Astaxanthin Ameliorates Skeletal Muscle Atrophy in Mice With Cancer Cachexia.

Astaxanthin (AST) is a natural marine carotenoid with a variety of biological activities. This study aimed to demonstrate the possible mechanisms by which AST improves skeletal muscle atrophy in cancer cachexia. In this study, the effects of different doses of AST (30 mg/kg b.w., 60 mg/kg b.w. and 120 mg/kg b.w.) on skeletal muscle functions were explored in mice with cancer cachexia. The results showed that AST (30, 60 and 120 mg/kg b.w.) could effectively protect cachexia mice from body weight and skeletal muscle loss. AST dose-dependently ameliorated the decrease in myofibres cross-sectional area and increased the expression of myosin heavy chain (MHC). AST treatment decreased both the serum and muscle level of IL-6 but not TNF-α in C26 tumor-bearing cachexia mice. Moreover, AST alleviated skeletal muscle atrophy by decreasing the expression of two muscle-specific E3 ligases MAFBx and MuRF-1. AST improved mitochondrial function by downregulating the levels of muscle Fis1, LC3B and Bax, upregulating the levels of muscle Mfn2 and Bcl-2. In conclusion, our study show that AST might be expected to be a nutritional supplement for cancer cachexia patients.

Identify production area, growth mode, species, and grade of Astragali Radix using metabolomics "big data" and machine learning.

BACKGROUND: Astragali Radix (AR) is a widely used herbal medicine. The quality of AR is influenced by several key factors, including the production area, growth mode, species, and grade. However, the markers currently used to distinguish these factors primarily focus on secondary metabolites, and their validation on large-scale samples is lacking. PURPOSE: This study aims to discover reliable markers and develop classification models for identifying the production area, growth mode, species, and grade of AR. METHODS: A total of 366 batches of AR crude slices were collected from six provinces in China and divided into learning (n = 191) and validation (n = 175) sets. Three ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods were developed and validated for determining 22 primary and 10 secondary metabolites in AR methanol extract. Based on the quantification data, seven machine learning algorithms, such as Nearest Neighbors and Gradient Boosted Trees, were applied to screen the potential markers and build the classification models for identifying the four factors associated with AR quality. RESULTS: Our analysis revealed that secondary metabolites (e.g., astragaloside IV, calycosin-7-O-ß-D-glucoside, and ononin) played a crucial role in evaluating AR quality, particularly in identifying the production area and species. Additionally, fatty acids (e.g., behenic acid and lignoceric acid) were vital in determining the growth mode of AR, while amino acids (e.g., alanine and phenylalanine) were helpful in distinguishing different grades. With both primary and secondary metabolites, the Nearest Neighbors algorithm-based model was constructed for identifying each factor of AR, achieving good classification accuracy (>70%) on the validation set. Furthermore, a panel of four metabolites including ononin, astragaloside II, pentadecanoic acid, and alanine, allowed for simultaneous identification of all four factors of AR, offering an accuracy of 86.9%. CONCLUSION: Our findings highlight the potential of integrating large-scale targeted metabolomics and machine learning approaches to accurately identify the quality-associated factors of AR. This study opens up possibilities for enhancing the evaluation of other herbal medicines through similar methodologies, and further exploration in this area is warranted.

A contrast of emerging contaminants rac- and l-menthol toxicities to Microcystis aeruginosa through biochemical, physiological, and morphological investigations.

Fragrances rac- and l-menthol extracted from peppermint are widely used and considered as emerging contaminants recently, which are persistent in the environment. Menthol has always been considered as a safe chemical for humans, but its potential adverse ecological effects on aquatic organisms and the toxic mechanisms have not yet been fully understood. The present study aims to investigate the physiological response of Microcystis aeruginosa after exposure to the two menthol isomers, and to explore the toxic mechanisms and ecological risks of these two chemicals. Results showed that rac-menthol exhibited a hormesis effect on the cell growth, chlorophyll a and protein contents; while l-menthol showed an inhibition effect. Adenosine triphosphate (ATP) content increased significantly at day 3 and then decreased markedly at day 6 after exposure to the two chemicals. Compared with rac-menthol, l-menthol can cause damage to the antioxidant system and plasmalemma more severely, promote the production and release of microcystins-LR (MC-LR) more dramatically, upregulate the expression of MC-transportation-related gene mcyH, and induce higher apoptosis rates. Overall results revealed that the toxic effects of l-menthol on cyanobacteria were significantly greater than those of rac-menthol. The significant increase in the malondialdehyde (MDA) content and the ultrastructural characteristics of the cells indicated that the plasma membranes were damaged. Thus, further attention should be paid to the scientific use, ecological and environmental risk assessment of chiral menthol. This study will also provide a scientific basis for future water quality criteria establishment on emerging contaminants such as fragrances.

Qualitative and quantitative analysis of the component variations of Raphani Semen during the stir-frying process and elucidation of transformation pathways of multiple components.

Raphani Semen (RS) encompasses two distinct application forms in Chinese clinical practice: raw RS (RRS) and stir-fried RS (SRS). They exhibit divergent drug properties and effects, as described in traditional Chinese medicine theory known as "Sheng shu yi zhi, sheng sheng shu jiang". The dissimilarity in RS's drug properties is intrinsically linked to alterations in its internal components during the stir-frying process. Previous studies have demonstrated that stir-frying renders myrosinase inactive, thereby preventing the enzymatic hydrolysis of glucosinolates in RS. However, the precise enzymatic hydrolysis pathway and products of glucosinolates remain unclear. Furthermore, it remains uncertain whether other components undergo changes influenced by endogenous enzymes. The objective of this study is to systematically analyze the chemical components disparities between RRS and SRS using high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-TOF-MS). Additionally, it seeks to elucidate the potential transformation pathways of multiple components from an enzymatic hydrolysis perspective. We have developed a sensitive and efficient high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-QQQ-MS) method for quantifying the content of 5 characteristic components, including glucoraphenin, sinapine thiocyanate, sulforaphene, sinapic acid, and 3',6-disinapoylsucrose. Based on retention time and MS spectra, we have identified 19 characteristic components in both SRS and RRS, encompassing glucosinolates and sulfur-containing derivatives, oligosaccharide esters, and small-molecule phenolic acids. Notably, 18 of these components undergo changes during the enzymatic hydrolysis process, leading to the identification of 4 transformation pathways: glucoraphenin, 6-sinapoylglucoraphenin, 3',6-disinapoylsucrose and ß-D-(3,4-disinapoyl) furanofructosyl-α-D-(6-sinapisoyl) glucoside, along with 3'-O-sinapoyl-6-O-feruloylsucrose. Quantitative analysis reveals significant differences, including lower levels of glucoraphenin in RRS compared to SRS, higher sulforaphene and sinapic acid levels in RRS, while sinapine thiocyanate and 3',6-disinapoylsucrose remain unchanged before and after stir-frying. The results of this study highlight distinct chemical compositions between RRS and SRS. Additionally, the method of characterization and content determination constructed in this paper has strong practical value and provides a useful approach for comprehensively evaluating the chemical composition and quality of RS.

Dietary supplementation with astaxanthin enhances anti-tumor immune response and aids the enhancement of molecularly targeted therapy for hepatocellular carcinoma.

Astaxanthin is a naturally occurring compound that possesses immunomodulatory properties. The results of our previous investigation indicated that astaxanthin has the potential to augment the anticancer effectiveness of the targeted medication sorafenib. However, the precise molecular mechanism underlying this phenomenon remains unclear. H22 tumor-bearing mice were treated with sorafenib at 30 mg kg-1 per day and their diet was supplemented with 60 mg kg-1 day-1 astaxanthin orally for a period of 18 days. The study revealed that the addition of astaxanthin to the diet facilitated the transition of tumor-associated macrophages from the M2 phenotype to the M1 phenotype. The application of astaxanthin resulted in an augmentation of CD8+ T cell infiltration within the tumor microenvironment through the activation of the CXCL9/CXCR3 signaling axis. Astaxanthin was found to enhance the production of cytokines that possess antitumor properties, including Granzyme B. Furthermore, the administration of astaxanthin resulted in alterations to the intestinal microbiota in H22-bearing mice, leading to the growth of bacteria that possess anti-tumor immune properties, such as Akkermansia. The findings of these studies indicate that astaxanthin has the potential to augment the immune response against tumors when used in conjunction with sorafenib. These studies offer a novel framework for the advancement of astaxanthin as an immunomodulatory agent and a dietary supplement for individuals with tumors.

Astaxanthin Supplementation Assists Sorafenib in Slowing Skeletal Muscle Atrophy in H22 Tumor-Bearing Mice via Reversing Abnormal Glucose Metabolism.

SCOPE: Cachexia, which is often marked by skeletal muscular atrophy, is one of the leading causes of death in cancer patients. Astaxanthin, a carotenoid obtained from marine organisms that can aid in the prevention and treatment of a variety of disorders. In this study, to assess whether astaxanthin ameliorates weight loss and skeletal muscle atrophy in sorafenib-treated hepatocellular carcinoma mice is aimed. METHODS AND RESULTS: H22 mice are treated with 30 mg kg-1  day-1 of sorafenib and 60 mg kg-1  day-1 of astaxanthin by gavage lasted for 18 days. Sorafenib does not delay skeletal muscle atrophy and weight loss, although it does not reduce tumor burden. Astaxanthin dramatically delays weight loss and skeletal muscle atrophy in sorafenib-treating mice, without affecting the food intake. Astaxanthin inhibits the tumor glycolysis, slows down gluconeogenesis, and improves insulin resistance in tumor-bearing mice. Astaxanthin increases glucose competition in skeletal muscle by targeting the PI3K/Akt/GLUT4 signaling pathway, and enhances glucose utilization efficiency in skeletal muscle, thereby slowing skeletal muscle atrophy. CONCLUSION: The findings show the significant potential of astaxanthin as nutritional supplements for cancer patients, as well as the notion that nutritional interventions should be implemented at the initiation of cancer treatment, as instead of waiting until cachexia sets in.

Extraction, purification, structure characteristics, biological activities and pharmaceutical application of Bupleuri Radix Polysaccharide: A review.

Bupleuri Radix (BR), as a well-known plant medicine of relieving exterior syndrome, has a long history of usage in China. Bupleuri Radix Polysaccharide (BRP), as the main component and an important bioactive substance of BR, has a variety of pharmacological activities, including immunoregulation, antioxidant, antitumor, anti-diabetic and anti-aging, etc. In this review, the advancements on extraction, purification, structure characteristics, biological activities and pharmaceutical application of BRP from different sources (Bupleurum chinense DC., Bupleurum scorzonerifolium Willd., Bupleurum falcatum L. and Bupleurum smithii Woiff. var. Parvifolium Shan et Y. Li.) are summarized. Meanwhile, this review makes an in-depth discussion on the shortcomings of the research on BRP, and new valuable insights for the future researches of BRP are proposed.

The protective effects of procyanidin supplementation on PM2.5-induced acute cardiac injury in rats.

OBJECTIVE: Numerous epidemiological and experimental studies have indicated that ambient fine particulate matter (PM2.5) exposure can lead to myocardial injury by inhibiting oxidative stress and apoptosis. The effects of procyanidin (PC) on PM2.5-induced cardiovascular diseases (CVDs) are still unknown. The purpose of this study was to explore the protective effect of PC supplementation on PM2.5-induced oxidative stress and cardiomyocyte apoptosis in rats. METHOD: Rats were treated by gavage with three different PC concentrations (50, 100 and 200 mg/kg) for 21 days prior to exposure to 10 mg/kg PM2.5 suspension liquid by intratracheal instillation every other day for three times. We determined myocardial reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the myocardium were measured. The expression levels of apoptosis-related proteins, including p-Akt/Akt, Bcl-2, caspase-3 and Bax, were determined. In addition, histopathological examination was used to evaluate cardiac injury. RESULTS: PM2.5 exposure noticeably elevated the contents of MDA and ROS and decreased the activities of GSH-Px and SOD. PM2.5 exposure inhibited Bcl-2 expression and up-regulated caspase-3 and Bax expression in the myocardium of rats. The anti-apoptosis-related index p-Akt/Akt was reduced. Moreover, pretreatment with PC could attenuate these PM2.5-induced changes. However, remarkable differences in the protective effect of different PC doses did not exist. CONCLUSIONS: The results indicated that PC supplementation could effectively attenuate the oxidative stress and apoptosis induced by PM2.5 in rat myocardial tissue.

Traditional uses, phytochemistry, transformation of ingredients and pharmacology of the dried seeds of Raphanus sativus L. (Raphani Semen), A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Raphani Semen (Lai Fu-zi in Chinese, RS), the dried seeds of Raphanus sativus L., is a traditional Chinese herbal medicine. RS has long been used for eliminating bloating and digestion, antitussive, expectorant and anti-asthmatic in clinical treatment of traditional Chinese medicine. AIM OF THE STUDY: This review provides a critical and comprehensive summary of traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS based on research data that have been reported, aiming at providing a basis for further study on RS. MATERIALS AND METHODS: The search terms "Raphani Semen", "the seeds of Raphanus sativus L." and "radish seed" were used to obtain the information from electronic databases such as Web of Science, China National Knowledge Infrastructure, PubMed and other web search instruments. Traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS were summarized. RESULTS: RS has been traditionally used to treat food dyspeptic retention, distending pain in the epigastrium and abdomen, constipation, diarrhea and dysentery, panting, and cough with phlegm congestion in the clinical practice. The chemical constituents of RS include glucosinolates and sulfur-containing derivatives, phenylpropanoid sucrosides, small organic acids and derivatives, flavone glycosides, alkaloids, terpenoids, steroids, oligosaccharides and others. Among them, glucosinolates can be transformated to isothiocyanates by plant myrosinase or the intestinal flora, which display a variety of activities, such as anti-tumor, anti-inflammatory, antioxidant, antibacterial, treatment of metabolic diseases, central nervous system protection, anti-osteoporosis. RS has a variety of pharmacological activities, including treatment of metabolic diseases, anti-inflammatory, anti-tumor, antioxidant, antibacterial, antihypertensive, central nervous system protection, anti-osteoporosis, etc. This review will provide useful insight for exploration, further study and precise medication of RS in the future. CONCLUSIONS: According to its traditional uses, phytochemistry, transformation of ingredients and pharmacology, RS is regarded as a promising medical plant with various chemical compounds and numerous pharmacological activities. However, the material bases and mechanisms of traditional effect of RS need further study.

Network-driven targeted analysis reveals that Astragali Radix alleviates doxorubicin-induced cardiotoxicity by maintaining fatty acid homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR) is a popular traditional Chinese medicine that has been used for more than 2000 years. It is a well-known tonic for weak people with chronic diseases, such as heart failure and cerebral ischemia. Previous studies have reported that AR could support the "weak heart" of cancer patients who suffered from doxorubicin (DOX)-induced cardiotoxicity (DIC). However, the underlying mechanism remains unclear. AIM OF THE STUDY: This study aimed to uncover the critical pathways and molecular determinants for AR against DIC by fully characterizing the network-based relationship. MATERIALS AND METHODS: We integrated ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) profiling, database and literature searching, and the human protein-protein interactome to discover the specific network module associated with AR against DIC. To validate the network-based findings, a low-dose, long-term DIC mouse model and rat cardiomyoblast H9c2 cells were employed. The levels of potential key metabolites and proteins in hearts and cells were quantified by the LC-MS/MS targeted analysis and western blotting, respectively. RESULTS: We constructed one of the most comprehensive AR component-target network described to date, which included 730 interactions connecting 64 unique components and 359 unique targets. Relying on the network-based evaluation, we identified fatty acid metabolism as a putative critical pathway and peroxisome proliferator-activated receptors (PPARα and PPARγ) as potential molecular determinants. We then confirmed that DOX caused the accumulation of fatty acids in the mouse failing heart, while AR promoted fatty acid metabolism and preserved heart function. By inhibiting PPARγ in H9c2 cells, we further found that AR could alleviate DIC by activating PPARγ to maintain fatty acid homeostasis. CONCLUSIONS: Our findings imply that AR is a promising drug candidate that treats DIC by maintaining fatty acid homeostasis. More importantly, the network-based method developed here could facilitate the mechanism discovery of AR therapy and help catalyze innovation in its clinical application.

Attenuation of doxorubicin-induced oxidative damage in rat brain by regulating amino acid homeostasis with Astragali Radix.

The nervous system disorders caused by doxorubicin (DOX) are among the severe adverse effects that dramatically reduce the quality of life of cancer survivors. Astragali Radix (AR), a popular herbal drug and dietary supplement, is believed to help treat brain diseases by reducing oxidative stress and maintaining metabolic homeostasis. Here we show the protective effects of AR against DOX-induced oxidative damage in rat brain via regulating amino acid homeostasis. By constructing a clinically relevant low-dose DOX-induced toxicity rat model, we first performed an untargeted metabolomics analysis to discover specific metabolic features in the brain after DOX treatment and AR co-treatment. It was found that the amino acid (AA) metabolism pathways altered most significantly. To accurately characterize the brain AA profile, we established a sensitive, fast, and reproducible hydrophilic interaction chromatography-tandem mass spectrometry method for the simultaneous quantification of 22 AAs. The targeted analysis further confirmed the changes of AAs between different groups of rat brain. Specifically, the levels of six AAs, including glutamate, glycine, serine, alanine, citrulline, and ornithine, correlated (Pearson |r| > 0.47, p < 0.05) with the brain oxidative damage that was caused by DOX and rescued by AR. These findings present that AAs are among the regulatory targets of DOX-induced brain toxicity, and AR is a promising therapeutic agent for it.

Immune Response: A Missed Opportunity Between Vitamin D and Radiotherapy.

Radiotherapy (RT) is a mainstay treatment in several types of cancer and acts by mediating various forms of cancer cell death, although it is still a large challenge to enhance therapy efficacy. Radiation resistance represents the main cause of cancer progression, therefore, overcoming treatment resistance is now the greatest challenge for clinicians. Increasing evidence indicates that immune response plays a role in reprogramming the radiation-induced tumor microenvironment (TME). Intriguingly, radiation-induced immunosuppression possibly overwhelms the ability of immune system to ablate tumor cells. This induces an immune equilibrium, which, we hypothesize, is an opportunity for radiosensitizers to make actions. Vitamin D has been reported to act in synergistic with RT by potentiating antiproliferative effect induced by therapeutics. Additionally, vitamin D can also regulate the TME and may even lead to immunostimulation by blocking immunosuppression following radiation. Previous reviews have focused on vitamin D metabolism and epidemiological trials, however, the synergistic effect of vitamin D and existing therapies remains unknown. This review summarizes vitamin D mediated radiosensitization, radiation immunity, and vitamin D-regulated TME, which may contribute to more successful vitamin D-adjuvant radiotherapy.