Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but pose a challenge of immune-related adverse events (irAEs), particularly endocrine toxicity, that can severely compromise patient well-being. Existing research has often been limited in scope and has not provided comprehensive safety profiles across the diverse range of ICI therapies. We addressed this gap by performing a network meta-analysis on 55 randomized controlled trials involving 32,522 patients. Using STATA to calculate the surface under the cumulative ranking curve, we ranked the safety of various ICI monotherapies and combination therapies. ICIs were found to increase the risk of endocrine toxicities, such as hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency; this risk was greater with dual ICI regimens. Specifically, cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors, such as ipilimumab, are closely associated with hypophysitis, whereas programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, notably pembrolizumab and nivolumab, predispose patients to thyroid-related dysfunction, such as hyperthyroidism, hypothyroidism, and thyroiditis. Interestingly, nivolumab showed no elevated risk of adrenal dysfunction, in contrast to the elevated risk observed with other ICI treatments. This study provides critical evidence-based insights for optimizing the risk-benefit balance of ICI therapies in clinical practice.

Elevated cellular oxidative stress is a common marker of cancer cell dysregulation caused by malignant transformation. Thioredoxin reductase (TrxR, encoded by TXNRD) is a crucial enzyme that regulates cellular oxidative stress and the survival of many types of cancer cells. Therefore, targeting TrxR may lead to selective cell death in cancer cells. Pristimerin, a plant triterpenoid, increases the accumulation of reactive oxygen species (ROS) in cells, but its specific regulatory mechanism is unclear. Herein, we found that pristimerin selectively targets TrxR and subsequently induces apoptosis in human non-small cell lung cancer cells, and inhibits tumor growth in vivo with low toxicity to normal cells. Pristimerin was found to inhibit cancer cell growth primarily by inhibiting cellular TrxR, thereby compromising TrxR’s antioxidant function in cells and resulting in the accumulation of oxidized Trx. Furthermore, excessive ROS accumulation stimulated by pristimerin triggered tumor-specific amplification of oxidative stress in cancer cells and ultimately led to targeted destruction of cancer cells. Our data may support the development of potential therapeutic molecules as selective anticancer agents targeting highly enriched TrxR in cancer cells.

The 3C-like protease (3CLpro) is a crucial target in anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) drug design. Herein, we performed high-throughput synthesis of catechol derivatives from the bioactive catechol-terminal alkyne scaffold A4, by using modular click chemistry. Subsequently, we conducted two rounds of SARS-CoV-2 3CLpro inhibition screening and selected seven compounds for synthesis and further efficacy validation. Compound P1-E11 had potent inhibitory effects toward SARS-CoV-2 3CLpro (IC50 = 2.54 ± 0.46 μM); exhibited good selectivity toward the human cysteine proteases cathepsins B and L; and demonstrated superior anti-SARS-CoV-2 potency (EC50 = 4.66 ± 0.58 μM) with low cytotoxicity (CC50 > 100 μM) in A549-hACE2-TMPRSS2 cells. The irreversible covalent mechanism of P1-E11 was confirmed through time-dependent experiments, enzyme kinetic studies, and dilution and dialysis assays. The binding affinity between P1-E11 and SARS-CoV-2 3CLpro with a KD value of 0.57 μM was validated through surface plasmon resonance (SPR) experiments. Molecular docking provided insights into the binding mode of P1-E11 to the target protein. This study demonstrated the feasibility and efficacy of modular click reactions in natural-product-based structural modifications and presents a novel approach for leveraging this strategy in antiviral drug discovery.

Ribonucleic acid for injection II is a clinical adjuvant cancer therapy treatment based on immunotherapy, which exerts its effects by enhancing immune function and suppressing tumor growth. However, the mechanism underlying the ameliorative effect on immunosuppressed hematopoietic dysfunction remains unclear. This study confirmed the immune-boosting and hematopoietic-promoting effects of ribonucleic acid for injection II, which has a wide distribution of molecular weights and is rich in amino acids and nucleotides. Ribonucleic acid for injection II influences the gut microbiota and serum metabolites to enhance immunity in immunosuppressed mice induced by CTX, while also mitigating bone marrow injury and increasing hematopoietic cells through mediating macrophage M1 differentiation, thereby improving hematopoietic dysfunction in mice.

Acute lymphoblastic leukemia (ALL) is a malignant disease of the hematologic system. The current treatment is based on chemotherapeutic drugs, which are becoming less effective due to drug resistance. TNF-related apoptosis-inducing ligand (TRAIL) is an apoptotic protein used to treat cancer that does not affect healthy cells. In recent years, however, ALL cells (e.g., U937) have become more resistant to TRAIL. A novel andrographolide derivative (AND7) with high efficiency and low toxicity was synthesized and combined with TRAIL after the optimal combination ratio was screened using U937 cells. We used peripheral blood mononuclear cells (PBMCs) from patients before the initial treatment of ALL as a model and PBMCs from healthy subjects as a control to determine the mechanism underlying ALL treatment. AND7/TRAIL combination treatment was shown to prevent the original TRAIL-resistant cells from activating the caspase-8/caspase-3 pathway through DR4/DR5 and promote apoptosis via expression of ROS and the apoptotic gene, P53, to achieve an anti-cancer effect. Notably, this study demonstrated that the AND7/TRAIL combination enhanced the anti-cancer effect of AND7 and improved TRAIL resistance. Therefore, the AND7/TRAIL combination is promising for treating ALL and lays the foundation for clinical research.

G protein-coupled receptors (GPCRs) are important, potential drug targets for the treatment of metabolic disorders, such as obesity. GPCRs crosstalk with several transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. GPCR-biased agonism has raised the potential of novel drug development to preferentially activate therapeutic signaling pathways over pathways that lead to unwanted side effects. The obesity epidemic and its metabolic complications continue to be a major global public health threat but effective treatments are limited. The accelerated development of structural techniques, like X-ray crystallography and cryo-electron microscopy, has paved the way to understanding how biased agonism measured at GPCRs results in specific downstream physiologic responses. Herein some well-validated GPCR targets are briefly summarized and several new and promising receptors for obesity treatment are outlined. This review highlights the significance of deciphering the role of GPCRs in obesity pathology and biased signaling for drug development. We anticipate the review will facilitate the development of novel GPCR-targeted anti-obesity drugs that lead to heightened therapeutic efficacy with decreased side effect profiles.

Endocrine therapy which blocking the signaling of estrogen receptor, has long been effective for decades as a primary treatment choice for breast cancer patients expressing ER. However, the issue of drug resistance poses a significant clinical challenge. It's critically important to create new therapeutic agents that can suppress ERα activity, particularly in cases of ESR1 mutations. This review highlights recent efforts in drug development of next generation ER-targeted agents, including oral selective ER degraders (SERDs), proteolysis targeting chimera (PROTAC) ER degraders, other innovative molecules such as complete estrogen receptor antagonists (CERANs) and selective estrogen receptor covalent antagonists (SERCAs). The drug design, efficacy and clinical trials for each compound were detailed.

Chemoresistance to gemcitabine (Gem) remains a substantial obstacle in the treatment of pancreatic ductal adenocarcinoma carcinoma (PDAC). Nrf2, a transcription factor responsive to oxidative stress, has been implicated as a key contributor to chemoresistance. Previous studies have demonstrated anti-tumor effects of brusatol (BRT) in PDAC. Herein, we aimed to investigate the efficacy of BRT in enhancing chemosensitivity to Gem and to elucidate the underlying mechanisms involving Nrf2. Gain- and-loss-of-function experiments revealed that Nrf2 exacerbated Gem chemoresistance in PDAC cells. Additionally, BRT effectively inhibited PDAC cell proliferation and enhanced Gem chemosensitivity. Mechanistic investigations demonstrated that BRT sensitized PDAC cells to Gem by suppressing Nrf2 at the transcriptional level. Activation of Nrf2 conteracted BRT’s effects on chemosensitivity. In contrast, combination treatment with Nrf2 silencing and BRT demonstrated a more potent inhibitory effect on Gem in vitro and in vivo, thereby indicating the Nrf2 dependence of BRT action. These findings highlight BRT’s ability to enhance Gem chemosensitivity by inhibiting Nrf2 signaling in PDAC; therefore, BRT may serve as a potential adjuvant therapy for PDAC.

Cancer is the leading cause of morbidity and mortality worldwide and is an important barrier to lengthening life expectancy in every country. Natural products are receiving increased attention from researchers globally and increasing numbers of natural products are approved for clinical studies involving cancer in recent years. To gain more insight into natural products that have undergone clinical trials for cancer treatment, a comprehensive search was conducted. The https://clinicaltrials.gov website was searched for relevant clinical trials and natural product information up to December 2022. The search terms included different types of cancers, such as colorectal, lung, breast, gynecologic, kidney, bladder, melanoma, pancreatic, hepatocellular, gastric and haematologic. Then, PubMed and Web of Science were searched for relevant articles up to February 2024. Hence, we listed existing clinical trials about natural products used in the treatment of cancers and discussed the preclinical and clinical studies of some promising natural products and their targets, indications, and underlying mechanisms of action. Our intent was to provide basic information to readers who are interested or majoring in natural products and obtain a deeper understanding of the progress and actions of natural product mechanisms of action.