Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer.

Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.

NPCDR: natural product-based drug combination and its disease-specific molecular regulation.

Natural product (NP) has a long history in promoting modern drug discovery, which has derived or inspired a large number of currently prescribed drugs. Recently, the NPs have emerged as the ideal candidates to combine with other therapeutic strategies to deal with the persistent challenge of conventional therapy, and the molecular regulation mechanism underlying these combinations is crucial for the related communities. Thus, it is urgently demanded to comprehensively provide the disease-specific molecular regulation data for various NP-based drug combinations. However, no database has been developed yet to describe such valuable information. In this study, a newly developed database entitled 'Natural Product-based Drug Combination and Its Disease-specific Molecular Regulation (NPCDR)' was thus introduced. This database was unique in (a) providing the comprehensive information of NP-based drug combinations & describing their clinically or experimentally validated therapeutic effect, (b) giving the disease-specific molecular regulation data for a number of NP-based drug combinations, (c) fully referencing all NPs, drugs, regulated molecules/pathways by cross-linking them to the available databases describing their biological or pharmaceutical characteristics. Therefore, NPCDR is expected to have great implications for the future practice of network pharmacology, medical biochemistry, drug design, and medicinal chemistry. This database is now freely accessible without any login requirement at both official (https://idrblab.org/npcdr/) and mirror (http://npcdr.idrblab.net/) sites.

The Extraction, Determination, and Bioactivity of Curcumenol: A Comprehensive Review.

Curcuma wenyujin is a member of the Curcuma zedoaria (zedoary, Zingiberaceae) family, which has a long history in traditional Chinese medicine (TCM) due to its abundant biologically active constituents. Curcumenol, a component of Curcuma wenyujin, has several biological activities. At present, despite different pharmacological activities being reported, the clinical usage of curcumenol remains under investigation. To further determine the characteristics of curcumenol, the extraction, determination, and bioactivity of the compound are summarized in this review. Existing research has reported that curcumenol exerts different pharmacological effects in regard to a variety of diseases, including anti-inflammatory, anti-oxidant, anti-bactericidal, anti-diabetic, and anti-cancer activity, and also ameliorates osteoporosis. This review of curcumenol provides a theoretical basis for further research and clinical applications.

Nanomaterial Delivery Vehicles for the Development of Neoantigen Tumor Vaccines for Personalized Treatment.

Tumor vaccines have been considered a promising therapeutic approach for treating cancer in recent years. With the development of sequencing technologies, tumor vaccines based on neoantigens or genomes specifically expressed in tumor cells, mainly in the form of peptides, nucleic acids, and dendritic cells, are beginning to receive widespread attention. Therefore, in this review, we have introduced different forms of neoantigen vaccines and discussed the development of these vaccines in treating cancer. Furthermore, neoantigen vaccines are influenced by factors such as antigen stability, weak immunogenicity, and biosafety in addition to sequencing technology. Hence, the biological nanomaterials, polymeric nanomaterials, inorganic nanomaterials, etc., used as vaccine carriers are principally summarized here, which may contribute to the design of neoantigen vaccines for improved stability and better efficacy.

ß-Elemene enhances erlotinib sensitivity through induction of ferroptosis by upregulating lncRNA H19 in EGFR-mutant non-small cell lung cancer.

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. ß-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that ß-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that ß-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Synthesis and Spectroscopic Properties of Selenophene[3, 2-b]-Fused BODIPYs.

Fusion selenophene endows the chromophore with more intrinsic and special functions. Herein, nonsymmetric selenophene-fused BODIPYs were designed and synthesized starting from the selenophene unit. The fused ring of selenophene not only maintains the rigid structure of BODIPY but also further modulates its spectral properties. The newly prepared dyes possessed many promising properties including large molar extinction coefficients, low fluorescence quantum yields, and moderate singlet oxygen generation. Quantum calculations affirmed that the smaller singlet-triplet energy gap and larger spin-orbit coupling cause efficient intersystem crossing, thus enhancing the singlet oxygen generation yield. Furthermore, selenophene-fused BODIPY exhibited significant phototoxicity with negligible dark cytotoxicity, based on the fluorescence imaging of the reactive oxygen species detection experiment.

In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment.

The treatment of diabetic ulcer (DU) remains a major clinical challenge due to the complex wound-healing milieu that features chronic wounds, impaired angiogenesis, persistent pain, bacterial infection, and exacerbated inflammation. A strategy that effectively targets all these issues has proven elusive. Herein, we use a smart black phosphorus (BP)-based gel with the characteristics of rapid formation and near-infrared light (NIR) responsiveness to address these problems. The in situ sprayed BP-based gel could act as 1) a temporary, biomimetic "skin" to temporarily shield the tissue from the external environment and accelerate chronic wound healing by promoting the proliferation of endothelial cells, vascularization, and angiogenesis and 2) a drug "reservoir" to store therapeutic BP and pain-relieving lidocaine hydrochloride (Lid). Within several minutes of NIR laser irradiation, the BP-based gel generates local heat to accelerate microcirculatory blood flow, mediate the release of loaded Lid for "on-demand" pain relief, eliminate bacteria, and reduce inflammation. Therefore, our study not only introduces a concept of in situ sprayed, NIR-responsive pain relief gel targeting the challenging wound-healing milieu in diabetes but also provides a proof-of-concept application of BP-based materials in DU treatment.

Roles of lncRNAs in pancreatic ductal adenocarcinoma: Diagnosis, treatment, and the development of drug resistance.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, primarily due to its late diagnosis, high propensity to metastasis, and the development of resistance to chemo-/radiotherapy. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are intimately involved in the treatment resistance of pancreatic cancer cells via interacting with critical signaling pathways and may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. DATA SOURCES: We carried out a systematic review on lncRNAs-based research in the context of pancreatic cancer and presented an overview of the updated information regarding the molecular mechanisms underlying lncRNAs-modulated pancreatic cancer progression and drug resistance, together with their potential value in diagnosis, prognosis, and treatment of PDAC. Literature mining was performed in PubMed with the following keywords: long non-coding RNA, pancreatic ductal adenocarcinoma, pancreatic cancer up to January 2022. Publications relevant to the roles of lncRNAs in diagnosis, prognosis, drug resistance, and therapy of PDAC were collected and systematically reviewed. RESULTS: LncRNAs, such as HOTAIR, HOTTIP, and PVT1, play essential roles in regulating pancreatic cancer cell proliferation, invasion, migration, and drug resistance, thus may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. They participate in tumorigenesis mainly by targeting miRNAs, interacting with signaling molecules, and involving in the epithelial-mesenchymal transition process. CONCLUSIONS: The functional lncRNAs play essential roles in pancreatic cancer cell proliferation, invasion, migration, and drug resistance and have potential values in diagnosis, prognostic prediction, and treatment of PDAC.

N,O-Chelated Organoboron Complexes with Seven-Membered Rings.

Organoboron complexes have gained considerable attention owing to their versatile chemical structures and excellent optical properties. Nevertheless, stable seven-membered organoboron complexes have rarely been reported because of their challenging synthesis. Herein, seven-membered N,O-boron-chelated dyes, whose photophysical properties have been thoroughly studied via spectroscopic tests and theoretical calculations, were synthesized from commercially available materials via a facile method. Single-crystal X-ray diffraction studies provided evidence of their seven-membered ring N,O-boron-chelated skeleton. These complexes produced singlet oxygen species under laser irradiation, endowing them with potential application as a photosensitizer to treat superficial tumors (B16 cells). Our study provided a new skeleton to construct versatile organoboron compounds and offered a strategy to design heavy-atom-free photosensitizers.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

2D Monoelemental Germanene Quantum Dots: Synthesis as Robust Photothermal Agents for Photonic Cancer Nanomedicine.

As a new family member of the emerging two-dimensional (2D) monoelemental materials (Xenes), germanene has shown promising advantages over the prototypical 2D Xenes, such as black phosphorus (BP) and graphene. However, efficient manufacture of novel germanene nanostructures is still a challenge. Herein, a simple top-down approach for the liquid-exfoliation of ultra-small germanene quantum dots (GeQDs) is presented. The prepared GeQDs possess an average lateral size of about 4.5 nm and thickness of about 2.2 nm. The functionalized GeQDs were demonstrated to be robust photothermal agents (PTAs) with outstanding photothermal conversion efficacy (higher than those of graphene and BPQDs), superior stability, and excellent biocompatibility. As a proof-of-principle, 2D GeQDs-based PTAs were used in fluorescence/photoacoustic/photothermal-imaging-guided hyperpyrexia ablation of tumors. This work could expand the application of 2D germanene to the field of photonic cancer nanomedicine.

Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment.

Metformin, a biguanide derivative that is widely used for treating type 2 diabetes mellitus, has recently been shown to exert potential anticancer effects. Many retrospective data and laboratory studies suggest the idea that metformin has antineoplastic activity, but some other studies reach conflicting conclusions. Although the precise molecular mechanisms by which metformin affects various cancers have not been fully elucidated, activation of AMPK-dependent and AMPK-independent pathways along with energy metabolism aberration, cell cycle arrest and apoptosis or autophagy induction have emerged as crucial regulators in this process. In this Review, we describe the role of metformin in the prevention and treatment of a variety of cancers and summarize the molecular mechanisms that are currently well documented in the ability of metformin as an anticancer agent. In addition, the scientific and clinical hurdles regarding the potential role of metformin in cancer will be discussed.

Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers.

Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ∼95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours.

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies.

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

Active metabolites combination therapies: towards the next paradigm for more efficient and more scientific Chinese medicine.

Traditional Chinese medicine (TCM) formulae have been studied extensively in various human diseases and have proven to be effective due to their multi-component, multi-target advantage. However, its active metabolites are not clear and the specific mechanisms are not well established, which limits its scientific application. Recently, combination therapies are attracting increasing attention from the scientific community in the past few years and are considered as the next paradigm in drug discovery. Here, we tried to define a new concept of "active metabolites combination therapies (AMCT)" rules to elucidate how the bioactive metabolites from TCMs to produce their synergistic effects in this review. The AMCT rules integrate multidisciplinary technologies like molecular biology, biochemistry, pharmacology, analytical chemistry and pharmacodynamics, etc. Meanwhile, emerging technologies such as multi-omics combined analysis, network analysis, artificial intelligence conduce to better elucidate the mechanisms of these combination therapies in disease treatment, which provides new insights for the development of novel active metabolites combination drugs. AMCT rules will hopefully further guide the development of novel combination drugs that will promote the modernization and international needs of TCM.

ß-Elemene Reverses Gefitinib Resistance in NSCLC Cells by Inhibiting lncRNA H19-Mediated Autophagy.

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. ß-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between ß-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether ß-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and ß-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of ß-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, ß-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, ß-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. ß-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation.

BACKGROUND: Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. METHODS: Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. RESULTS: The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties' markers, KLF4 and OCT4, in these cell lines. CONCLUSION: Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.

Honokiol enhances the sensitivity of cetuximab in KRASG13D mutant colorectal cancer through destroying SNX3-retromer complex.

Rationale : the proto-oncogene KRAS is frequently mutated in colorectal cancer (CRC), leading to inherent resistance against monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), such as cetuximab. Therefore, addressing the primary resistance and expanding the indications for target therapy have become critical challenges. Methods : the screening of a natural product library against KRAS mutant CRC cells was conducted, leading to the discovery of a small molecule compound that sensitive to the KRASG13D mutation site. The anti-tumor activity of this small molecule compound in combination with cetuximab was evaluated using the KRASG13D mutant CRC models both in vivo and in vitro. This evaluation includes an examination of its effects on cell proliferation, viability, apoptosis, cell cycle progression, and tumor growth. Furthermore, RNA sequencing, western blot analysis, immunofluorescence, real-time quantitative PCR, and pull-down assays were employed to explore the molecular mechanisms underlying the synergistic anti-tumor effect of this small molecule compound in combination with cetuximab. Results : our study screened 882 compounds in KRAS mutant CRC cells and identified honokiol, a small molecule compound that exhibits specific sensitivity to KRASG13D mutant CRC cells. Furthermore, we revealed that the synergistic augmentation of cetuximab's sensitivity in vivo and in vitro models of KRASG13D mutant CRC in combination with honokiol. Mechanistically, honokiol suppresses SNX3-retromer mediated trafficking, thereby impeding lysosomal proteolytic capacity and inhibiting autophagy and macropinocytosis fluxes. Moreover, honokiol inhibits the conversion of RAS GDP to RAS GTP, heightening the susceptibility of KRASG13D CRC mutant cells to cetuximab. Conclusions : honokiol enhances the sensitivity of cetuximab by destroying SNX3 retromer in KRASG13D mutant CRC preclinical model. These findings present a promising strategy for expanding the indications of target therapy in KRAS mutant colorectal cancer patients.

Natural products for enhancing the sensitivity or decreasing the adverse effects of anticancer drugs through regulating the redox balance.

Redox imbalance is reported to play a pivotal role in tumorigenesis, cancer development, and drug resistance. Severe oxidative damage is a general consequence of cancer cell responses to treatment and may cause cancer cell death or severe adverse effects. To maintain their longevity, cancer cells can rescue redox balance and enter a state of resistance to anticancer drugs. Therefore, targeting redox signalling pathways has emerged as an attractive and prospective strategy for enhancing the efficacy of anticancer drugs and decreasing their adverse effects. Over the past few decades, natural products (NPs) have become an invaluable source for developing new anticancer drugs due to their high efficacy and low toxicity. Increasing evidence has demonstrated that many NPs exhibit remarkable antitumour effects, whether used alone or as adjuvants, and are emerging as effective approaches to enhance sensitivity and decrease the adverse effects of conventional cancer therapies by regulating redox balance. Among them are several novel anticancer drugs based on NPs that have entered clinical trials. In this review, we summarize the synergistic anticancer effects and related redox mechanisms of the combination of NPs with conventional anticancer drugs. We believe that NPs targeting redox regulation will represent promising novel candidates and provide prospects for cancer treatment in the future.

Zinc Transporters Serve as Prognostic Predictors and their Expression Correlates with Immune Cell Infiltration in Specific Cancer: A Pan-cancer Analysis.

The disruption of zinc (Zn) homeostasis has been implicated in cancer development and progression through various signaling pathways. Maintaining intracellular zinc balance is crucial in the context of cancer. Human cells rely on two families of transmembrane transporters, SLC30A/ZNT and SLC39A/ZIP, to coordinate zinc homeostasis. While some ZNTs and ZIPs have been linked to cancer progression, limited information is available regarding the expression patterns of zinc homeostasis-related genes and their potential roles in predicting prognosis and developing therapeutic strategies for specific cancers. In this study, a systematic analysis was conducted to examine the expression of all genes from the SLC30A and SLC39A families at both mRNA and protein levels across different cancers. As a result, three SLC39A genes (SLC39A1, SLC39A4, and SLC39A8) were found to be significantly dysregulated in specific cancers, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), liver hepatocellular carcinoma (LIHC), pancreatic adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP). Moreover, the dysregulation of these genes was tightly associated with the prognosis of patients with those cancers. Furthermore, we found that the gene SLC39A8 exhibited the lowest mutation frequency in KIRP, whereas mutations in SLC39A4 were found to significantly impact overall survival (OS), disease-free (DF), and progress-free survival (PFS) in cancer patients, particularly in those with PAAD. Additionally, immune infiltration analysis revealed that SLC39A1, SLC39A4, and SLC39A8 may function as immune regulators in cancers. This provides new insights into understanding the complex relationship between zinc homeostasis and cancer progression.