Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers-Mediated Photodynamic Therapy.

Photodynamic therapy (PDT) has recently been considered a potential tumor therapy due to its time-space specificity and non-invasive advantages. PDT can not only directly kill tumor cells by using cytotoxic reactive oxygen species but also induce an anti-tumor immune response by causing immunogenic cell death of tumor cells. Although it exhibits a promising prospect in treating tumors, there are still many problems to be solved in its practical application. Tumor hypoxia and immunosuppressive microenvironment seriously affect the efficacy of PDT. The hypoxic and immunosuppressive microenvironment is mainly due to the abnormal vascular matrix around the tumor, its abnormal metabolism, and the influence of various immunosuppressive-related cells and their expressed molecules. Thus, reprogramming the tumor microenvironment (TME) is of great significance for rejuvenating PDT. This article reviews the latest strategies for rejuvenating PDT, from regulating tumor vascular matrix, interfering with tumor cell metabolism, and reprogramming immunosuppressive related cells and factors to reverse tumor hypoxia and immunosuppressive microenvironment. These strategies provide valuable information for a better understanding of the significance of TME in PDT and also guide the development of the next-generation multifunctional nanoplatforms for PDT.

Pectin: Health-promoting properties as a natural galectin-3 inhibitor.

Galectin-3 has a variety of important pathophysiological significance in the human body. Much evidence shows that the abnormal expression of galectin-3 is related to the formation and development of many diseases. Pectin is mostly obtained from processed citrus fruits and apples and is a known natural inhibitor of galactin-3. A large number of peels produced each year are discarded, and it is necessary to recycle some of the economically valuable active compounds in these by-products to reduce resource waste and environmental pollution. By binding with galectin-3, pectin can directly reduce the expression level of galectin-3 on the one hand, and regulate the expression level of cytokines by regulating certain signaling pathways on the other hand, to achieve the effect of treating diseases. This paper begins by presenting an overview of the basic structure of pectin, subsequently followed by a description of the structure of galectin-3 and its detrimental impact on human health when expressed abnormally. The health effects of pectin as a galectin-3 inhibitor were then summarized from the perspectives of anticancer, anti-inflammatory, ameliorating fibrotic diseases, and anti-diabetes. Finally, the challenges and prospects of future research on pectin are presented, which provide important references for expanding the application of pectin in the pharmaceutical industry or developing functional dietary supplements.

Expression of Concern: Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway.

Expression of Concern for 'Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway' by Zhi-Yong Tian et al., Org. Biomol. Chem., 2009, 7, 4651-4660, https://doi.org/10.1039/B912685F.

A New Potent Inhibitor against α-Glucosidase Based on an In Vitro Enzymatic Synthesis Approach.

Inhibiting the activity of intestinal α-glucosidase is considered an effective approach for treating type II diabetes mellitus (T2DM). In this study, we employed an in vitro enzymatic synthesis approach to synthesize four derivatives of natural products (NPs) for the discovery of therapeutic drugs for T2DM. Network pharmacology analysis revealed that the betulinic acid derivative P3 exerted its effects in the treatment of T2DM through multiple targets. Neuroactive ligand-receptor interaction and the calcium signaling pathway were identified as key signaling pathways involved in the therapeutic action of compound P3 in T2DM. The results of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations indicate that compound P3 exhibits a more stable binding interaction and lower binding energy (-41.237 kcal/mol) with α-glucosidase compared to acarbose. In addition, compound P3 demonstrates excellent characteristics in various pharmacokinetic prediction models. Therefore, P3 holds promise as a lead compound for the development of drugs for T2DM and warrants further exploration. Finally, we performed site-directed mutagenesis to achieve targeted synthesis of betulinic acid derivative. This work demonstrates a practical strategy of discovering novel anti-hyperglycemic drugs from derivatives of NPs synthesized through in vitro enzymatic synthesis technology, providing potential insights into compound P3 as a lead compound for anti-hyperglycemic drug development.

Cold stress regulates accumulation of flavonoids and terpenoids in plants by phytohormone, transcription process, functional enzyme, and epigenetics.

Plants make different defense mechanisms in response to different environmental stresses. One common way is to produce secondary metabolites. Temperature is the main environmental factor that regulates plant secondary metabolites, especially flavonoids and terpenoids. Stress caused by temperature decreasing to 4-10 °C is conducive to the accumulation of flavonoids and terpenoids. However, the accumulation mechanism under cold stress still lacks a systematic explanation. In this review, we summarize three aspects of cold stress promoting the accumulation of flavonoids and terpenoids in plants, that is, by affecting (1) the content of endogenous plant hormones, especially jasmonic acid and abscisic acid; (2) the expression level and activity of important transcription factors, such as bHLH and MYB families. This aspect also includes post-translational modification of transcription factors caused by cold stress; (3) key enzyme genes expression and activity in the biosynthesis pathway, in addition, the rate-limiting enzyme and glycosyltransferases genes are responsive to cold stress. The systematic understanding of cold stress regulates flavonoids, and terpenoids will contribute to the future research of genetic engineering breeding, metabolism regulation, glycosyltransferases mining, and plant synthetic biology.

Hosts engineering and in vitro enzymatic synthesis for the discovery of novel natural products and their derivatives.

Novel natural products (NPs) and their derivatives are important sources for drug discovery, which have been broadly applied in the fields of agriculture, livestock, and medicine, making the synthesis of NPs and their derivatives necessarily important. In recent years, biosynthesis technology has received increasing attention due to its high efficiency in the synthesis of high value-added novel products and its advantages of green, environmental protection, and controllability. In this review, the technological advances of biosynthesis strategies in the discovery of novel NPs and their derivatives are outlined, with an emphasis on two areas of host engineering and in vitro enzymatic synthesis. In terms of hosts engineering, multiple microorganisms, including Streptomyces, Aspergillus, and Penicillium, have been used as the biosynthetic gene clusters (BGCs) provider and host strain for the expression of BGCs to discover new compounds over the past years. In addition, the use of in vitro enzymatic synthesis strategy to generate novel compounds such as triterpenoid saponins and flavonoids is also hereby described.

Diosgenin alleviates nonalcoholic steatohepatitis through affecting liver-gut circulation.

Nonalcoholic steatohepatitis (NASH), as the aggressive form of nonalcoholic fatty liver disease (NAFLD), rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NASH treatment. Diosgenin possesses multiple beneficial effects towards inhibition of lipid accumulation, cholesterol metabolism, fibrotic progression and inflammatory response. However, there has been no report concerning its effects on NASH so far. Using methionine and choline-deficient (MCD) feeding mice, we evaluated the anti-NASH effects of diosgenin. 16 S rDNA was used to investigate gut microbiota composition. Transcriptome sequencing, LC/MS and GC/MS analysis were used to evaluate bile acids (BAs) metabolism and their related pathway. Compared with the MCD group, diosgenin treatment improved the hepatic dysfunction, especially decreased the serum and hepatic TC, TG, ALT, AST and TBA to nearly 50%. Content of BAs, especially CA and TCA, were decreased from 59.30 and 26.00-39.71 and 11.48 ng/mg in liver and from 0.96 and 2.1-0.47 and 1.13 µg/mL in serum, and increased from 7.01 and 11.08-3.278 and 5.11 ng/mg in feces, respectively. Antibiotic and fecal microbiota transplantation (FMT) treatment further confirmed the therapeutic effect of diosgenin on gut microbiota, especially Clostridia (LDA score of 4.94), which regulated BAs metabolism through the hepatic FXR-SHP and intestinal FXR-FGF15 pathways. These data indicate that diosgenin prevents NASH by altering Clostridia and BAs metabolism. Our results shed light on the mechanisms of diosgenin in treating NASH, which pave way for the design of novel clinical therapeutic strategies.

Recent progress in plant-derived polysaccharides with prebiotic potential for intestinal health by targeting gut microbiota: a review.

Natural products of plant origin are of high interest and widely used, especially in the food industry, due to their low toxicity and wide range of bioactive properties. Compared to other plant components, the safety of polysaccharides has been generally recognized. As dietary fibers, plant-derived polysaccharides are mostly degraded in the intestine by polysaccharide-degrading enzymes secreted by gut microbiota, and have potential prebiotic activity in both non-disease and disease states, which should not be overlooked, especially in terms of their involvement in the treatment of intestinal diseases and the promotion of intestinal health. This review elucidates the regulatory effects of plant-derived polysaccharides on gut microbiota and summarizes the mechanisms involved in targeting gut microbiota for the treatment of intestinal diseases. Further, the structure-activity relationships between different structural types of plant-derived polysaccharides and the occurrence of their prebiotic activity are further explored. Finally, the practical applications of plant-derived polysaccharides in food production and food packaging are summarized and discussed, providing important references for expanding the application of plant-derived polysaccharides in the food industry or developing functional dietary supplements.

Demonstrating analytical similarity of a biosimilar HLX04 to bevacizumab with a panel of state-of-the-art methods and tiering of quality attributes.

Therapeutical monoclonal antibodies are structurally and functionally complex, whereas the innovator's manufacturing processes are proprietary. With respect to the similarity assessment, a proposed biosimilar product needs to demonstrate a side-by-side comparison between the reference product (RP) and candidate product in terms of physicochemical properties and biological activities, as well as nonclinical and clinical outcomes. Here, a comprehensive analytical similarity assessment was performed for in-depth comparison of HLX04, China-sourced Avastin® (CN-Avastin®), and Europe-sourced Avastin® (EU-Avastin®) following a tier-based quality attribute (QA) evaluation. A series of orthogonal and state-of-the-art analytical techniques were developed for the assessment. Ten lots of HLX04 were compared with 29 lots bevacizumab RP. Referred to the characterization results, HLX04 is highly similar to the RPs with respect to physicochemical properties and biological functions. In addition, HLX04 was found with similar stability and degradation behaviors upon multiple stressed conditions to bevacizumab. Minor differences were observed in glycosylation, aggregates, FcγRIIIa(F), and FcγRIIIa(V) binding activities; nevertheless, they were evaluated and demonstrated not to impact clinical outcomes. According to the reported clinical results, the totality of evidence, including the pharmacokinetic, efficacy, safety, and immunogenicity, further shows that HLX04 is similar to CN-/EU-Avastin®.

Mitochondria-targeted pentacyclic triterpenoid carbon dots for selective cancer cell destruction via inducing autophagy, apoptosis, as well as ferroptosis.

Natural products have been an important database for anti-cancer drug development. However, low water solubility and poor biocompatibility limit the efficacy of natural products. Carbon dots (CDs), as an emerging 0D material, have unique properties in bioimaging, water solubility and biocompatibility. Here, we prepared three pentacyclic triterpenoids (PTs) included glycyrrhetinic acid (GA), ursolic acid (UA) and oleanolic acid (OA), which have anticancer activity but poor water solubility, as raw materials into CDs to improve disadvantages. Our data indicated that the active surface groups of all three CDs were largely preserved and were able to excite green fluorescence. Their carboxyl edges not only exhibited excellent water solubility, but also specifically targeted tumor cell mitochondria due to high sensitivity to ROS-induced damage and high internal oxidative stress. In cancer cells, the PT-CDs induced cell death through three pathways (apoptosis, ferroptosis, and autophagy), which is essentially the same way their raw materials induce death, but the effect was much stronger than raw materials. Notably, functionalized PT-CDs also exhibited extremely low toxicity. In summary, PT-CDs not only have improved water solubility and biocompatibility, but also retain the structure of their raw materials well and exert better efficacy, which provides new ideas for the development of anti-cancer natural product drugs.

Dual targeting of wild-type p53 and gut microbiota by Magnolol represses key metabolic process and kills CRC cells.

Cancer cells consume considerable glucose quantities and majorly employ glycolysis for ATP generation. This metabolic signature (the Warburg effect) allows cancer cells to channel glucose to biosynthesis to support and maintain their dramatic growth along with proliferation. Currently, our understanding of the metabolic and mechanistic implications of the Warburg effect along with its relationship with biosynthesis remains unclear. Herein, we illustrate that the tumor repressor p53 mediate Magnolol (MAG) triggers colon cancer cell apoptosis. And MAG regulates the glycolytic and oxidative phosphorylation steps through transcriptional modulation of its downstream genes TP53-induced glycolysis modulator and biosynthesis of cytochrome c oxidase, attenuating cell proliferation and tumor growth in vivo and in vitro. Meanwhile, we show that MAG cooperates with its own intestinal microflora characteristic metabolites to repress tumors, especially remarkably declined kynurenine (Kyn)/tryptophan (Trp) ratio. Besides, strong relationships of MAG influenced genes, microbiota, as well as metabolites, were explored. Therefore, we established that p53-microbiota-metabolites function as a mechanism, which enable therapy approaches against metabolism-implicated colorectal cancer, in particular MAG as a prospective candidate for treating colorectal cancer.

Targeting adipokines: A new strategy for the treatment of myocardial fibrosis.

Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life and health, causing huge economic losses.Therefore, it is very significant to find an effective treatment for myocardial fibrosis. Adipokines are mainly derived from adipose tissue and have an prominent regulatory effect on glucose and lipid metabolism, inflammation, immune response and cardiovascular function. Adipose tissue is composed of a variety of cell types, including adipocytes, endothelial cells, macrophages and smooth muscle cells. Adipokines mainly include adiponectin, leptin, resistin, visfatin and omentin, which are synthesized and secreted by adipocytes. More and more evidence shows that adipokines can regulate the progress of cardiac fibrosis. This scientific review provides new ideas for targeting adipokines in the treatment of myocardial fibrosis and provides strategies for the development of new, safe, and effective pharmacological antagonists against myocardial fibrosis based on adipokines activity.

p53: A double-edged sword in tumor ferroptosis.

Ferroptosis is a type of lipid peroxidation-induced cell death that can be regulated in various ways, from changing the activity of antioxidant enzymes to the levels of transcription factors. The p53 tumor suppressor gene is the "guardian of the genome" and is involved in controlling cell survival and division under various pressures. In addition to its effects on apoptosis, autophagy, and cell cycle, p53, through the way of transcription dependent or independent two-way, also regulates the biological processes of tumor cell sensitivity to ferroptosis, including the metabolism of amino acids, nicotinamide adenine dinucleotide phosphate, and lipid peroxidation, as well as the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. As reviewed here, we summarized the metabolic network of p53 and its signaling pathway in regulating ferroptosis and elucidated possible factors and potential clinical application of p53 regulating ferroptosis. This review will provide a basis for further understanding the role of p53 in tumor ferroptosis and new strategies for cancer therapeutic avenues.

Melanin-like nanoparticles: advances in surface modification and tumour photothermal therapy.

Currently, tumor treatments are characterized by intelligence, diversity and personalization, but the therapeutic reagents used are often limited in clinical efficacy due to problems with water solubility, targeting, stability and multidrug resistance. To remedy these shortcomings, the application of multifunctional nanotechnology in the biomedical field has been widely studied. Synthetic melanin nanoparticles (MNPs) surfaces which contain highly reactive chemical groups such as carboxyl, hydroxyl and amine groups, can be used as a reaction platform on which to graft different functional components. In addition, MNPs easily adhere to substrate surface, and serve as a secondary reaction platform to modify it. The multifunctionality and intrinsic biocompatibility make melanin-like nanoparticles promising as a multifunctional and powerful nanoplatform for oncological applications. This paper first reviews the preparation methods, polymerization mechanisms and physicochemical properties of melanin including natural melanin and chemically synthesized melanin to guide scholars in MNP-based design. Then, recent advances in MNPs especially synthetic polydopamine (PDA) melanin for various medical oncological applications are systematically and thoroughly described, mainly focusing on bioimaging, photothermal therapy (PTT), and drug delivery for tumor therapy. Finally, based on the investigated literature, the current challenges and future directions for clinical translation are reasonably discussed, focusing on the innovative design of MNPs and further elucidation of pharmacokinetics. This paper is a timely and comprehensive and detailed study of the progress of MNPs in tumor therapy, especially PTT, and provides ideas for the design of personalized and customizable oncology nanomedicines to address the heterogeneity of the tumor microenvironment.

Combining network pharmacology with chromatographic fingerprinting and multicomponent quantitative analysis for the quality evaluation of Astragali Radix.

Nowadays, cultivated variants and adulterants of Astragali Radix (AR) have flooded the market, causing the quality assurance of AR to be challenging. To address this issue, we combined network pharmacology with chromatographic fingerprinting and multicomponent quantitative analysis for the quality evaluation of AR. Specifically, through network pharmacology, a complete understanding of the active components and pharmacological activities of AR was established. In addition, establishing fingerprint profiles and multicomponent quantitation by high-performance liquid chromatography (HPLC) is convenient and comprehensive, and can more fully reflect the overall situation of the distribution of various chemical components. To evaluate and differentiate AR from different origins, hierarchical cluster analysis and principal component analysis were performed. The result showed that AR acts synergistically through multiple targets and pathways. The content of chemical components in AR from different origins varied significantly. Combining network pharmacology and multicomponent quantification results, astragaloside II and IV and formononetin can be used as quality markers for the quality control of AR. This study provides a comprehensive and reliable strategy for the quality evaluation of AR and identifies its quality markers to ensure the quality of the herb.

Quality evaluation of different varieties of rhubarb based on multicomponents and bioactivity: Application to quality control in the production of rhubarb decoction pieces.

In this work, we developed a novel HPLC method for the simultaneous determination of 16 bioactive components in rhubarb and used it to determine the contents. Through the determination of bioactive components and in vitro activity, we compared the differences between 18 batches of different varieties of rhubarb. The contents of 16 bioactive components in Rheum officinale Baill., Rheum tanguticum Maxim. ex Balf., and Rheum palmatum Linn. were 57.53-76.09, 98.88-130.61 and 36.18-48.66 mg/g, respectively. The average inhibition rates of alkaline phosphatase in R. tanguticum were the highest, reaching 79.53%. The average inhibition rates of thrombin and Na+ /K+ -ATPase in R. palmatum were the highest, reaching 80.93 and 62.42%, respectively. These results showed that there were significant differences in effective components and biological activities among different varieties of rhubarb. Through chemometric analysis, we preliminarily compared the differences in chemical composition of different varieties of rhubarb, and established a Fisher discriminant function which could accurately distinguish different varieties of rhubarb. Through correlation analysis and molecular docking, three potential components as quality markers of rhubarb were identified. The obtained results provide a comprehensive strategy for the quality control of multisource Chinese medicine and related products.

Accumulation of functional metabolites and transcriptomics in postharvest fume-drying and air-drying process in rhubarb.

BACKGROUND: The active component content is an important factor affecting quality of traditional Chinese medicines. The fume-drying process can effectively improve the content of active components in rhubarb, but the accumulation dynamics and molecular mechanisms are not known. In this study, variations in the active components of rhubarb during the drying process were determined, and the most intense changes in the active components were preferred for transcriptome inquiry. RESULTS: The results showed that the accumulation of active ingredients could be significantly promoted in the early stage of fume-drying and air-drying. In particular, the active ingredients increased by 61.57% (from 44.58 to 72.02 mg g-1 ) on the fourth day of fume-drying. A total of 4191 DEGs (differentially expressed genes) were identified by transcriptome analysis when the active components changed significantly. Transcriptome data of different dried rhubarb samples revealed, that the fume-drying process could significantly improve the expression of genes relevant to respiration, phenolic acid, and anthraquinone synthesis pathways in rhubarb, which was more conducive to the synthesis and accumulation of the active components. CONCLUSION: Fume-drying stimulated respiration and secondary metabolite synthesis in rhubarb cells by exerting strong external stress on freshly harvested rhubarb. This study revealed the variations and molecular mechanism of active component accumulation in the rhubarb drying process and might serve as a guide for the development of alternative methods for rhubarb fumigation and drying process. © 2022 Society of Chemical Industry.

Engineering of triterpene metabolism and overexpression of the lignin biosynthesis gene PAL promotes ginsenoside Rg3 accumulation in ginseng plant chassis.

The ginsenoside Rg3 found in Panax species has extensive pharmacological properties, in particular anti-cancer effects. However, its natural yield in Panax plants is limited. Here, we report a multi-modular strategy to improve yields of Rg3 in a Panax ginseng chassis, combining engineering of triterpene metabolism and overexpression of a lignin biosynthesis gene, phenylalanine ammonia lyase (PAL). We first performed semi-rational design and site mutagenesis to improve the enzymatic efficiency of Pq3-O-UGT2, a glycosyltransferase that directly catalyzes the biosynthesis of Rg3 from Rh2 . Next, we used clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to knock down the branch pathway of protopanaxatriol-type ginsenoside biosynthesis to enhance the metabolic flux of the protopanaxadiol-type ginsenoside Rg3 . Overexpression of PAL accelerated the formation of the xylem structure, significantly improving ginsenoside Rg3 accumulation (to 6.19-fold higher than in the control). We combined overexpression of the ginsenoside aglycon synthetic genes squalene epoxidase, Pq3-O-UGT2, and PAL with CRISPR/Cas9-based knockdown of CYP716A53v2 to improve ginsenoside Rg3 accumulation. Finally, we produced ginsenoside Rg3 at a yield of 83.6 mg/L in a shake flask (7.0 mg/g dry weight, 21.12-fold higher than with wild-type cultures). The high-production system established in this study could be a potential platform to produce the ginsenoside Rg3 commercially for pharmaceutical use.

Endophytes, biotransforming microorganisms, and engineering microbial factories for triterpenoid saponins production.

Triterpenoid saponins are structurally diverse secondary metabolites. They are the main active ingredient of many medicinal plants and have a wide range of pharmacological effects. Traditional production of triterpenoid saponins, directly extracted from cultivated plants, cannot meet the rapidly growing demand of pharmaceutical industry. Microorganisms with triterpenoid saponins production ability (especially Agrobacterium genus) and biotransformation ability, such as fungal species in Armillaria and Aspergillus genera and bacterial species in Bacillus and Intestinal microflora, represent a valuable source of active metabolites. With the development of synthetic biology, engineering microorganisms acquired more potential in terms of triterpenoid saponins production. This review focusses on potential mechanisms and the high yield strategies of microorganisms with inherent production or biotransformation ability of triterpenoid saponins. Advances in the engineering of microorganisms, such as Saccharomyces cerevisiae, Yarrowia lipolytica, and Escherichia coli, for the biosynthesis triterpenoid saponins de novo have also been reported. Strategies to increase the yield of triterpenoid saponins in engineering microorganisms are summarized following four aspects, that is, introduction of high efficient gene, optimization of enzyme activity, enhancement of metabolic flux to target compounds, and optimization of fermentation conditions. Furthermore, the challenges and future directions for improving the yield of triterpenoid saponins biosynthesis in engineering microorganisms are discussed.

Autophagy in vascular dementia and natural products with autophagy regulating activity.

Chronic Cerebral Hypoperfusion(CCH)-induced vascular dementia(VD) is a common neurodegenerative disease which seriously affects the patient's quality of life. Therefore, it is critical to find an effective treatment of VD. Autophagy is a natural regulated mechanism that can remove dysfunctional proteins and organelles, however, over-activation or under-activation can of autophagy can induce the apoptosis of cells. Although autophagy plays a role in the central nervous system is unquestionable, the effects of autophagy in the ischemic brain are still controversial. Some autophagy regulators have been tested, suggesting that both activation and inhibition of autophagy can improve the cognitive function. This article reviews the role of autophagy in CCH-induced VD to discuss whether autophagy has the potential to become a target for drug development and provides several potential compounds for treating vascular dementia.