Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

Astragali radix (Huangqi): a time-honored nourishing herbal medicine.

Astragali radix (AR, namded Huangqi in Chinese) is the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. As a widely used ethnomedicine, the biological activities of AR include immunomodulatory, anti-hyperglycemic, anti-oxidant, anti-aging, anti-inflammatory, anti-viral, anti-tumor, cardioprotective, and anti-diabetic effects, with minimum side effects. Currently, it is known that polysaccharides, saponins, and flavonoids are the indispensable components of AR. In this review, we will elaborate the research advancements of AR on ethnobotany, ethnopharmacological practices, phytochemicals, pharmacological activities, clinical uses, quality control, production developments, and toxicology. The information is expected to assist clinicians and scientists in developing useful therapeutic medicines with minimal systemic side effects.

METTL3 regulates M6A methylation-modified EBV-pri-miR-BART3-3p to promote NK/T cell lymphoma growth.

OBJECTIVE: N6-methyladenosine (M6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of M6A modification. Methyltransferase promote the processing of mature miRNA in an M6A-dependent manner, thereby participating in disease occurrence and development. However, the regulatory mechanism of M6A in NK/T cell lymphoma (NKTCL) remains unclear. PATIENTS AND METHODS: We determined the expression of METTL3 and its correlation with clinicopathological features using qRT-PCR and immunohistochemistry. We evaluated the effects of METTL3 on NKTCL cells using dot blot assay, CCK8 assay and subcutaneous xenograft experiment. We then applied M6A sequencing combined with gene expression omnibus data to screen candidate targets of METTL3. Finally, we investigated the regulatory mechanism of METTL3 in NKTCL by methylated RNA immunoprecipitation and RNA immunoprecipitation (RIP) assays. RESULTS: We demonstrated that METTL3 was highly expressed in NKTCL cells and tissues and indicated poor prognosis. The METTL3 expression was associated with NKTCL survival. Functionally, METTL3 promoted the proliferation capability of NKTCL cells in vitro and in vivo. Furthermore, EBV-miR-BART3-3p was identified as the downstream effector of METTL3, and silencing EBV-miR-BART3-3p inhibited the proliferation of NKTCL. Finally, we confirmed that PLCG2 as a target gene of EBVmiR-BART3-3p by relative assays. CONCLUSIONS: We identified that METTL3 is significantly up-regulated in NKTCL and promotes NKTCL development. M6A modification contributes to the progression of NKTCL via the METTL3/EBV-miR-BART3-3p/PLCG2 axis. Our study is the first to report that M6A methylation has a critical role in NKTCL oncogenesis, and could be a potential target for NKTCL treatment.

Electroacupuncture facilitates vascular normalization by inhibiting Glyoxalase1 in endothelial cells to attenuate glycolysis and angiogenesis in triple-negative breast cancer.

Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell metabolism. This study highlights the underexplored therapeutic potential of peri-tumoral electroacupuncture, a globally accepted non-pharmacological intervention for TNBC, and molecular mechanisms. Our study showed that peri-tumoral electroacupuncture effectively reduced the density of microvasculature and enhanced vascular functionality in 4T1 breast cancer xenografts, with optimal effects on day 3 post-acupuncture. The timely integration of peri-tumoral electroacupuncture amplified the anti-tumor efficacy of paclitaxel. Multi-omics analysis revealed Glyoxalase 1 (Glo1) and the associated methylglyoxal-glycolytic pathway as key mediators of electroacupuncture-induced vascular normalization. Peri-tumoral electroacupuncture notably reduced Glo1 expression in the endothelial cells of 4T1 xenografts. Using an in vivo matrigel plug angiogenesis assay, we demonstrated that either Glo1 knockdown or electroacupuncture inhibited angiogenesis. In contrast, Glo1 overexpression increased blood vessel formation. In vitro pharmacological inhibition and genetic knockdown of Glo1 in human umbilical vein endothelial cells inhibited proliferation and promoted apoptosis via downregulating the methylglyoxal-glycolytic pathway. The study using the Glo1-silenced zebrafish model further supported the role of Glo1 in vascular development. This study underscores the pivotal role of Glo1 in peri-tumoral electroacupuncture, spotlighting a promising avenue for enhancing vascular normalization and improving TNBC treatment outcomes.

Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies.

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.

The role of ABCC10/MRP7 in anti-cancer drug resistance and beyond.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Natural products for combating multidrug resistance in cancer.

Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery.

Therapeutic challenges in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies. Compared to our knowledge of B-cell tumors, our understanding of T-cell leukemia and lymphoma remains less advanced, and a significant number of patients are diagnosed with advanced stages of the disease. Unfortunately, the development of drug resistance in tumors leads to relapsed or refractory peripheral T-Cell Lymphomas (r/r PTCL), resulting in highly unsatisfactory treatment outcomes for these patients. This review provides an overview of potential mechanisms contributing to PTCL treatment resistance, encompassing aspects such as tumor heterogeneity, tumor microenvironment, and abnormal signaling pathways in PTCL development. The existing drugs aimed at overcoming PTCL resistance and their potential resistance mechanisms are also discussed. Furthermore, a summary of ongoing clinical trials related to PTCL is presented, with the aim of aiding clinicians in making informed treatment decisions.

The pharmacological effects and safety of the raw and prepared folium of Epimedium brevicornu Maxim. on improving kidney-yang deficiency syndrome and sexual dysfunction.

Background: Kidney-Yang deficiency syndrome (KDS) is a group of diseases related to hypothalamic-pituitary-adrenal (HPA) axis and sexual dysfunction. The folium of Epimedium brevicornu Maxim. (FEB) includes raw and prepared slices, named RFEB and PFEB, respectively. PFEB is traditionally believed to be good for tonifying kidney-Yang and improving sexual dysfunction. However, there are few studies comparing the pharmacological effects of RFEB and PFEB, and their underlying mechanisms. In this study, we aimed to compare the effects and safety of RFEB and PFEB on the HPA axis and sexual function. Additionally, the mechanisms of their roles in relation to the neuroendocrine-immune (NEI) network in the KDS model mice were explored. Methods: Male adult C57BL/6 mice were treated with corticosterone to establish a KDS mouse model, and RFEB and PFEB were administered intragastrically. Corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), testosterone levels and oxidative damage indexes were measured. The mRNA and protein levels of CRH and ACTH in hypothalamus and pituitary, endothelial nitric oxide synthase (eNOS) and phosphodiesterase 5 (PDE5) in corpus cavernosum were examined. TNFα, IL-6, NF-κB, eNOS and PDE5 were investigated in mouse corpus cavernosum. Results: Our results showed that PFEB was more effective than RFEB in increasing corticosterone-suppressed ACTH levels, enhancing CRH levels and cAMP/cGMP ratio, and reducing oxidative damage. In vivo, PFEB significantly increased eNOS and inhibited PDE5 expression in corpus cavernosum. PFEB showed stronger protective effect on normal spleen lymphocytes from apoptosis both in vitro and in vivo. Additionally, it noticeably inhibited the levels of inflammatory cytokines in corpus cavernosum. Both RFEB and PFEB were safe and did not cause any clinical signs of toxicity in mice at the dosage of 20 times dosages of that in the Chinese Pharmacopeia. Conclusion: We demonstrated that PFEB was better than RFEB at tonifying the kidney-Yang by comparing their effects on improving the NEI network, which includes the HPA axis, immune system and corpus cavernosum. This study revealed that PFEB could significantly improve the sexual function of KDS mice by regulating the HPA axis and activating the immune system through the NEI network.

Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum.

AIMS: We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the Kelch13 C580Y mutation. METHODS: Using fluorescence labeling and activity-based protein profiling, we systematically profile the ART activation levels in P. falciparum during the entire intra-erythrocytic developmental cycle (IDC), and determined the ART-targets profile of the ART-sensitive and -resistant strains at different stages. We retrieved and integrated datasets of single-cell transcriptomics and label-free proteomics across three IDC stages of wild-type P. falciparum. We also employed lipidomics to validate lipid metabolic reprogramming in the resistant strain. RESULTS: The activation and expression patterns of genes and proteins of ART-targets in both ART-sensitive and resistant strains varied at different stages and periods of P. falciparum development, with the late trophozoite stage harboring the largest number of ART targets. We identified and validated 36 overlapping targets, such as GAPDH, EGF-1a, and SpdSyn, during the IDC stages in both strains. We revealed the ART-insensitivity of fatty acid-associated activities in the partially resistant strain at both the early ring and early trophozoite stages. CONCLUSIONS: Our multi-omics strategies provide novel insights into the mechanisms of ART partial resistance in Kelch13 mutant P. falciparum, demonstrating the stage-specific interaction between ART and malaria parasites.

CAR T-Cell therapy for the management of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin lymphoma (NHL) of mature B-cells characterized by translocation, which is typically due to excess expression of Cyclin D1. Although with the progress in our knowledge of the causes for MCL and available treatments for MCL, this cancer is still incurable. Age, male gender, rapid advancement, significant nodal involvement, elevated serum lactate dehydrogenase level, and prognostic indications including increased expression of Ki-67 and presence of TP53 mutation, are symbols of poor outcome. Advanced immunotherapy using chimeric antigen receptor (CAR)-T cells is advantageous for patients suffering from B-cell malignancies and MCL. Targeting B-cell antigens on the cell surface is a feasible approach in re-occurring (R/R) MCL because of significant responses obtained in other B-cell cancers. USFDA has approved brexucabtagene autoleucel (Tecartus, KTE-X19), a novel CAR T-cell therapy to be used in patients with MCL who have not responded to previous treatments or have relapsed. The FDA approved this new treatment depending on the outcomes of the ZUMA-2 clinical trial. Serious adverse reactions, moderate anti-tumor activity, allergen withdrawal, antigen escape, limited tumor infiltration, and trafficking are major barriers to successful CAR T-cell therapy. This review is a brief synopsis of the development of CAR T-cell therapy for MCL.

Association of lung-intestinal microecology and lung cancer therapy.

In recent years, the incidence of lung cancer is increasing. Lung cancer has become one of the most malignant tumors with the highest incidence in the world, which seriously affects people's health. The most important cause of death of lung cancer is metastasis. Therefore, it is crucial to understand the mechanism of lung cancer progression and metastasis. This review article discusses the physiological functions, pathological states and disorders of the lung and intestine based on the concepts of traditional Chinese medicine (TCM), and analyzes the etiology and mechanisms of lung cancer formation from the perspective of TCM. From the theory of "the exterior and interior of the lung and gastrointestinal tract", the theory of "the lung-intestinal axis" and the progression and metastasis of lung cancer, we proposed e "lung-gut co-treatment" therapy for lung cancer. This study provides ideas for studying the mechanism of lung cancer and the comprehensive alternative treatment for lung cancer patients.

Current therapy and drug resistance in metastatic castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC), especially metastatic castration-resistant prostate cancer (mCRPC) is one of the most prevalent malignancies and main cause of cancer-related death among men in the world. In addition, it is very difficult for clinical treatment because of the natural or acquired drug resistance of CRPC. Mechanisms of drug resistance are extremely complicated and how to overcome it remains an urgent clinical problem to be solved. Thus, a comprehensive and thorough understanding for mechanisms of drug resistance in mCRPC is indispensable to develop novel and better therapeutic strategies. In this review, we aim to review new insight of the treatment of mCRPC and elucidate mechanisms governing resistance to new drugs: taxanes, androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Most importantly, in order to improve efficacy of these drugs, strategies of overcoming drug resistance are also discussed based on their mechanisms respectively.

Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase.

High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound D26, which exerted a strong antiproliferative effect on several cancer cells and decreased mitochondrial-related genes expression. In addition, mechanism studies demonstrated that D26 arrested cell cycle at the G1 phase and had no effect on apoptosis, depolarized mitochondria, or reactive oxidative stress generation in A2780 cells. Importantly, D26 exhibited more potent anticancer activity than the lead IMT1B in A2780 xenograft nude mice and had no observable toxic effect. All results suggest that D26 deserves to be further investigated as a potent and safe antitumor candidate.

Exosomal circular RNAs: A chief culprit in cancer chemotherapy resistance.

Chemotherapy is one of the primary treatments for malignant tumors. However, the acquired drug resistance hinders clinical efficacy and leads to treatment failure in most patients. Exosomes are cell-derived vesicles with a diameter of 30-150 nm carrying and delivering substances such as DNAs, RNAs, lipids, and proteins for cellular communication in tumor development. Circular RNAs (circRNAs) present covalently closed-loop RNA structures, which regulate tumor cell proliferation, apoptosis, and metastasis by controlling different genes and signaling pathways. CircRNAs are abundant and stably expressed in exosomes. Recent studies have shown that they play critical roles in chemotherapy resistance in various cancers. In this review, we summarized the origin of exosomes and discussed the regulation mechanism of exosomal circRNAs in cancer drug resistance.