-cycle inhibitors for inactivating CDC25A phosphatase (NSC95397) and the cyclin E2/cyclin-dependent kinase 2 complex (purvalanol A) increased the dome number independently of MTA. Altogether, our results indicate that MTA is the minimum unit required to induce dome formation, with the down-regulation of CDC25A and possibly CCNE2 being important steps in this process., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H 2 S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H 2 S/SS in blood and/or tissues, and are amenable to treatment by H 2 S supplementation, development of safe and efficacious H 2 S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S 8 ) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H 2 S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H 2 S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H 2 S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H 2 S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H 2 S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new "supramolecular tuning" paradigm.

Background/aim: The clinical course of acute leukemia is complicated, and it is often necessary to combine or change treatment methods due to the rapid increase and spread of malignant cells. In this study, the potential anti-leukemia activities of prepared garlic essential oil (GEO) and some organosulfur compounds contained therein were examined., Materials and Methods: Garlic essential oil component identification by gas chromatography-mass spectrometry (GC-MS). MTT assay evaluated cytotoxicity of tested samples. Leukemia cell differentiation was determined by NBT assay. Apoptosis and related mechanisms were investigated by western blotting., Results: GC-MS analysis confirmed that the two most abundant constituents, diallyl disulfide (DADS) and diallyl trisulfide (DATriS), constituted 80% of the composition. GEO and DADS exhibited the best effects in terms of significant production of intracellular reactive oxygen species (ROS), induction apoptosis and potentiation differentiation of human promyelocytic leukemia cell line HL-60 cells. The GEO-mediated apoptosis was alleviated by the free radical scavenger N-acetyl-L-cysteine (NAC)., Conclusion: The anti-leukemia activity of GEO and organosulfur compound DADS through the action of ROS elevation was herein confirmed., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Density functional theory calculations were performed on the structure of the nitrosyl iron-sulfur cluster (Me 4 N) 2 [Fe 2 S 2 (NO) 4 ]. The IR spectra were assigned and the electronic ground-state properties in different solvents were analyzed. Dynamic conversion of [Fe 2 S 2 (NO) 4 ] 2- was analyzed quantitatively using the time-resolved IR spectra in different solvents. Photo irradiation and polarity of solvent obviously affect the reaction rates, which are faster in CH 3 CN and CH 3 OH than those in DMSO and water. The calculated orbital energies of HOMOs are higher and those of LUMO-HOMO gap are smaller in CH 3 CN and CH 3 OH than those in DMSO and water, which is consistent with the reaction rate and explains the experimental observation. Moreover, the photo-induced nitric oxide (NO) release and cluster conversion was identified using EPR spectra. The photocleavage of pBR322 DNA was observed, both NO and oxygen related free radicals play key roles in the process. The study provides an effective method to monitor the photodynamic reactions for better understanding of the physiological activity of nitrosyl iron-sulfur clusters., Competing Interests: Declaration of competing interest All of the authors declare that they have no competing interests. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The manuscript is not currently under consideration for publication elsewhere., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Sixteen derivatives of dithiin diisoimide 2a-2p have been synthesized and screened for antibacterial and antifungal activity. Compounds 2a-2g and 2i-2p are almost same or more active than gentamicine against Acinetobacter. Whereby compound 2,6-didodecyl- 1 H,5H-pyrrolo[3',4',5,6][1,4]dithiino[2,3-c]pyrrole-1,3,5,7(2H,6H)-tetrone (2d) having zone of inhibition 20 mm against Acinetobacter is the most potent among all these compounds and can be used as lead compound for the treatment of Acinetobacter infection.

Cellular reprogramming is an emerging strategy for delaying the aging processes. However, a number of challenges, including the impaired genome integrity and decreased pluripotency of induced pluripotent stem cells (iPSCs) derived from old donors, may hinder their potential clinical applications. The longevity gene, Sirtuin 6 (SIRT6), functions in multiple biological processes such as the maintenance of genome integrity and the regulation of somatic cell reprogramming. Here, for the first time, we demonstrate that MDL-800, a recently developed selective SIRT6 activator, improved genomic stability by activating two DNA repair pathways-nonhomologous end joining (NHEJ) and base excision repair (BER) in old murine-derived iPSCs. More interestingly, we found that pretreating old murine iPSCs, which normally exhibit a restricted differentiation potential, with MDL-800 promoted the formation of teratomas comprised of all three germ layers and robustly stimulated chimera generation. Our findings suggest that pharmacological activation of SIRT6 holds great promise in treating aging-associated diseases with iPSC-based cell therapy., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Photodynamic therapy (PDT) is a light-based modality for tumor treatment that involves the generation of reactive oxygen species (ROS) by the combination of light, a photosensitizer, and molecular oxygen. Nevertheless, the therapeutic effects of PDT are limited by hypoxic conditions that worsen with oxygen consumption during the PDT process. Photo/chemodynamic therapy (PCDT) based on the Fenton reaction is one strategy to improve ROS generation, provided a highly effective Fenton reagent is developed. In this research, SiO 2 @Cu 7 S 4 nanotubes (NTs) were synthesized as a PCDT agent. This double-valence metal-sulfide composite material can react with H 2 O 2 at the tumor site. SiO 2 @Cu 7 S 4 NTs can produce more ROS than the traditional PDT agents, and besides, they can also be used as a photothermal therapy (PTT) agent. SiO 2 @Cu 7 S 4 NTs will trigger the PTT effect under 808 nm irradiation and generate a large amount of heat to eradicate cancer cells. This heat will also promote the PCDT effect by increasing the reaction rate. Thus, the SiO 2 @Cu 7 S 4 NT is a suitable material for PCDT and PTT synergistic oncotherapy. The 808 nm laser is selected as the appropriate excitation source, providing adequate penetration and minimal harm to normal cells. The experimental data presented herein demonstrate the promising photosensitive, Fenton-like, and photothermal performance of SiO 2 @Cu 7 S 4 NTs. Furthermore, the findings could promote the development of PCDT and PTT synergistic therapy. Thus, this research provides a feasible method to design a single, multifunctional material for cancer treatment.

Allium subhirsutum , known as hairy garlic, is a bulbous plant widespread in the Mediterranean area and locally used as a food and spice. In the present study, the chemical profile of the ethanolic extracts from bulbs (BE) and aerial parts (APE) were analyzed by HPLC-ESI-MS n , and antioxidant properties were evaluated by DPPH, ABTS and TEAC assays. The traditional use in the diet, and the well documented biological activity of Allium species suggest a potential as a new nutraceutical. For this reason, the potential usefulness of this food can be considered in the treatment and prevention of degenerative Alzheimer disease. For this reason, acetylcholinesterase inhibitory property was investigated. Furthermore, due to the observed presence of sulfur-containing and phenolic constituents, the cytotoxicity on tumor cells line was investigated. Results revealed significant AChE inhibitory activity for BE and APE. Both extracts exhibited also moderate antioxidant properties in the in vitro assays. Finally, limited cytotoxic activity was observed towards Human colon carcinoma and adenocarcinoma cell line, with differences between the individual parts tested. HPLC-ESI-MS n analysis showed that hairy garlic is a good source of sulphur compounds, flavonoids and phenylpropanoids derivatives, thus being a valid alternative to the common garlic ( A. sativum ). This work opens new opportunities for the application of A. subhirsutum as a health-promoting food.

Sulfoxaflor, the first commercially available sulfoximine insecticide, has been used for the control of sap-feeding insect pests such as plant bugs and aphids on a variety of crops. However, its sublethal effects on the mirid bug Apolygus lucorum, one of the key insect pests of Bt cotton and fruit trees in China, have not been fully examined. Here, we evaluated the demography and feeding behaviour of A. lucorum exposed to sulfoxaflor. The leaf-dipping bioassay showed that the LC10 and LC30 of sulfoxaflor against 3rd-instar nymphs of this insect were 1.23 and 8.37 mg L-1, respectively. The LC10 significantly extended the nymphal duration and decreased the oviposition period by 5.29 days and female fecundity by 56.99% in the parent generation (F0). The longer duration of egg, 5th-instar nymphs, preadult, and male adult longevity were observed in the F1 generation (F1) at LC10. At the LC30, the duration of egg and 1st-instar nymph, female adult longevity, and oviposition period of the F1 were significantly shorter, while the nymphal duration in the F0 and duration of 5th-instar nymphs, preadult survival rate, and male adult longevity in the F1 significantly increased. The net reproductive rate (R0), intrinsic rate of increase (r), and finite rate of increase (λ) in the F1 were not significantly affected by these two concentrations, whereas the mean generation time (T) was lower at the LC30. Additionally, the probe counts and cells mixture feeding time were markedly lengthened by the LC10 and LC30, respectively, when A. lucorum nymphs exposed to sulfoxaflor fed on Bt cotton plants without insecticides. These results clearly indicate that sulfoxaflor causes sublethal effects on A. lucorum and the transgenerational effects depend on the tested concentrations., Competing Interests: The authors have declared that no competing interests exist.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol ( 3b ) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ 1 receptors. Within the series, 14a showed improved DAT affinity ( K i = 23 nM) over 3b ( K i = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.

The endogenous gasotransmitter H 2 S plays an important role in the central nervous, respiratory and cardiovascular systems. Accordingly, slow-releasing H 2 S donors are powerful tools for basic studies and innovative pharmaco-therapeutic agents for cardiovascular and neurodegenerative diseases. Nonetheless, the effects of H 2 S-releasing agents on the growth of stem cells have not been fully investigated. H 2 S preconditioning can enhance mesenchymal stem cell survival after post-ischaemic myocardial implantation; therefore, stem cell therapy combined with H 2 S may be relevant in cell-based therapy for regenerative medicine. Here, we studied the effects of slow-releasing H 2 S agents on the cell growth and differentiation of cardiac Lin - Sca1 + human mesenchymal stem cells (cMSC) and on normal human dermal fibroblasts (NHDF). In particular, we investigated the effects of water-soluble GSH-garlic conjugates (GSGa) on cMSC compared to other H 2 S-releasing agents, such as Na 2 S and GYY4137. GSGa treatment of cMSC and NHDF increased their cell proliferation and migration in a concentration dependent manner with respect to the control. GSGa treatment promoted an upregulation of the expression of proteins involved in oxidative stress protection, cell-cell adhesion and commitment to differentiation. These results highlight the effects of H 2 S-natural donors as biochemical factors that promote MSC homing, increasing their safety profile and efficacy after transplantation, and the value of these donors in developing functional 3D-stem cell delivery systems for cardiac muscle tissue repair and regeneration.

Background: Gracilaria has been shown to be an important source of marine bioactive natural biomaterials and compounds. Although there are no enough patents used Gracilaria worldwide, the current study tries to put the Gracilaria on the spot for further important patents in the future., Objective: The current study investigates the pharmaceuticals and biochemical activity of Gracilaria because no previous studies have been carried out to examine the biochemical and pharmaceutical activates of Gracilaria from the Suez Canal of Egypt as an excellent source for bioactive compounds., Methods: Different advanced experimental models and analytical techniques, such as cytotoxicity, total antioxidant capacity, anticancer, and anti-inflammatory profiling were applied. The phytochemical analysis of different constituents was also carried out., Results: The mineral analysis revealed the presence of copper (188.3 ppm) and iron (10.07 ppm) in addition to a remarkable wealth of selenium and sulfur contents giving up to 36% of its dry mass. The elemental analysis showed high contents of sulfur and nitrogen compounds. The GCMS profiling showed varieties of different bioactive compounds, such as fatty acids, different types of carotenoids in addition to pigments, alkaloids, steroids. Many other compounds, such as carbohydrates and amino acids having antioxidant, anti-inflammatory, and antiviral activities, etc. were identified. The cytotoxicity activity of Gracilaria marine extract was very effective against cancerous cell lines and showed high ability as a potent antitumor due to their bioactive constituents. Specialized screening assays using two anticancer experimental models, i.e., PTK and SKH1 revealed 77.88% and 84.50% inhibition anticancer activity; respectively. The anti-inflammatory activities investigated using four different experimental models, i.e., COX1, COX2, IL6, and TNF resulted in 68%, 81.76%, 56.02% and 78.43% inhibition; respectively. Moreover, Gracilaria extracts showed potent anti-Alzheimer with all concentrations., Conclusion: Gracilaria proved to be a multi-product source of marine natural products for different biotechnological applications. Our recommendation is to investigate the Gracilaria bioactive secondary metabolites in order to create and innovate in more patents from current important seaweeds (Gracilaria)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gamma-glutamyl transpeptidase (GGT) is a cell surface enzyme involved in glutathione metabolism and maintenance of redox homeostasis. High expression of GGT on tumor cells is associated with an increase of cell proliferation and resistance against chemotherapy. GGT inhibitors that have been evaluated in clinical trials are too toxic for human use. We have previously identified ovothiols, 5(Nπ)-methyl-thiohistidines of marine origin, as non-competitive-like inhibitors of GGT that are more potent than the known GGT inhibitor, 6-diazo-5-oxo-l-norleucine (DON), and are not toxic for human embryonic cells. We extended these studies to the desmethylated form of ovothiol, 5-thiohistidine, and confirmed that this ovothiol derivative also acts as a non-competitive-like GGT inhibitor, with a potency comparable to ovothiol. We also found that both 5-thiohistidine derivatives act as reversible GGT inhibitors compared to the irreversible DON. Finally, we probed the interactions of 5-thiohistidines with GGT by docking analysis and compared them with the 2-thiohistidine ergothioneine, the physiological substrate glutathione, and the DON inhibitor. Overall, our results provide new insight for further development of 5-thiohistidine derivatives as therapeutics for GGT-positive tumors., Competing Interests: The authors declare no conflict of interest.

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S -alkenyl-l-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S -allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds.