Integrated serum pharmacochemistry, network pharmacology and experimental verification to explore the mechanism of Aconiti Lateralis Radix Praeparata in treatment of lung cancer.

Aconiti Lateralis Radix Praeparata (Fuzi) is a traditional Chinese medicine (TCM) widely used in treating cancer. Our formerly investigations confirmed the anti-lung cancer efficacy of Fuzi, but systematic analysis of the ingredients of Fuzi absorbed into serum and the corresponding molecular mechanism in treating lung cancer remained unknown. In this work, UPLC-Q-TOF-MS was applied to detect the ingredients of Fuzi in rat serum. Next, the possible targets and key pathways of the components absorbed into serum of Fuzi were predicted by network pharmacology. Then, the binding activity of components and potential targets were performed by molecular docking. Afterwards, the proliferation, mitochondrial membrane potential (MMP), apoptosis and reactive oxygen species (ROS) of lung cancer cells after treatment with Fuzi-containing serum were determined by MTT assay, JC-1 fluorescent probe, Annexin V-FITC/PI double staining and DCFH-DA respectively. Finally, the predicted target was further validated with qRT-PCR. In total, identification of 20 components of Fuzi derived from rat serum were achieved. The prediction of network pharmacology indicated that these compounds might exert their therapeutic effects by modulating mTOR. The findings from molecular docking proved that fuziline, songorine, napelline and hypaconitine exhibited binding potential with the mTOR. Cancer cell experiments revealed that the Fuzi-containing serum inhibited cell proliferation, induced apoptosis, reduced MMP and increased ROS. Additionally, Fuzi-containing serum significantly reduced the mRNA expression of mTOR. This study revealed that fuziline, songorine, napelline and hypaconitine were the main ingredients of Fuzi absorbed into serum. Furthermore, Fuzi-containing serum demonstrated inhibitory effects on the proliferation of lung cancer cells and induced the apoptosis. Combined with the results of network pharmacology, molecular docking and biological verification, Fuzi-containing serum might exert its anti-lung cancer effect by inhibiting mTOR. This study would provide a deeper understanding of Fuzi in treating lung cancer and offer a scientific reference for its clinical utilization.

The role of botanical triterpenoids and steroids in bile acid metabolism, transport, and signaling: Pharmacological and toxicological implications.

Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.

Alkaloids of Aconiti Lateralis Radix Praeparata inhibit growth of non-small cell lung cancer by regulating PI3K/Akt-mTOR signaling and glycolysis.

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.

Tumor Metabolism: A New Field for the Treatment of Glioma.

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

Boosting Checkpoint Immunotherapy with Biomimetic Nanodrug Delivery Systems.

Immune checkpoint blockade (ICB) has achieved unprecedented progress in tumor immunotherapy by blocking specific immune checkpoint molecules. However, the high biodistribution of the drug prevents it from specifically targeting tumor tissues, leading to immune-related adverse events. Biomimetic nanodrug delivery systems (BNDSs) readily applicable to ICB therapy have been widely developed at the preclinical stage to avoid immune-related adverse events. By exploiting or mimicking complex biological structures, the constructed BNDS as a novel drug delivery system has good biocompatibility and certain tumor-targeting properties. Herein, the latest findings regarding the aforementioned therapies associated with ICB therapy are highlighted. Simultaneously, prospective bioinspired engineering strategies can be designed to overcome the four-level barriers to drug entry into lesion sites. In future clinical translation, BNDS-based ICB combination therapy represents a promising avenue for cancer treatment.

Modulation of cellular metabolism and alleviation of bacterial dysbiosis by Aconiti Lateralis Radix Praeparata in non-small cell lung cancer treatment.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a highly prevalent and fatal form of lung cancer. In China, Aconiti Lateralis Radix Praeparata (Fuzi in Chinese), derived from the lateral root of Aconitum carmichaeli Debx. (Ranunculaceae, Aconitum), is extensively prescribed to treat cancer in traditional medicine and clinical practice. However, the precise mechanism by which Fuzi treats NSCLC remains unknown. PURPOSE: This article aims to assess the efficacy of Fuzi against NSCLC and elucidate its underlying mechanism. METHODS: Marker ingredients of Fuzi decoction were quantified using UPLC-TSQ-MS. The effectiveness of Fuzi on NSCLC was evaluated using a xenograft mouse model. Subsequently, a comprehensive approach involving network pharmacology, serum metabolomics, and 16S rDNA sequencing was employed to investigate the anti-NSCLC mechanism of Fuzi. RESULTS: Pharmacological evaluation revealed significant tumour growth inhibition by Fuzi, accompanied by minimal toxicity. Network pharmacology identified 29 active Fuzi compounds influencing HIF-1, PI3K/Akt signalling, and central carbon metabolism in NSCLC. Integrating untargeted serum metabolomics highlighted 30 differential metabolites enriched in aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and the tricarboxylic acid (TCA) cycle. Targeted serum metabolomics confirmed elevated glucose content and reduced levels of pyruvate, lactate, citrate, α-ketoglutarate, succinate, fumarate, and malate following Fuzi administration. Furthermore, 16S rDNA sequencing assay showed that Fuzi ameliorated the dysbiosis after tumorigenesis, decreased the abundance of Proteobacteria, and increased that of Firmicutes and Bacteriodetes. PICRUSt analysis revealed that Fuzi modulated the pentose phosphate pathway of the gut microbiota. Spearman correlation showed that Proteobacteria and Escherichia_Shigella accelerated the TCA cycle, whereas Bacteroidota, Bacteroides, and Lachnospiraceae_NK4A136_group suppressed the TCA cycle. CONCLUSIONS: This study firstly introduces a novel NSCLC mechanism involving Fuzi, encompassing energy metabolism and intestinal flora. It clarifies the pivotal role of the gut microbiota in treating NSCLC and modulating the TCA cycle. Moreover, these findings offer valuable insights for clinical practices and future research of Fuzi against NSCLC.

Targeted delivery of hybrid nanovesicles for enhanced brain penetration to achieve synergistic therapy of glioma.

Blood-brain barrier (BBB) obstructing brain drug delivery severely hampers the therapeutic efficacy towards glioma. An efficient brain delivery strategy is of paramount importance for the treatment of glioma. Inspired by brain targeting exosome, biomimetic BBB penetrated hybrid (pHybrid) nanovesicles, engineered by membrane fusion between blood exosome and tLyp-1 peptide modified liposome, is explored for brain targeting drug delivery. Transferrin receptor (TfR) on pHybrid nanovesicles facilitates the BBB transcytosis into brain parenchyma, and eventually endocytosed by glioma cells and diffusion to extra-vascular tumor tissues under the guidance of tLyp-1 peptide. pHybrid nanovesicles co-loaded with salvianolic acid B (SAB) and cryptotanshinone (CPT), which is constructed by membrane hybridization of blood exosome loaded with SAB and tLyp-1 modified liposome loaded with CPT, are explored for cytotoxic and anti-angiogenetic therapy towards glioma. Upon accumulation at tumor site, the loaded CPT and SAB shows synergistic effects towards glioma from cytotoxicity on cancer cells and anti-angiogenesis on tumor, respectively. Overall, this study provides a biomimetic nanoplatform for increased BBB transcytosis into brain parenchyma, which serves as a prospective strategy for delivering therapeutic agents against glioma through synergistic mechanisms.

Nanotechnologies meeting natural sources: Engineered lipoproteins for precise brain disease theranostics.

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity, from preventive and diagnostic to therapeutic fields. Lipoproteins, because of their inherent blood-brain barrier permeability and lesion-homing capability, have been identified as promising strategies for high-performance theranostics of brain diseases. However, the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes, which can be critical for individual therapeutics and clinical translation. To address these issues, lipoprotein-inspired nano drug-delivery systems (nano-DDSs), which have been learned from nature, have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions. In this review, the barriers in brain disease treatment, advantages of state-of-the-art lipoprotein-inspired nano-DDSs, and bio-interactions of such nano-DDSs are highlighted. Furthermore, the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized. Specifically, the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed. Finally, the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles, such as exosomes, cell membranes, and bacteria, are discussed.

Transferrin-Modified Triptolide Liposome Targeting Enhances Anti-Hepatocellular Carcinoma Effects.

Triptolide (TP) is an epoxy diterpene lactone compound isolated and purified from the traditional Chinese medicinal plant Tripterygium wilfordii Hook. f., which has been shown to inhibit the proliferation of hepatocellular carcinoma. However, due to problems with solubility, bioavailability, and adverse effects, the use and effectiveness of the drug are limited. In this study, a transferrin-modified TP liposome (TF-TP@LIP) was constructed for the delivery of TP. The thin-film hydration method was used to prepare TF-TP@LIP. The physicochemical properties, drug loading, particle size, polydispersity coefficient, and zeta potential of the liposomes were examined. The inhibitory effects of TF-TP@LIP on tumor cells in vitro were assessed using the HepG2 cell line. The biodistribution of TF-TP@LIP and its anti-tumor effects were investigated in tumor-bearing nude mice. The results showed that TF-TP@LIP was spherical, had a particle size of 130.33 ± 1.89 nm and zeta potential of -23.20 ± 0.90 mV, and was electronegative. Encapsulation and drug loading were 85.33 ± 0.41% and 9.96 ± 0.21%, respectively. The preparation was stable in serum over 24 h and showed biocompatibility and slow release of the drug. Flow cytometry and fluorescence microscopy showed that uptake of TF-TP@LIP was significantly higher than that of TP@LIP (p < 0.05), while MTT assays indicated mean median inhibition concentrations (IC50) of TP, TP@LIP, and TF-TP@ of 90.6 nM, 56.1 nM, and 42.3 nM, respectively, in HepG2 cell treated for 48 h. Real-time fluorescence imaging indicated a significant accumulation of DiR-labeled TF-TP@LIPs at tumor sites in nude mice, in contrast to DiR-only or DiR-labeled, indicating that modification with transferrin enhanced drug targeting to the tumor tissues. Compared with the TP and TP@LIP groups, the TF-TP@LIP group had a significant inhibitory effect on tumor growth. H&E staining results showed that TF-TP@LIP inhibited tumor growth and did not induce any significant pathological changes in the heart, liver, spleen, and kidneys of nude mice, with all liver and kidney indices within the normal range, with no significant differences compared with the control group, indicating the safety of the preparation. The findings indicated that modification by transferrin significantly enhanced the tumor-targeting ability of the liposomes and improved their anti-tumor effects in vivo. Reducing its distribution in normal tissues and decreasing its toxic effects suggest that the potential of TF-TP@LIP warrants further investigation for its clinical application.

A Gellan Gum/Sodium Alginate-based gastric-protective hydrogel loaded with a combined herbal extract consisting of Panax notoginseng, Bletilla striata and Dendrobium officinale.

One Chinese herbal combination consisting of Panax notoginseng, Bletilla striata and Dendrobium officinale (PBD) is an effective Traditional Chinese Medicine (TCM) prescription and is widely used in clinics to treat gastric ulcers due to their safety and effectiveness compared with chemical agents, such as aspirin and omeprazole. Herein, an in situ forming gel (ISFG) based on Gellan Gum (GG) and Sodium Alginate (SA) was designed to deliver extracts of PBD prescription (EPBDP). The central composite design optimized prescription dosage was 0.1 % w/v of GG and 0.5 % w/v of SA. Gels prepared with this formulation demonstrated outstanding fluidity and instantaneous gel formation. In vitro release data showed that sustained drug release occurred in the gel, and the gel was pH-sensitive. The rheological tests confirmed the formation of stable gel, which exhibited strong viscosity and elasticity. In vitro adhesion assays revealed that the gel had strong gastric mucosal adhesion, while in vivo residual rate experiments of active ingredients revealed that the gel might greatly improve the gastric retention of active ingredients. Animal studies demonstrated that the gel was effective in treating gastric ulcers. Hence, the results of the study show that EPBDP-ISFG, a highly pH-sensitive sustained-release system, is effective.

Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood-Brain Barrier for Chemo-immunotherapy against Glioblastoma.

Effective drug delivery and prevention of postoperative recurrence are significant challenges for current glioblastoma (GBM) treatment. Poor drug delivery is mainly due to the presence of the blood-brain barrier (BBB), and postoperative recurrence is primarily due to the resistance of GBM cells to chemotherapeutic drugs and the presence of an immunosuppressive microenvironment. Herein, a biomimetic nanodrug delivery platform based on endogenous exosomes that could efficiently target the brain without targeting modifications and co-deliver pure drug nanomicelles and immune adjuvants for safe and efficient chemo-immunotherapy against GBM is prepared. Inspired by the self-assembly technology of small molecules, tanshinone IIA (TanIIA) and glycyrrhizic acid (GL), which are the inhibitors of signal transducers and activators of transcription 3 from traditional Chinese medicine (TCM), self-assembled to form TanIIA-GL nanomicelles (TGM). Endogenous serum exosomes are selected to coat the pure drug nanomicelles, and the CpG oligonucleotides, agonists of Toll-like receptor 9, are anchored on the exosome membrane to obtain immune exosomes loaded with TCM self-assembled nanomicelles (CpG-EXO/TGM). Our results demonstrate that CpG-EXO/TGM can bind free transferrin in blood, prolong blood circulation, and maintain intact structures when traversing the BBB and targeting GBM cells. In the GBM microenvironment, the strong anti-GBM effect of CpG-EXO/TGM is mainly attributed to two factors: (i) highly efficient uptake by GBM cells and sufficient intracellular release of drugs to induce apoptosis and (ii) stimulation of dendritic cell maturation and induction of tumor-associated macrophages polarization by CpG oligonucleotides to generate anti-GBM immune responses. Further research found that CpG-EXO/TGM can not only produce better efficacy in combination with temozolomide but also prevent a postoperative recurrence.

Platycodon grandiflorus root extract activates hepatic PI3K/PIP3/Akt insulin signaling by enriching gut Akkermansia muciniphila in high fat diet fed mice.

BACKGROUND: Increasing hepatic insulin signaling is found to be an important mechanism of Platycodon grandiflorus root to alleviate metabolic syndrome (MetS) symptoms such as insulin resistance, obesity, hyperlipidemia and hepatic steatosis, but the details are not yet clear. Since the main constituents of Platycodon grandiflorus root were hard to be absorbed by gastrointestinal tract, getting opportunity to interact with gut microbiota, we speculate the gut microorganisms may mediate its effect. PURPOSE: Our work aimed to confirm the critical role of gut microbes in the intervention of Platycodon grandiflorus root extract (PRE) on MetS, and investigate the mechanism. METHODS: Biochemical analyses, glucose tolerance test and hepatic lipidomics analysis were used to evaluate the anti-MetS effect of PRE on high fat diet (HFD) fed mice. Perform 16S rDNA analysis, qPCR analysis and in vitro co-incubation experiment to study its effect on gut microbes, followed by fecal microbiota transplantation (FMT) experiment and antibiotics intervention experiment. Also, the effect of Akkermansia muciniphila treatment on HFD mice was investigated. RESULTS: PRE alleviated lipid accumulation and insulin resistance in HFD mice and remodeled the fecal microbiome. It also increased the gene expression of colonic tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced TNF-α induced hepatic JNK-dependent IRS-1 serine phosphorylation and the impairment of PI3K/PIP3/Akt insulin signaling pathway. A. muciniphila was one of the most significantly enriched microbes by PRE treatment, and its administration to HFD mice showed similar effects to PRE, repairing the gut barrier and activating hepatic PI3K/PIP3/Akt pathway. Finally, anti-MetS effect of PRE could be delivered to FMT recipients, and PRE could not further attenuate MetS in gut microbiota depleted mice. CONCLUSION: We demonstrated for the first time that PRE alleviated MetS in a gut microbiota dependent manner, and found activation of hepatic insulin signaling mediated by gut A. muciniphila was a potential mechanism of it.

Bio-fabricated nanodrugs with chemo-immunotherapy to inhibit glioma proliferation and recurrence.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with high mortality. Knowledge of the stemness concept has developed recently, giving rising to a novel hallmark with therapeutic potential that can help in management of GBM recurrence and prognosis. However, limited blood-brain barrier (BBB) penetration, non-discriminatory distribution, and deficiency of diagnosis remain three major obstacles need to be overcome for further facilitating therapeutic effects. Herein, D4F and α-Melittin (a-Mel) are co-assembled to construct bio-fabricated nanoplatforms, which endowed with inherent BBB permeability, precise tumor accumulation, deep penetration, and immune activation. After carrying arsenic trioxide (ATO) and manganese dichloride (MnCl2), these elaborated nanodrugs, Mel-LNPs/MnAs, gather in tumor foci by natural pathways and respond to microenvironment to synchronously release Mn2+ and As3+, achieving real-time navigating-diagnosis and tumor cell proliferation inhibition. Through down regulating CD44 and CD133 expression, the GBM stemness was suppressed to overcome its high recurrence, invasion, and chemoresistance. After being combined with temozolomide (TMZ), the survival rate of GBM-bearing mice is significantly enhanced, and the rate of recurrence is powerfully limited. Collectively, this tumor-specific actuating multi-modality nanotheranostics provide a promising candidate for clinical application with high security.

The Bioavailability of Glycyrrhizinic Acid Was Enhanced by Probiotic Lactobacillus rhamnosus R0011 Supplementation in Liver Fibrosis Rats.

Glycyrrhizinic acid (GL) is clinically applied to treat liver injury, and the bioavailability of orally administered GL is closely related to the gut microbiota. Therefore, the dysbiosis of gut flora in liver injury could significantly influence GL bioavailability. Still, less is known about the impact of probiotic supplementation on the bio-absorption process of oral medication, especially under a pathological state. Herein, probiotic L. rhamnosus R0011 (R0011) with a high viability in the harsh gastrointestinal environment was selected, and the effect of R0011 on the GL bioavailability in rats was investigated. Four groups of rats (n = 6 per group) were included: the normal group (N group), the normal group supplemented with R0011 (NLGG group), CCl4-induced chronic liver injury model (M group), and the model group supplemented with R0011 (MLGG group). Our results showed that liver injury was successfully induced in the M and MLGG groups via an intraperitoneal injection of 50% (v/v) CCl4 solution. Healthy rats supplemented with R0011 could increase the bioavailability of GL by 1.4-fold compared with the normal group by plasma pharmacokinetic analysis. Moreover, the GL bioavailability of MLGG group was significantly increased by 4.5-fold compared with the model group. R0011 directly improved gut microbial glucuronidase and downregulated the host intestinal drug transporter gene expression of multidrug resistance protein 2 (MRP2). More critically, R0011 restored the gut microbiota composition and regulated the metabolic function, significantly enhancing the microbial tryptophan metabolic pathway compared with the pathological state, which may indirectly promote the bioavailability of GL. Overall, these data may provide possible strategies by which to address the low bioavailability of traditional medicine through probiotic intervention.

[Mechanism of Cordyceps militaris against non-small cell lung cancer: based on serum metabolomics].

This study investigated the potential mechanism of Cordyceps militaris(CM) against non-small cell lung cancer(NSCLC) based on serum untargeted metabolomics. Specifically, Balb/c nude mice were used to generate the human lung cancer A549 xenograft mouse model. The tumor volume, tumor weight, and tumor inhibition rate in mice in the model, cisplatin, Cordyceps(low-, medium-, and high-dose), and CM(low-, medium-, and high-dose) groups were compared to evaluate the influence of CM on lung cancer. Gas chromatography-mass spectrometry(GC-MS) was used for the analysis of mouse serum, SIMCA 13.0 for the compa-rison of metabolic profiles, and MetaboAnalyst 5.0 for the analysis of metabolic pathways. According to the pharmacodynamic data, the tumor volume and tumor weight of mice in high-dose CM group and cisplatin group decreased as compared with those in the model group(P<0.05 or P<0.01). The results of serum metabolomics showed that the metabolic profiles of the model group were significantly different from those of the high-dose CM group, and the content of endogenous metabolites was adjusted to different degrees. A total of 42 differential metabolites and 7 differential metabolic pathways were identified. In conclusion, CM could significantly inhibit the tumor growth of lung cancer xenograft mice. The mechanism is the likelihood that it influences the aminoacyl-tRNA biosynthesis, the metabolism of D-glutamine and D-glutamate, metabolism of alanine, aspartate, and glutamate, metabolism of glyoxylate and dicarboxylic acid, biosynthesis of phenylalanine, tyrosine, and tryptophan, arginine biosynthesis as well as nitrogen metabolism. This study elucidated the underlying mechanism of CM against NSCLC from the point of metabolites. The results would lay a foundation for the anticancer research and clinical application of CM.

Aconiti Lateralis Radix Praeparata as Potential Anticancer Herb: Bioactive Compounds and Molecular Mechanisms.

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is a traditional herbal medicine widely used in China and other Asian countries. In clinical practice, it is often used to treat heart failure, rheumatoid arthritis, and different kinds of pains. Fuzi extract and its active ingredients exert considerable anticancer, anti-inflammatory, and analgesic effects. The main chemical substances of Fuzi include alkaloids, polysaccharides, flavonoids, fatty acids, and sterols. Among of them, alkaloids and polysaccharides are responsible for the anticancer efficacy. Most bioactive alkaloids in Fuzi possess C19 diterpenoid mother nucleus and these natural products show great potential for cancer therapy. Moreover, polysaccharides exert extraordinary tumor-suppressive functions. This review comprehensively summarized the active ingredients, antineoplastic effects, and molecular mechanisms of Fuzi by searching PubMed, Web of Science, ScienceDirect, and CNKI. The anticancer effects are largely attributed to inducing apoptosis and autophagy, inhibiting proliferation, migration and invasion, regulating body immunity, affecting energy metabolism, as well as reversing multidrug resistance. Meanwhile, several signaling pathways and biological processes are mainly involved, such as NF-κB, EMT, HIF-1, p38 MAPK, PI3K/AKT/mTOR, and TCA cycle. Collectively, alkaloids and polysaccharides in Fuzi might serve as attractive therapeutic candidates for the development of anticancer drugs. This review would lay a foundation and provide a basis for further basic research and clinical application of Fuzi.

Gather wisdom to overcome barriers: Well-designed nano-drug delivery systems for treating gliomas.

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

A novel antimicrobial peptide found in Pelophylax nigromaculatus.

BACKGROUND: Many active peptides have been found in frog skin secretions. In this paper, our research focused on Pelophylax nigromaculatus and found a broad-spectrum antimicrobial peptide Nigrocin-PN based on the molecular cloning technique. Thereafter, the "Rana box" function was briefly studied by two mutated peptides (Nigrocin-M1 and Nigrocin-M2). Furthermore, in vitro and in vivo assays were used to characterize the peptide's biofunctions, and the peptide's function in treating multidrug-resistant pathogens was also studied. RESULTS: Nigrocin-PN not only displayed potent antimicrobial abilities in vitro but also significantly ameliorated pulmonary inflammation induced by Klebsiella pneumoniae in vivo. By comparing, leucine-substituted analogue Nigrocin-M1 only displayed bactericidal abilities towards gram-positive bacteria, while the shorter analogue Nigrocin-M2 lost this function. More strikingly, Nigrocin-PN exhibited synergistic effects with commonly used antibiotics; in vitro evolution experiments revealed that coadministration between Nigrocin-PN and ampicillin could delay Staphylococcus aureus antibiotic resistance acquisition. Kinetics and morphology studies indicate that antibacterial mechanisms involved membrane destruction. Furthermore, toxicities and anticancer abilities of these peptides were also studied; compared to two analogues, Nigrocin-PN showed mild haemolytic activity and indistinctive cytotoxicity towards normal cell lines HMEC-1 and HaCaT. CONCLUSIONS: A broad-spectrum antimicrobial peptide Nigrocin-PN was discovered from the skin secretion of Pelophylax nigromaculatus. Structurally, "Rana box" played a crucial role in reducing toxicities without compromising antibacterial abilities, and Nigrocin-PN could be a desired therapeutic candidate.

Tumor-derived exosomes reversing TMZ resistance by synergistic drug delivery for glioma-targeting treatment.

Temozolomide (TMZ), as the first-line chemotherapeutic agent, relies on inducing DNA methylation of O6-guanine for treating glioma. However, the survival time of patients are hardly exceeded 14.5 months, attributing to inevitable drug resistance and systematic toxicity after long-term administration. Herein, reassembly-exosomes (R-EXO) deriving from homologous glioma cells is proposed to carry TMZ and Dihydrotanshinone (DHT) for reversing drug resistance and enhancing lesions-targeted drug delivery, defined as R-EXO-TMZ/DHT (R-EXO-T/D). It is found that R-EXO-T/D share various advantages, including preferable blood-brain barrier (BBB)-penetrating ability with nanomemter size, tumor-homing accumulation with homologous effects, as well as potentiated antitumor activity with overcoming TMZ resistance and triggering immune response. This work develops a new strategy for site-specific drug delivery, showing a promising application of drug compatibility in glioma treatment.