Plant-derived Glycosides Research Articles

Plant-derived glycosides in cancer treatment: diverse strategies for tumor suppression

Plant-derived glycosides have emerged as promising candidates for cancer therapy due to their diverse biological activities. These compounds exert their anti-cancer effects through multiple mechanisms, including apoptosis induction, cell cycle arrest, inhibition of angiogenesis, suppression of metastasis, and immune modulation. Cardiac glycosides, flavonoid glycosides, and saponins are among the key types of glycosides showing potential in preclinical studies. By selectively targeting cancer cells, these glycosides demonstrate the ability to induce programmed cell death and interfere with cancer progression without harming normal cells. In addition, their role in inhibiting blood vessel formation and reducing cancer cell spread positions them as valuable components of future cancer treatment strategies. Preclinical evidence, supported by emerging clinical data, underscores the potential of plant-derived glycosides as novel agents in oncology, either as standalone treatments or in combination with conventional therapies. Ongoing research will determine their full therapeutic potential in cancer management.

Hybrid biomaterial hydrogel loading iRGD&PS double modified lipid nanoparticles ameliorates diabetic wound healing through promoting efferocytosis and glycolysis-related macrophage reprogramming

Efferocytosis is a critical process whereby macrophages residing in the wound area play a key role in the efficient clearing and degradation of apoptotic neutrophils. This process is followed by a phenotypic transition toward an anti-inflammatory state, essential for inflammation resolution and tissue repair. The cystine/glutamate antiporter SLC7A11 has recently been identified as an inhibitor of efferocytosis, and its blockade has been found to enhance wound healing. In this study, we demonstrated that tiliroside, a plant-derived glycoside containing flavones, binds directly to SLC7A11 and pyruvate kinase isozyme M2 (PKM2). This was established by molecular docking predictions and activity-based protein profiling (ABPP). Cytological experiments revealed that tiliroside promoted the process of efferocytosis and led to glycolysis-related macrophage reprogramming. To facilitate targeted drug delivery to macrophages at diabetic wound sites, we designed a novel hybrid biomaterial. This hybrid biomaterial, prepared as Gel@Til iRGD&PS@PLGA NPs is manufactured by loading tiliroside (Til)-conjugated iRGD&PS double modified lipid nanoparticles (iRGD&PS@PLGA NPs) into a pH-responsive hydrogel matrix. The administration of Gel@Til iRGD&PS@PLGA NPs in diabetic cutaneous wound models has been shown to significantly promote tissue regeneration through the promotion of efferocytosis and glycolysis-related macrophage reprogramming. Therefore, this study introduces a novel approach to diabetic wound management by leveraging the promotion of efferocytosis.

High-yield production of β-arbutin by identifying and eliminating byproducts formation.

β-Arbutin is a plant-derived glycoside and widely used in cosmetic and pharmaceutical industries because of its safe and effective skin-lightening property as well as anti-oxidant, anti-microbial, and anti-inflammatory activities. In recent years, microbial fermentation has become a highly promising method for the production of β-arbutin. However, this method suffers from low titer and low yield, which has become the bottleneck for its widely industrial application. In this study, we used β-arbutin to demonstrate methods for improving yields for industrial-scale production in Escherichia coli. First, the supply of precursors phosphoenolpyruvate and uridine diphosphate glucose was improved, leading to a 4.6-fold increase in β-arbutin production in shaking flasks. The engineered strain produced 36.12g/L β-arbutin with a yield of 0.11g/g glucose in a 3-L bioreactor. Next, based on the substrate and product's structural similarity, an endogenous O-acetyltransferase was identified as responsible for 6-O-acetylarbutin formation for the first time. Eliminating the formation of byproducts, including 6-O-acetylarbutin, tyrosine, and acetate, resulted in an engineered strain producing 43.79g/L β-arbutin with a yield of 0.22g/g glucose in fed-batch fermentation. Thus, the yield increased twofold by eliminating byproducts formation. To the best of our knowledge, this is the highest titer and yield of β-arbutin ever reported, paving the way for the industrial production of β-arbutin. This study demonstrated a systematic strategy to alleviate undesirable byproduct accumulation and improve the titer and yield of target products. KEY POINTS: •A systematic strategy to improve titer and yield was showed •Genes responsible for 6-O-acetylarbutin formation were firstly identified •43.79g/L β-arbutin was produced in bioreactor, which is the highest titer so far.

Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity.

Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1–12) and evaluated their inhibitory efficacy against the AG83 strain of Leishmania donovani. Among the synthesized glycosides, the in vitro inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on L. donovani promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure–activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote–macrophage infection model in vitro as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of L. donovani promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL.

Identification of Glycoside Transporters From the Human Gut Microbiome.

Transport is a crucial step in the metabolism of glycosides by bacteria, which is itself key for microbiota function and equilibrium. However, most transport proteins are function-unknown or only predicted, limiting our understanding of how bacteria utilize glycosides. Here, we present an activity-based screening method to identify functional glycoside transporters from microbiomes. The method is based on the co-expression in Escherichia coli of genes encoding transporters and carbohydrate-active enzymes (CAZymes) from metagenomic polysaccharide utilization loci (PULs) cloned in fosmids. To establish the proof of concept of the methodology, we used two different metagenomic libraries derived from human gut microbiota to select 18 E. coli clones whose metagenomic sequence contained at least one putative glycoside transporter and one functional CAZyme, identified by screening for various glycoside-hydrolase activities. Growth tests were performed on plant-derived glycosides, which are the target substrates of the CAZymes identified in each PUL. This led to the identification of 10 clones that are able to utilize oligosaccharides as sole carbon sources, thanks to the production of transporters from the PTS, ABC, MFS, and SusCD families. Six of the 10 hit clones contain only one transporter, providing direct experimental evidence that these transporters are functional. In the six cases where two transporters are present in the sequence of a clone, the transporters’ function can be predicted from the flanking CAZymes or from similarity with transporters characterized previously, which facilitates further functional characterization. The results expand the understanding of how glycosides are selectively metabolized by bacteria and offers a new approach to screening for glycoside-transporter specificity toward oligosaccharides with defined structures.

The Sweet Side of Plant-Specialized Metabolism.

Glycosylation plays a major role in the structural diversification of plant natural products. It influences the properties of molecules by modifying the reactivity and solubility of the corresponding aglycones, so influencing cellular localization and bioactivity. Glycosylation of plant natural products is usually carried out by uridine diphosphate(UDP)-dependent glycosyltransferases (UGTs) belonging to the carbohydrate-active enzyme glycosyltransferase 1 (GT1) family. These enzymes transfer sugars from UDP-activated sugar moieties to small hydrophobic acceptor molecules. Plant GT1s generally show high specificity for their sugar donors and recognize a single UDP sugar as their substrate. In contrast, they are generally promiscuous with regard to acceptors, making them attractive biotechnological tools for small molecule glycodiversification. Although microbial hosts have traditionally been used for heterologous engineering of plant-derived glycosides, transient plant expression technology offers a potentially disruptive platform for rapid characterization of new plant glycosyltransferases and biosynthesis of complex glycosides.

Plant-derived Glycosides with α-Glucosidase Inhibitory Activity: Current Standing and Future Prospects.

The α-glucosidase (EC 3.2.1.20), a calcium-containing intestinal enzyme which is positioned in the cells which cover the intestinal microvilli brush border. The carbohydrates require metabolism by α-glucosidase before being absorbed into the small intestine, and as a result, this enzyme represents a significant drug target for the effective management of diabetes. There are few α- glucosidase inhibitors in the clinical practice that is challenged by several limitations. Thus, new effective and safe therapeutic agents in this class are required. In this regard, plant secondary metabolites are a very promising source to be investigated. Herein in this review, we have focused on the preclinical studies on various glycosides with in vitro α-glucosidase inhibitory activity. The literature available on various websites such as GoogleScholar, PubMed, Scopus. All the peer-reviewed articles were included without considering the impact factor. The surveyed literature revealed marked inhibitory profile of various glycosides derived from plants, and some of them were extremely potent relatively to the standard, acarbose in preclinical trials and exhibited multiple targeted effects. Keeping in view the results, these glycosides are strong candidates for further, more detailed studies to ascertain their clinical potential and for effective contribution in effective management of diabetes, where multiple targets are required to address.

Enhanced biosynthesis of arbutin by engineering shikimate pathway in Pseudomonas chlororaphis P3

BackgroundArbutin is a plant-derived glycoside with potential antioxidant, antibacterial and anti-inflammatory activities. Currently, it is mainly produced by plant extraction or enzymatic processes, which suffers from expensive processing cost and low product yield. Metabolic engineering of microbes is an increasingly powerful method for the high-level production of valuable biologicals. Since Pseudomonas chlororaphis has been widely engineered as a phenazine-producing platform organism due to its well-characterized genetics and physiology, and faster growth rate using glycerol as a renewable carbon source, it can also be engineered as the cell factory using strong shikimate pathway on the basis of synthetic biology.ResultsIn this work, a plasmid-free biosynthetic pathway was constructed in P. chlororaphis P3 for elevated biosynthesis of arbutin from sustainable carbon sources. The arbutin biosynthetic pathway was expressed under the native promoter Pphz using chromosomal integration. Instead of being plasmid and inducer dependent, the metabolic engineering approach used to fine-tune the biosynthetic pathway significantly enhanced the arbutin production with a 22.4-fold increase. On the basis of medium factor optimization and mixed fed-batch fermentation of glucose and 4-hydroxybenzoic acid, the engineered P. chlororaphis P3-Ar5 strain led to the highest arbutin production of 6.79 g/L with the productivity of 0.094 g/L/h, with a 54-fold improvement over the initial strain.ConclusionsThe results suggested that the construction of plasmid-free synthetic pathway displays a high potential for improved biosynthesis of arbutin and other shikimate pathway derived biologicals in P. chlororaphis.

Antiplatelet Potential of Plant-Derived Glycosides as Possible Lead Compounds.

Blood platelets are crucial for maintaining hemostasis and several events in the woundhealing. However, platelet up-regulation leads to the development and the complications of several cardiovascular diseases. For the effective management of these complications, several synthetic drugs are in clinical practice such as aspirin, warfarin and other drugs. since a long time. But some adverse reactions like aspirin resistance and bleed disorders cause patient incompliance and reduce their therapeutic potential. Thus, the search for potent and safer antiplatelet agents is of great interest. Various search engines such as Google, GoogleScholar, PubMed and ScienceDirect were used for the search of antiplatelet glycosides. All peered review journals were considered in the review. Glycoside is a class of naturally-occurring organic compounds that are frequently found in the plant kingdom. Similarly, platelet aggregation beyond the purpose of hemostasis is the underlying cause of blood clottingrelated diseases. The results showed strong potential of plant derived glycosides in various preclinical studies. This review presents a thorough understanding of plant-derived glycosides as antiplatelet agents with a possible mechanism of action based on the existing literature. In addition, this review discusses the possibility of formulating antiplatelet medications from plant glycosides with strong safety profile. On the basis of strong finding, clinical studies are recommended to ascertain their therapeutic utility.

Cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry for screening bioactive capilliposide C metabolites generated by rat intestinal microflora

Many plant-derived glycosides are used as medications. It is common that these glycosides show poor intestinal absorption but their metabolites generated by intestinal microflora demonstrate strong bioactivity. Hence, it is crucial to develop a method for the identification and characterization of the metabolites, and consequently reveal the pathway in which the glycosides are processed in gut. In this study, cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) were developed for rapid discovery and evaluation of the metabolites of a glycoside compound, capilliposide C (LC-C). 92.7% of LC-C was biotransformed by rat intestinal microflora after 36-h incubation at 37°C. Human cancer cell lines HepG2, PC-3 and A549 was treated with metabolites pool, respectively, which was followed by cell viability assays and characterization of metabolites using UHPLC-QTOF-MS/MS. As a result, significant cytotoxicity was observed for the metabolites pool, from which six metabolites were identified. Based on the metabolites identified, deglycosylation and esterolysis were proposed as the major metabolic pathways of LC-C in rat intestinal microflora. In addition, M4, an esterolysis product of LC-C, was obtained and evaluated for its bioactivity in vitro. As a result, M4 exhibited a reduction in cell viability in HepG2 with an IC50 value of 17.46±1.55μg/mL.

Prospects for hormonal contraception in the male

Female-dependent methods of contraception have been the subject of considerable scientific advance since the introduction of the combined contraceptive pill, offering effective and male-independent contraception, but there is an emerging emphasis that men should be more involved in family planning. The supremacy of modern, female methods in the developed world obscures the fact that one-third of all couples worldwide rely on a male-dependent method of contraception, mostly the condom or withdrawal, methods that have been used since antiquity. Potential methods of male contraception include withdrawal of the gonadotrophic support to the testis, interference with spermatogenesis within the seminiferous tubules, or with post-testicular functions. Effects on maturation within the epididymis can be induced by chloro-6-deoxy sugars or plant-derived glycosides. Although advances in assisted conception, particularly associated with intracytoplasmic sperm injection (ICSI), have demonstrated the functional competence of the nucleus and centriole of testicular spermatozoa and other less mature forms, it has been suggested that normal passage through the male reproductive tract is necessary for conventional conception. Advances in both testicular and post-testicular methods of contraception have been hampered by toxicity and remain in preclinical testing, reflecting the limited extent of (and thus the need for) scientific knowledge in this area. While progress in these areas is fully acknowledged, the pretesticular hormonal approach is currently at a considerably more advanced stage of development with prospects for a real product becoming increasingly likely on a realistic time-scale. This review will therefore confine itself to this, the hormonal approach.

Polyunsaturated phosphatidylcholine micelle-induced decrease of atherogenicity of the serumin vitro

It is shown that polyunsaturated phosphatidylcholine administered in micelles stabilized by a plant-derived glycoside prevents the accumulation of cholesterol by cells incubated in atherogenic serum and, moreover, in certain cases causes a 1.4–1.5-fold drop of intracellular cholesterol as compared to control cells. The optimum antiatherogenic effect was achieved when using a micelle concentration of 100–200 μg/ml and an incubation time of at least 4 hours. The antiatherogenic effect was analogous to the effect of high density serum lipoproteins.

Mass spectral analysis of some derivatives and in vitro metabolites of steviol, the aglycone of the natural sweeteners, stevioside, rebaudioside A, and rubusoside.

Steviol (ent-13-hydroxykaur-16-en-19-oic acid), the aglycone of various plant-derived glycoside sweeteners consumed by human populations, is known to be mutagenic toward Salmonella tymphimurium strain TM677 when metabolically activated using a 9000 x g supernatant fraction derived from the liver of Aroclor 1254-pretreated rats. Mass spectral analysis of this diterpenoid and some analogs revealed characteristic patterns reflecting differential stereochemistry at the C/D rings and variations in the nature of the substituents present. Such information has been used to help identify several in vitro metabolites of steviol in conditions known to produce a mutagenic response, when analyzed by gas chromatography/mass spectrometry. The major pathways of such steviol mammalian metabolism proved to be allylic oxidation and epoxidation. 15-Oxosteviol, a product of oxidation of the major steviol metabolite, 15alpha-hydroxysteviol, was found to be a direct-acting mutagen [corrected].