Targeted gene delivery systems for T-cell engineering.

T lymphocytes are indispensable for the host systems of defense against pathogens, tumors, and environmental threats. The therapeutic potential of harnessing the cytotoxic properties of T lymphocytes for antigen-specific cell elimination is both evident and efficacious. Genetically engineered T-cells, such as those employed in CAR-T and TCR-T cell therapies, have demonstrated significant clinical benefits in treating cancer and autoimmune disorders. However, the current landscape of T-cell genetic engineering is dominated by strategies that necessitate in vitro T-cell isolation and modification, which introduce complexity and prolong the development timeline of T-cell based immunotherapies. This review explores the complexities of gene delivery systems designed for T cells, covering both viral and nonviral vectors. Viral vectors are known for their high transduction efficiency, yet they face significant limitations, such as potential immunogenicity and the complexities involved in large-scale production. Nonviral vectors, conversely, offer a safer profile and the potential for scalable manufacturing, yet they often struggle with lower transduction efficiency. The pursuit of gene delivery systems that can achieve targeted gene transfer to T cell without the need for isolation represents a significant advancement in the field. This review assesses the design principles and current research progress of such systems, highlighting the potential for in vivo gene modification therapies that could revolutionize T-cell based treatments. By providing a comprehensive analysis of these systems, we aim to contribute valuable insights into the future development of T-cell immunotherapy.

Caffeine in Hepatocellular Carcinoma: Cellular Assays, Animal Experiments, and Epidemiological Investigation.

The use of caffeine in treating various liver diseases has made substantial progress in the past decade owing to advances in science, technology, and medicine. However, whether caffeine has a preventive effect on hepatocellular carcinoma (HCC) and its mechanism are still worth further investigation. In this review, we summarize and analyze the efficacy and safety of caffeine in the prevention of HCC. We conducted a review of articles published in PubMed and Web of Science in the past 2 decades until December 6, 2023, which were searched for using the terms "Caffeine" and "Hepatocellular Carcinoma." Studies have found that coffee intake is negatively correlated with HCC risk, especially caffeinated coffee. Recent studies have found that caffeine has beneficial effects on liver health, decreasing levels of enzymes responsible for liver damaging and slowing the progression of hepatic fibrosis and cirrhosis. Caffeine also acts against liver fibrosis through adenosine receptors (ARs), which promote tissue remodeling by inducing fibrin and collagen production. Additionally, new studies have found that moderate consumption of caffeinated beverages can decrease various the levels of various collagens in patients with chronic hepatitis C. Furthermore, polyphenolic compounds in coffee can improve fat homeostasis, reduce oxidative stress, and prevent liver steatosis and fibrosis. Moreover, many in vitro studies have shown that caffeine can protect liver cells and inhibit the activation and proliferation of hepatic stellate cells. Taken together, we describe the benefits of caffeine for liver health and highlight its potential values as a drug to prevent various hepatic diseases. As a protective agent of liver inflammation, non-selective AR inhibitor caffeine can inhibit the growth of HCC cells by inhibiting adenosine and AR binding to initiate immune response, providing a basis for the future development of caffeine as an adjuvant drug against HCC.

Case fatality rates of COVID-19 during epidemic periods of variants of concern: A meta-analysis by continents.

OBJECTIVES: To calculate the case fatality rates (CFR) of COVID-19 during epidemic periods of different variants of concern (VOC) by continents. METHODS: We systematically searched five authoritative databases (Web of Science, PubMed, Embase, Cochrane Library, and MedRxiv) for epidemiological studies on the CFR of COVID-19 published between January 1, 2020, and March 31, 2023. After identifying the epidemic trends of variants, we used a random-effects model to calculate the pooled CFRs during periods of different VOCs. This meta-analysis was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered with PROSPERO (CRD42023431572). RESULTS: There were variations in the CFRs among different variants of COVID-19 (Alpha: 2.62%, Beta: 4.19%, Gamma: 3.60%, Delta: 2.01%, Omicron: 0.70%), and disparities in CFRs also existed among continents. On the whole, the CFRs of COVID-19 in Europe and Oceania were slightly lower than in other continents. There was a statistically significant association between the variant, HDI value, age distribution, coverage of full vaccination of cases, and the CFR. CONCLUSIONS: The CFRs of COVID-19 varied across the epidemic periods of different VOCs, and disparities existed among continents. The CFR value reflected combined effects of various factors within a certain context. Caution should be exercised when comparing CFRs due to disparities in testing capabilities and age distribution among countries, etc.

GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2f/fLyz2-Cre+/- mice. Synovial inflammation and M1 polarization were improved in GRK2f/fLyz2-Cre+/- mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPARγ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPARγ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA.

New insights into fibrotic signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) mostly occurs in the background of liver fibrosis, and activated hepatic stellate cells (HSCs) exist in HCC tissues and adjacent tissues. HSC activation is involved throughout the development of HCC precancerous lesions, which has gradually attracted the attention of related researchers. In addition, HCC can promote the activation of HSCs, which in turn accelerates the occurrence and development of HCC by promoting tumor angiogenesis. In this review, we reviewed 264 studies from PubMed and ScienceDirect to summarize and analyze current significant fibrotic signaling in HCC. As a result, we found 10 fibrotic signaling pathways that are closely related to the activation, proliferation, invasion, migration, and promotion of apoptosis of HCC cells. In addition, we found that crosstalk between various fibrotic signaling pathways of HCC, hypoxia-induced energy metabolic reprogramming of HCC cells, matrix stiffness and stemness of HCC cells, and ferroptosis of HCC cells and HSCs are the latest research hotspots. Furthermore, related drugs that have been found to target these 10 fibrotic signaling pathways of HCC are listed. Our study provides a new reference for developing anti-HCC drugs.

[Preparation of vitexin albumin nanoparticles and its pharmacokinetic study].

This study aims to prepare vitexin albumin nanoparticles(VT-BSA-NPs) to alleviate the low bioavailability of vitexin(VT) in vivo due to its poor water solubility. VT micro powders were prepared by the antisolvent crystallization method, and the morphology, size, and physicochemical properties of VT micro powders were studied. The results showed that the VT micro powder had a particle size of(187.13±7.15) nm, an approximate spherical morphology, and a uniform size distribution. Compared with VT, the chemical structure of VT micro powders has not changed. VT-BSA-NPs were prepared from VT micro powders by desolvation-crosslinking curing method. The preparation process was screened by single factor test and orthogonal test, and the quality evaluation of the optimal prescription particle size, PDI, Zeta potential, EE, and morphology was performed. The results showed that the average particle size of VT-BSA-NPs was(124.33±0.47) nm; the PDI was 0.184±0.012; the Zeta potential was(-48.83±2.20) mV, and the encapsulation rate was 83.43%±0.39%, all of which met the formulation-related requirements. The morphological results showed that the VT-BSA-NPs were approximately spherical in appearance, regular in shape, and without adhesion on the surface. In vitro release results showed a significantly reduced release rate of VT-BSA-NPs compared with VT, indicating a good sustained release effect. LC-MS/MS was used to establish an analytical method for in vivo analysis of VT and study the plasma pharmacokinetics of VT-BSA-NPs in rats. The results showed that the specificity of the analytical method was good, and the extraction recovery was more than 90%. Compared with VT and VT micro powders, VT-BSA-NPs could significantly increase AUC, MRT, and t_(1/2), which was beneficial to improve the bioavailability of VT.

Chimeric Antigen Receptor-T Cell Therapy Decreases Distant Metastasis and Inhibits Local Recurrence Post-surgery in Mice.

Distant metastasis and primary tumor relapse are the two main hurdles to the success of surgical treatment for cancer patients. Circulating tumor cells (CTCs) and incomplete surgical resection are the primary cause of distant metastasis and local recurrence of tumors, respectively. Chimeric antigen receptor (CAR)-modified T cells target residual carcinomas and CTCs hold the potential to inhibit primary recurrence and reduce tumor metastasis, but the experimental evidence is lacking. Here, we developed a surgery-induced tumor metastasis model in immunocompetent mice to investigate the efficacy of CAR-T cells therapy in preventing metastasis and local recurrence. We observed that subcutaneous tumor resection has induced a large number of CTCs intravasated into circulation. EpCAM-specific CAR-T was effective in clearing CTCs following surgical removal of the tumor. This resulted in less pulmonary metastasis and longer survival in mice when compared to mice treated with surgery followed by Mock-T cells infusion. In addition, the local relapse was obviously inhibited at the surgical site followed by EpCAM-CAR-T cell treatment. This study demonstrated that CAR-T cell therapy can be an adjuvant treatment following surgery to prevent tumor metastasis and inhibit primary tumor relapse for cancer patients.

Activation of CYP3A by Accelerated Blood Clearance Phenomenon Potentiates the Hepatocellular Carcinoma-Targeting Therapeutic Effects of PEGylated Anticancer Prodrug Liposomes.

Reduced enzyme activity in hepatocellular carcinoma (HCC) and poor targeting limit the application of enzyme-activating prodrugs, which is also detrimental to the effective treatment of HCC. Here, we investigated whether accelerated blood clearance (ABC) phenomenon occurs in HCC models following repeated injections of PEGylated liposomes (PEG-L), thus inducing prodrug accumulation and activation in the liver and exerting highly effective and low-toxicity therapeutic effects on HCC. First, PEGylated liposomal cyclophosphamide was prepared by solvent injection and characterized. Importantly, preinjection of PEG-L induced the ABC phenomenon and activation of CYP3A in both HCC rats and HCC mice by studying the effects of repeated injections of PEG-L on pharmacokinetics and tissue distribution. Next, the efficacy and toxicity of repeated injections of PEG-L in HCC mice were examined, and our data indicate that repeated injections are administered in a manner that significantly enhances the antitumor effect compared with controls, with little or no toxicity to other organs. To further reveal the pharmacokinetic mechanism of PEG-L repeated administration for the treatment of HCC, the protein expression of hepatic CYP3A and the concentration of cyclophosphamide in the liver and spleen of HCC mice by inhibiting CYP3A were analyzed. These results revealed that inducing CYP3A to accelerate the rapid conversion of prodrugs that accumulate significantly in the liver is a key mechanism for the treatment of HCC with repeated injections of PEG-L. Collectively, this work taps into the application potential of the ABC phenomenon and provides new insights into the clinical application of PEGylated nanoformulations. SIGNIFICANCE STATEMENT: This study revealed that repeated injections of PEGylated liposomes could induce the accelerated blood clearance (ABC) phenomenon characterized by hepatic accumulation and CYP3A activation based on hepatocellular carcinoma (HCC) rats and HCC mice. Furthermore, it was verified that induction of the ABC phenomenon dependent on hepatic accumulation and CYP3A activation could enhance the antihepatocellular carcinoma effects of PEGylated anticancer prodrugs in HCC mice. This elucidated the relevant pharmacokinetic mechanisms and unearthed new clues for solving the clinical application of PEGylated nanoparticles.

Co-infusion of CAR T cells with aAPCs expressing chemokines and costimulatory ligands enhances the anti-tumor efficacy in mice.

Chimeric antigen receptor-modified T (CAR-T) cell therapy has shown curable efficacy for treating hematological malignancies, while in solid tumors, the immunosuppressive microenvironment causes poor activation, expansion and survival of CAR-T cells, accounting mainly for the unsatisfactory efficacy. The artificial antigen-presenting cells (aAPCs) have been used for ex vivo expansion and manufacturing of CAR-T cells. Here, we constructed a K562 cell-based aAPCs expressing human epithelial cell adhesion molecule (EpCAM), chemokines (CCL19 and CCL21) and co-stimulatory molecular ligands (CD80 and 4-1BBL). Our data demonstrated that the novel aAPCs enhanced the expansion, and increased the immune memory phenotype and cytotoxicity of CAR-T cells recognizing EpCAM, in vitro. Of note, co-infusion CAR-T and aAPC enhances the infiltration of CAR-T cells in solid tumors, which has certain potential for the treatment of solid tumors Moreover, IL-2-9-21, a cytokine cocktail, prevents CAR-T cells from entering the state of exhaustion prematurely after continuous antigen engagement and boosts the anti-tumor activity of CAR-T cells co-infused with aAPCs. These data provide a new strategy to enhance the therapeutic potential of CAR-T cell therapy for the treatment of solid tumors.

A celastrol-based nanodrug with reduced hepatotoxicity for primary and metastatic cancer treatment.

BACKGROUND: Cancer is the world's leading cause of death and a key hindrance to extending life expectancy. Celastrol, a bioactive compound derived from Tripterygium wilfordii, has been shown to have excellent antitumor activity, but its poor solubility and severe organ toxicity side effects have hampered its clinical application. METHODS: In this study, a self-assembled nanodrug (PLC-NP) was designed to deliver celastrol to tumor sites while efficiently reducing its side effects by conjugating celastrol with the bioactive material LMWH and P-selectin targeting peptide (PSN). Extensive in vitro and in vivo experiments were performed to investigate both therapeutic efficacy and adverse effects. Furthermore, the specific mechanism of the antitumor activity has also been explored. FINDING: The PLC-NP nanodrugs were spherical in shape, with a mean particle size of 115.83 ± 6.93 nm. PLC-NP was sufficiently stable during blood circulation, with a selective target to P-selectin-highly expressed tumor cells, followed by releasing the containing celastrol under acidic environment and high levels of esterase in tumor cells. Both in vitro and in vivo results confirmed that celastrol's antitumor and anti-metastatic abilities were not attenuated and were actually strengthened after being formed into nanodrugs. More importantly, the organ toxicities of the modified celastrol nanodrug were dramatically reduced. Mechanistic study indicated that the inactivation of PI3K/Akt/mTOR signaling pathway and ROS-mediated mitochondrial dysfunction play critical roles in celastrol-mediated autophagy and apoptosis. INTERPRETATION: Our findings could offer a potential strategy for the translation of toxic compounds into clinical therapeutic nanomedicine. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Genomic analysis of chromosomal cointegrated bla NDM-1-carrying ICE and bla RSA-1-carrying IME from clinical multidrug resistant Aeromonas caviae.

Introduction: The objective of this study is to thoroughly analyze the detailed genomic characteristics of clinical strain 211703 of Aeromonas caviae, which co-carrying bla RSA-1 and bla NDM-1 genes. 211703 was isolated from the patient's cerebrospinal fluid drainage sample in a Chinese tertiary hospital. Methods: Carbapenemase NDM was detected by the immunocolloidal gold technique. The MIC values were determined by VITEK2. The whole genome sequence of 211703 was analyzed using phylogenetics, genomic comparison, and extensive dissection. Results: This study revealed that 211703 only contained a single 4.78 Mb chromosome (61.8% GC content), and no plasmids were discovered in 211703. 15 different types of resistant genes were detected in the genome of 211703, including bla RSA-1 harbored on integrative and mobilizable element (IME) Tn7413a, and bla NDM-1 harbored on integrative and conjugative element (ICE). The ICE and IME were all carried on the chromosome of 211703 (c211703). Detailed comparison of related IMEs/ICEs showed that they shared similar conserved backbone regions, respectively. Comprehensive annotation revealed that bla RSA-1 was carried by the gene cassette of a novel integron In2148 on Tn7413a, and bla NDM-1 was captured by an insertion sequence ISCR14-like on the ICE of 211703. We speculated that mobile genetic elements (MGEs) such as ICE and IME facilitated the spread of resistance genes such as bla RSA-1 and bla NDM-1. Discussion: In conclusion, this study provides an overall understanding of the genomic characterization of clinically isolated A. caviae 211703, and an in-depth discussion of multiple acquisition methods of drug resistance genes in Aeromonas. To the best of our knowledge, this is the first report of A. caviae carrying bla RSA-1 even both bla RSA-1 and bla NDM-1, and this is the first bacterium carrying bla RSA-1 isolated from the clinical setting.

Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis.

Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, that is, tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Previous in vivo and in vitro studies of our laboratory found repressing extracellular matrix (ECM) accumulation by restoring the balance between MMPs and TIMPs can alleviate liver fibrosis. We conducted a review of articles published in PubMed and Science Direct in the last decade until February 1, 2023, which were searched for using these words "MMPs/TIMPs" and "Hepatic Fibrosis." Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs. We found the MMP-TIMP-ECM interaction can result in better understanding of the pathogenesis and progression of hepatic fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for hepatic fibrosis. Additionally, we summarized and analyzed the drugs that have been found to reduce liver fibrosis by changing the ratio of MMPs/TIMPs, including medicine natural products.

Mediating role of psychological resilience in the relationship between self-efficacy and professional identity among nurses.

To explore the mediating role of resilience in the relationship between general self-efficacy and professional identity of nurses during the COVID-19 pandemic. A cross-sectional design was employed. A total of 982 nurses from four Grade III, class A hospitals in Shandong Province were investigated using general information questionnaire, nurses' professional identity rating scale, general self-efficacy scale (GSES), and Connor-Davidson flexibility scale (CD-RISC). SPSS22.0 and Amos21.0 were used for data analysis and structural equation modeling. p % counseling The nurses had a score of （27.038±5.933） for general self-efficacy score, 38.290±6.234 for psychological resilience, and （114.99±16.209） for professional identity. A positive correlation between general self-efficacy, professional identity, and psychological resilience (<0.01) was found. The SEM analysis shows that psychological resilience plays a mediating role between general self-efficacy and professional identity. The ratio of the effect is 75.155. During the COVID-19 pandemic, the levels of general self-efficacy and professional identity of nurses was medium, while psychological resilience was high. Nurses' general self-efficacy can affect their professional identity through psychological resilience. During the pandemic, the psychological status of nurses should not be ignored. Nursing managers should fully utilize of group and cognitive therapy based on mindfulness to improve nurses' psychological resilience and general self-efficacy, and to promote nurses' professional identity, so as to ensure the lower turnover rate.

PLGA Nanoparticles Containing VCAM-1 Inhibitor Succinobucol and Chemotherapeutic Doxorubicin as Therapy against Primary Tumors and Their Lung Metastases.

The treatment of malignant tumors is usually accompanied by poor prognosis due to metastasis of tumor cells. Hence, it is crucial to enhance anti-metastasis efficacy when anti-tumor treatments are conducted. It has been reported that the vascular cell adhesion molecule-1 (VCAM-1) is highly expressed on the surface of tumor cells and plays an essential role in the metastasis of tumor cells. Thus, reducing VCAM-1 expression offers hope for inhibiting the metastasis of tumor cells. Evidence has shown that succinobucol (Suc) can selectively and efficiently inhibit VCAM-1 expression. Inspired by these, we designed dual drug-loaded PLGA nanoparticles (Co-NPs) to co-deliver VCAM-1 inhibitor Suc and the chemotherapeutic doxorubicin (Dox) which could both effectively suppress primary melanoma and its lung metastases. Co-NPs were composed of PLGA encapsulated Suc and Dox as hydrophobic cores and DSPE-mPEG2000 as surface modification materials. With an appropriate particle size (122.4 nm) and a negatively charged surface (-6.77 mV) we could achieve prolonged blood circulation. The in vitro experiments showed that Co-NPs had potent cytotoxicity against B16F10 cells and could significantly inhibit VCAM-1 expression and migration of B16F10 cells. Additionally, the in vivo experiments showed that Co-NPs could efficiently suppress not only primary melanoma but also its lung metastases. In conclusion, PLGA nanoparticles containing VCAM-1 inhibitor Suc and chemotherapeutic Dox as therapy against primary tumors and their lung metastases provides a promising drug delivery strategy for the treatment of metastatic malignant tumors.

Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy.

Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzyme's activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human in vitro models and clinical studies, the pharmacokinetics of most anticancer drugs are influenced by the extent of induction or inhibition of CYP3A4-mediated metabolism, and these details are not fully recognized and highlighted. Therefore, this interindividual variability due to genetic and nongenetic factors, together with the narrow therapeutic index of most anticancer drugs, contributes to their unique set of exposures and responses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in individuals. To elucidate the mechanisms of CYP3A4-mediated activation/inactivation of anticancer drugs associated with personalized therapy, this review focuses on the underlying determinants that contribute to differences in CYP3A4 metabolic activity and provides a comprehensive and valuable overview of the significance of these factors, which differs from current considerations for dosing regimens in cancer therapy. We also discuss knowledge gaps, challenges, and opportunities to explore optimal dosing regimens for drug metabolic activation/inactivation in individual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity. SIGNIFICANCE STATEMENT: This review focuses on anticancer drugs that are activated/deactivated by CYP3A4 and highlights outstanding factors affecting the interindividual variability of CYP3A4 activity in order to gain a detailed understanding of CYP3A4-mediated drug metabolism mechanisms. A systematic analysis of available information on the underlying genetic and nongenetic determinants leading to variation in CYP3A4 metabolic activity to predict therapeutic response to drug exposure, maximize efficacy, and avoid unpredictable adverse events has clinical implications for the identification and development of CYP3A4-targeted cancer therapeutics.

Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction.

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4+ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4+ and CD8+ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

Research progress of quality control for the seed of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Suan-Zao-Ren) and its proprietary Chinese medicines.

ETHNOPHARMACOLOGICAL RELEVANCE: Semen Ziziphi Spinosae (SZS), the seed of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Chinese name Suan-Zao-Ren), is widely distributed in China, Laos, Myanmar, and Iran. It is a classic traditional Chinese medicine with sedative and sleeping effects. In clinical practice, there are more than 155 proprietary Chinese medicines containing SZS. However, many commercial SZS products are difficult to qualify using current methods. Moreover, there is a scarcity of quality standards for SZS in proprietary Chinese medicines. AIM OF THE STUDY: The purpose of this study was to clearly reveal the quality indicators during the entire production process of SZS and its products. MATERIALS AND METHODS: This study reviewed more than 230 articles and related books on the quality control of SZS and its proprietary Chinese medicines published over the last 40 years (from January 1979 to October 2022). Moreover, where available, information on the quality of SZS and its proprietary Chinese medicines was also collected from websites for comparison, including online publications (e.g. PubMed, CNKI, Google Scholar, and Web of Science), the information at Yaozhi website and China Medical Information Platform, along with some classic books on Chinese herbal medicine. The literature and information search were conducted using keywords such as "Suan-Zao-Ren", " Ziziphus jujuba" and "quality control", and the latest results from various databases were combined to obtain valid information. The active components, which in vivo exposure, and Q-markers were also summarized. RESULTS: The jujuboside A, jujuboside B, and spinosin were revealed as the key Q-markers for SZS. Moreover, the advancements and prospects of the quality control for SZS and its extract, proprietary Chinese medicines, health foods, and adulterants were comprehensively summarized. The high-performance liquid chromatography-UV/evaporative light scattering detection and fingerprint analysis were found to be the mainstream methods for the SZS quality control. In particular, the novel quality evaluation method based on the unit content was applied for SZS and its proprietary Chinese medicines. Significant fluctuations were found in the contents of Q-markers. Moreover, the mass transfer rule of Q-markers was comprehensively clarified based on the entire production process, including production origins, ripening time, primary process, processing, compatibility decoction/extract, and storage. Ultimately, the crushing and compatibility of SZS were found to be the key steps affecting the active components. CONCLUSIONS: In short, this study provides solid evidences to reveal quality indicators for the entire production process of developing rational quality standards for SZS and its products. Moreover, this study also provides a template quality control overview, which could be extended to other traditional Chinese medicines.

Caffeine in liver diseases: Pharmacology and toxicology.

We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using "caffeine" and "liver disease" as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.

Enhanced anti-breast cancer efficacy of co-delivery liposomes of docetaxel and curcumin.

The successful treatment of breast cancer is hampered by toxicity to normal cells, impaired drug accumulation at the tumor site, and multidrug resistance. We designed a novel multifunctional liposome, CUR-DTX-L, to co-deliver curcumin (CUR) and the chemotherapeutic drug docetaxel (DTX) for the treatment of breast cancer in order to address multidrug resistance (MDR) and the low efficacy of chemotherapy. The mean particle size, polydispersity index, zeta potential, and encapsulation efficiency of CUR-DTX-L were 208.53 ± 6.82 nm, 0.055 ± 0.001, -23.1 ± 2.1 mV, and 98.32 ± 2.37%, respectively. An in vitro release study and CCK-8 assays showed that CUR-DTX-L has better sustained release effects and antitumor efficacy than free drugs, the antitumor efficacy was verified by MCF-7 tumor-bearing mice, the CUR-DTX-L showed better antitumor efficacy than other groups, and the in vivo pharmacokinetic study indicated that the plasma concentration-time curve, mean residence time, and biological half-life time of CUR-DTX-L were significantly increased compared with free drugs, suggesting that it is a promising drug delivery system for the synergistic treatment of breast cancer.