Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematological malignancies. However, CAR-T therapy for solid tumors is still limited due to the unique solid-tumor microenvironment and heterogeneous target antigen expression, which leads to an urgent need of combining other therapies. At present, nano delivery system has become one of the most promising directions for the development of anti-tumor drugs. Based on the background of CAR-T and tumor treatment, we focus on the research progress of nanomedicine combined with CAR-T therapy, and systematically review the strategies and examples in recent years in the aspects of in vivo delivery of mRNA, regulation of tumor microenvironment, combination with photothermal therapy. And we also look forward to the future direction of this filed.
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Humans ; Receptors, Chimeric Antigen/therapeutic use* ; Pharmaceutical Preparations/metabolism* ; Antigens, Neoplasm/metabolism* ; Lung Neoplasms/metabolism* ; Neoplasms/metabolism* ; T-Lymphocytes ; Tumor Microenvironment ; Nanoparticles/therapeutic use*

This study investigated the mechanism of action of Scutellariae Radix-Coptidis Rhizoma(SR-CR) in intervening in non-alcoholic fatty liver disease(NAFLD) in rats based on lipidomics. Thirty-six SD rats were divided into a control group, a model group, SR-CR groups of different doses, and a simvastatin group, with six rats in each group. Rats in the control group were fed on a normal diet, while those in the remaining groups were fed on a high-lipid diet. After four weeks of feeding, drug treatment was carried out and rats were sacrificed after 12 weeks. Serum liver function and lipid indexes were detected using kits, and the pathomorphology of liver tissues was evaluated by hematoxylin-eosin(HE) staining and oil red O staining. Changes in lipid levels in rats were detected using the LC-MS technique. Differential lipid metabolites were screened by multivariate statistical analysis, and lipid metabolic pathways were plotted. The changes in lipid-related protein levels were further verified by Western blot. The results showed that compared with the control group, the model group showed increased levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.01), and decreased levels of γ-glutamyl transferase(γ-GT) and high-density lipoprotein cholesterol(HDL-c)(P<0.01), which were significantly recovered by the intervention of SR-CR. HE staining and oil red O staining showed that different doses of SR-CR could reverse the steatosis in the rat liver in a dose-dependent manner. After lipidomics analysis, there were significant differences in lipid metabolism between the model group and the control group, with 54 lipids significantly altered, mainly including glycerolipids, phosphatidylcholine, and sphingolipids. After administration, 44 differential lipids tended to normal levels, which indicated that SR-CR groups of different doses significantly improved the lipid metabolism level in NAFLD rats. Western blot showed that SR-CR significantly decreased TG-synthesis enzyme 1(DGAT1), recombinant lipin 1(LPIN1), fatty acid synthase(FASN), acetyl-CoA carboxylase 1(ACC1), and increased the phosphorylation level of ACC1. These changes significantly decreased the synthesis of TG and increased the rate of its decomposition, which enhanced the level of lipid metabolism in the body and finally achieved the lipid-lowering effect. SR-CR can improve NAFLD by inhibiting the synthesis of fatty acids and TG.
Rats ; Animals ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Scutellaria baicalensis ; Drugs, Chinese Herbal/therapeutic use* ; Pharmaceutical Preparations ; Rats, Sprague-Dawley ; Liver ; Triglycerides/metabolism* ; Cholesterol ; Diet, High-Fat ; Azo Compounds

OBJECTIVE: To study the effects of the neuro-microenvironment on the mass of mitochondria in hematopoietic stem and progenitor cells (HSPC), and to understand the potential mechanisms how nerve regulates HSPC. METHODS: 6-hydroxydopamine (6-OHDA) and capsaicin were used to interfere with the function of sympathetic nerve and nociceptive nerve in mitochondria-GFP reporter mice, respectively. The fluorescence intensity of GFP in bone marrow and spleen was measured by flow cytometry. The GFP median fluorescence intensity (MFI) of HSPC in normal bone marrow and spleen was analyzed and compared. The changes of the mitochondrial mass in HSPCs in each group after denervation were compared. RESULTS: Hematopoietic stem cells (HSC) had the highest mito-GFP MFI in steady-state (49 793±1 877), and the mito-GFP MFI gradually decreased during the differentiation of HSCs. Compared with control group, pharmaceutical nociceptive denervation significantly increased the mito-GFP MFI of bone marrow multipotent progenitor-1 (MPP1, 50 751±420 vs 44 020±510) and LKS^- cells (15 673±65 vs 13 979±103); pharmaceutical sympathetic denervation significantly reduced the mito-GFP MFI of bone marrow LKS⁺ cells (21 667±351 vs 29 249±973). CONCLUSION Sympathetic and nociceptive nerves can regulate the mass of mitochondria in HSPC and affect the function of HSPCs.
Animals ; Mice ; Hematopoietic Stem Cells ; Bone Marrow/metabolism* ; Cell Differentiation ; Mitochondria ; Pharmaceutical Preparations/metabolism*

Based on the target occupancy mathematical model, the binding kinetic process of potential active ingredients of lowering uric acid in Chrysanthemum morifolium with xanthine oxidase(XOD) was evaluated. The potential active ingredients of lowering uric acid in Ch. morifolium were screened by UPLC-Q-Exactivems MS technology, reference substance identification and in vitro enzymatic kinetics experiments. The binding kinetic parameters of xanthine oxidase and potential inhibitor in Ch. morifolium were determined by surface plasma resonance(SPR). The verified mathematical model of the XOD target occupancy evaluated the kinetic binding process of inhibitors and xanthine oxidase in vivo. According to UPLC-Q-Exactive MS and reference substance identification, 39 potential uric acid-lowering active ingredients in Ch. morifolium extracts were identified and the inhibitory activities of 23 compounds were determined. Three potential xanthine oxidase inhibitors were screened, namely genistein, luteolin, and apigenin. whose IC_(50 )were 1.23, 1.47 and 1.59 μmol·L~(-1), respectively. And the binding rate constants(K_(on)) were 1.26×10~6, 5.23×10~5 and 6.36×10~5 mol·L~(-1)·s~(-1), respectively. The dissociation rate constants(K_(off)) were 10.93×10~(-2), 1.59×10~(-2), and 5.3×10~(-2 )s~(-1), respectively. After evaluation by different administration methods, the three selected compounds can perform rapid and sustained inhibition of xanthine oxidase in vivo under combined administration. This study comprehensively evaluated the target occupancy process of three effective components in different ways of administration in vivo by UPLC-MS, concentration-response method, SPR technology and xanthine oxidase target occupancy model, which would provide a new research idea and method for screening active ingredients in traditional Chinese medicine.
Chromatography, Liquid ; Chrysanthemum ; Flavonoids ; Kinetics ; Pharmaceutical Preparations ; Tandem Mass Spectrometry ; Xanthine Oxidase/metabolism*

Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and transporters. Studies have shown that hypoxia increases the release of a series of inflammatory cytokines which can modulate drug metabolism. Besides, both hypoxia inducible factor 1α (HIF-1α) and microRNA-mediated pathways play a role in regulating drug metabolism. This article reviewed the impact and single-factor modulating mechanisms of drug metabolism under hypoxia, and put forward the speculation and prospects of multi-factor modulating mechanisms.
Cell Hypoxia ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; physiology ; Membrane Transport Proteins ; physiology ; MicroRNAs ; physiology ; Pharmaceutical Preparations ; metabolism

Statins are the first choice of pharmacological treatment for dyslipidemia to prevent atherosclerotic cardiovascular disease. Ample evidence demonstrates the benefits and safety of statin, including the lipid-lowering efficacy and the ability to improve clinical prognosis. High-intensity statin therapy is especially recommended in high-risk patients and those with cardiovascular disease. However, clinical trials, meta-analyses, and retrospective analyses have shown 9% to 13% increase in the risk of new-onset diabetes with statin therapy. The risk of new-onset diabetes with statin increased with higher statin doses, and the mechanisms are not yet fully understood. Mendelian randomization studies have suggested that new-onset diabetes with statin may be related to the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor. Patients with familial hypercholesterolemia did not show an increased risk of new-onset diabetes with statin compared to their unaffected relatives. Moreover, some studies have shown that different kinds of statins impaired pancreatic beta-cell function. Recently, genetic analysis studies have shown probable associations between changes in several proteins involving lipid metabolism and the increased risk of new-onset diabetes. Statin therapy should be emphasized to prevent and treat atherosclerotic cardiovascular disease on the basis of individual cardiovascular risk and clinical characteristics, especially in high-risk patients, such as those with diabetes. It is important to combine statin therapy with patient education and lifestyle modifications, including diet control, exercise, and weight changes, to manage dyslipidemia and minimize the risk of new-onset diabetes. Statin therapy should be considered more important and the risk of new-onset diabetes with statin should not be overemphasized.
Cardiovascular Diseases ; Diabetes Mellitus* ; Diet ; Dyslipidemias ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Hyperlipoproteinemia Type II ; Life Style ; Lipid Metabolism ; Oxidoreductases ; Patient Education as Topic ; Pharmaceutical Preparations ; Prognosis ; Random Allocation ; Receptors, LDL ; Retrospective Studies

OBJECTIVETo investigate the effects of Heijiangdan Ointment ( HJD) on oxidative stress in (60)Co γ-ray radiation-induced dermatitis in mice.

METHODSFemale Wistar mice with grade 4 radiation dermatitis induced by (60)Co γ-rays were randomly divided into four groups (n=12 per group); the HJD-treated, recombinant human epidermal growth factor (rhEGF)-treated, Trolox-treated, and untreated groups, along with a negative control group. On the 11th and 21st days after treatment, 6 mice in each group were chosen for evaluation. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and lactate dehydrogenase (LDH) were detected using spectrophotometric methods. The fibroblast mitochondria were observed by transmission electron microscopy (TEM). The expressions of fibroblast growth factor 2 (FGF-2) and transforming growth factor β1 (TGF-β1) were analyzed by western blot.

RESULTSCompared with the untreated group, the levels of SOD, MDA and LDH, on the 11th and 21st days after treatment showed significant difference (P<0.05). TEM analysis indicated that fibroblast mitochondria in the untreated group exhibited swelling and the cristae appeared fractured, while in the HJD group, the swelling of mitochondria was limited and the rough endoplasmic reticulum appeared more relaxed. The expressions of FGF-2 and TGF-β1 increased in the untreated group compared with the negative control group (P<0.05). After treatment, the expression of FGF-2, rhEGF and Trolox in the HJD group were significantly increased compared with the untreated group (P<0.05), or compared with the negative control group (P<0.05). The expression of TGF-β1 showed significant difference between untreated and negative control groups (P<0.05). HJD and Trolox increased the level of TGF-β1 and the difference was marked as compared with the untreated and negative control groups (P<0.05).

CONCLUSIONHJD relieves oxidative stress-induced injury, increases the antioxidant activity, mitigates the fibroblast mitochondrial damage, up-regulates the expression of growth factor, and promotes mitochondrial repair in mice.

Animals ; Biological Products ; pharmacology ; therapeutic use ; Cell Proliferation ; drug effects ; radiation effects ; Cobalt Radioisotopes ; Dermatitis ; complications ; drug therapy ; pathology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Fibroblast Growth Factor 2 ; genetics ; metabolism ; Fibroblasts ; drug effects ; pathology ; radiation effects ; Gamma Rays ; Humans ; L-Lactate Dehydrogenase ; metabolism ; Malondialdehyde ; metabolism ; Mice ; Mitochondria ; drug effects ; metabolism ; radiation effects ; Ointments ; Oxidative Stress ; drug effects ; radiation effects ; Pharmaceutical Preparations ; Radiation Injuries ; complications ; drug therapy ; pathology ; Superoxide Dismutase ; metabolism ; Transforming Growth Factor beta1 ; genetics ; metabolism ; Up-Regulation ; drug effects ; radiation effects

The special environmental features of high altitude, such as hypobaric hypoxia, low temperature, arid, high solar radiation, variable climate and geochemical anomaly, cause great effects on human physiology and health. It will provide valuable references and new ideas to study drug's metabolism in special environment of high altitude hypoxia, and give the guidance to clinical reasonable medication, avoiding adverse reactions and personalized medicine in plateau areas. This article reviewed the effect of high altitude hypoxia on drug metabolism, elaborated metabolic characteristics of some drugs and the activity and expression of drug metabolism enzymes under hypoxia environment at high altitude, and discussed related mechanism.
Altitude ; Climate ; Cold Temperature ; Humans ; Hypoxia ; Pharmaceutical Preparations ; metabolism

In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses. They often self-medicate themselves with various health products and over-the-counter (OTC) medicines apart from prescribed pharmaceutical drugs (PD). Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients; thus their usefulness is in doubt. The increasing popularity world-wide of using Chinese medicines (CM) and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects. In most cases the alleged causes of adverse effects are linked with herbal sources, although the authorised information on the interactions between CM-PD is not plentiful in the literature. There is an urgent need for such a data base. The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given. In actual practice the patients may receive both treatments intentionally or unintentionally, with or without the awareness of the practitioner. In these situations a reliable database for interactions between CM-PD will be extremely useful for consultation when treatment problems appear or during emergency situations. Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects. Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine. The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD. Examples will be given largely on those related to these disciplines as illustrations in this overview.
Delivery of Health Care ; Drug Interactions ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Integrative Medicine ; Pharmaceutical Preparations ; metabolism

Useful pharmacodynamic changes occur when some Chinese medicine are used together with some Western medicine, namely enhanced curative effect, lowered adverse reactions, reduced dosages, shortened treatment courses, enlarged indications scope, improved compliance of treatment and rational medication, which could be explored to provide scientific bases for further improving diagnosis and treatment levels and rational use of drugs.
Drugs, Chinese Herbal ; metabolism ; Humans ; Medicine, East Asian Traditional ; Pharmaceutical Preparations ; metabolism ; Pharmacokinetics ; Phytotherapy