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The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the 'C' subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called multidrug resistance proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C4 and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed. [ABSTRACT FROM AUTHOR]

In the context of globalization, the integration of cultural elements into scientific research, particularly through the incorporation of traditional Chinese cultural motifs in scientific illustrations, represents a novel frontier in enhancing the universality and appeal of scientific discoveries. This paper explores the innovative practice of embedding traditional Chinese cultural elements into scientific paper illustrations, highlighting its significant role in augmenting the global appeal of research findings, promoting diversity and innovation in scientific inquiry, and facilitating cross-cultural understanding. Through a series of case studies, including symbolic representations of ancient myths and the use of traditional themes to elucidate complex scientific phenomena, we demonstrate how this cultural integration not only makes scientific content more accessible and engaging but also fosters a deeper appreciation of Chinese heritage among international audiences. This approach not only bridges the gap between science and culture but also contributes to a more inclusive and interconnected global scientific community, underscoring the importance of cultural diversity in enriching scientific exploration and communication. [ABSTRACT FROM AUTHOR]

Loss of refreshment in nucleus pulposus (NP) cellularity leads to intervertebral disc (IVD) degeneration. Nevertheless, the cellular sequence of NP cell differentiation remains unclear, although an increasing body of literature has identified markers of NP progenitor cells (NPPCs). Notably, due to their fragility, the physical enrichment of NP‐derived cells has limited conventional transcriptomic approaches in multiple studies. To overcome this limitation, a spatially resolved transcriptional atlas of the mouse IVD is generated via the 10x Genomics Visium platform dividing NP spots into two clusters. Based on this, most reported NPPC‐markers, including Cathepsin K (Ctsk), are rare and predominantly located within the NP‐outer subset. Cell lineage tracing further evidence that a small number of Ctsk‐expressing cells generate the entire adult NP tissue. In contrast, Tie2, which has long suggested labeling NPPCs, is actually neither expressed in NP subsets nor labels NPPCs and their descendants in mouse models; consistent with this, an in situ sequencing (ISS) analysis validated the absence of Tie2 in NP tissue. Similarly, no Tie2‐cre‐mediated labeling of NPPCs is observed in an IVD degenerative mouse model. Altogether, in this study, the first spatial transcriptomic map of the IVD is established, thereby providing a public resource for bone biology. [ABSTRACT FROM AUTHOR]

Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA‐seq, flow cytometry, quantitative reverse transcription‐polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs‐Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA‐seq, bulk RNA‐seq, and bioinformatic approaches, and found the highly expressed miR‐27b‐3p in CPPs‐Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1‐CREB1 axis via exosomal miR‐27b‐3p. Our study offers a novel insight into the role of CPPs‐Exo in heart repair and highlights the potential of CPPs‐Exo as a promising therapeutic strategy for MI. [ABSTRACT FROM AUTHOR]

Highlights: Nanoferroptosis: a novel cell death process using various nanoparticles. Therapeutic potential of nanoferroptosis inducers in cancer. Synergistic approach of nanoferroptosis with immunotherapy, sonodynamic and photodynamic therapy. As a new form of regulated cell death, ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells. The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells. Due to their high loading and structural tunability, nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting. This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis. Additionally, we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury is caused by excessive production of reactive oxygen species (ROS) and inflammation accompanied by ischemic injury symptoms and blood–brain barrier (BBB) dysfunction. This causes neuronal damage, for which no effective treatments or drugs exist. Herein, we provided a stepwise targeted drug delivery strategy and successfully prepared multifunctional ORD@SHp@ANG nanoparticles (NPs) that consist of a stroke homing peptide (DSPE-PEG 2000 -SHp), BBB-targeting peptide (DSPE-PEG 2000 -ANG), and ROS-responsive Danshensu (salvianic acid A) chain self-assembly. ORD@SHp@ANG NPs effectively crossed the BBB by ANG peptide and selectively targeted the ischemic brain sites using stroke-homing peptide. The results showed that ORD@SHp@ANG NPs can effective at scavenging ROS, and protect SH-SY5Y cells from oxidative damage in vitro. Furthermore, ORD@SHp@ANG NPs showed excellent biocompatibility. These NPs recognized brain endothelial cells and crossed the BBB, regulated the transformation of microglia into the anti-inflammatory phenotype, and inhibited the production of inflammatory factors in a rat ischemia-reperfusion model, thereby reducing cerebral infarction, neuronal apoptosis and preserving BBB integrity. Sequencing revealed that ORD@SHp@ANG NPs promote cell proliferation, activate immune responses, suppress inflammatory responses, and ameliorate ischemic stroke. In conclusion, this study reports a simple and promising drug delivery strategy for managing ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

The degeneration of retinal pigment epithelium (RPE) plays an important role in the development of age-related macular degeneration (AMD). However, the underlying mechanism remains elusive. In this study, we identified that ZIP8, a metal-ion transporter, plays a crucial role in the degeneration of RPE cells mediated by ferroptosis. ZIP8 was found to be upregulated in patients with AMD through transcriptome analysis. Upregulated ZIP8 was also observed in both oxidative-stressed RPE cells and AMD mouse model. Importantly, knockdown of ZIP8 significantly inhibited ferroptosis in RPE cells induced by sodium iodate-induced oxidative stress. Blocking ZIP8 with specific antibodies reversed RPE degeneration and restored retinal function, improving visual loss in a mouse model of NaIO 3 -induced. Interestingly, the modification of the N-glycosylation sites N40, N72 and N88, but not N273, was essential for the intracellular iron accumulation mediated by ZIP8, which further led to increased lipid peroxidation and RPE death. These findings highlight the critical role of ZIP8 in RPE ferroptosis and provide a potential target for the treatment of diseases associated with retinal degeneration, including AMD. [Display omitted] • ZIP8 is upregulated in oxidative-stressed RPE cells in vitro and in vivo. • ZIP8 promotes RPE ferroptosis via increasing iron import, oxidative stress and lipid peroxidation. • N-Glycosylation is necessary for ZIP8 mediated RPE ferroptosis. • Blockage of ZIP8 reverses RPE degeneration and restores retinal function in NaIO 3 induced AMD animal model. [ABSTRACT FROM AUTHOR]

The increased use of low‐dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single‐cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin‐1 and angiotensin II receptor type 2 and a basal‐like molecular character. Furthermore, it identifies that cathepsin B+ tumor‐associated macrophages may over‐activate CD8+ T cells in MIA, leading to an enrichment of granzyme K+ senescent CD8+ T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects. [ABSTRACT FROM AUTHOR]

Divergent N6-methyladenosine (m6A) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by m6A regulators or m6A RNA methylation regulators, i.e., methyltransferases ("writers"), demethylases ("erasers"), and m6A-binding proteins ("readers"). Aberrant m6A modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant m6A regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of m6A regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that m6A regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of m6A regulators in cancer. The roles and mechanisms for epigenetic modification of m6A regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of m6A regulators. [ABSTRACT FROM AUTHOR]

Cancer is a grievous disease whose treatment requires a more efficient, non-invasive therapy, associated with minimal side effects. Gold nanoparticles possessing greatly impressive optical properties have been a forerunner in bioengineered cancer therapy. This theranostic system has gained immense popularity and finds its application in the field of molecular detection, biological imaging, cancer cell targeting, etc. The photothermal property of nanoparticles, especially of gold nanorods, causes absorption of the light incident by the light source, and transforms it into heat, resulting in tumor cell destruction. This review describes the different optical features of gold nanoparticles and summarizes the advance research done for the application of gold nanoparticles and precisely gold nanorods for combating various cancers including breast, lung, colon, oral, prostate, and pancreatic cancer. [ABSTRACT FROM AUTHOR]

In recent years, brain diseases have seriously threatened human health due to their high morbidity and mortality. Achieving efficient drug delivery to provide satisfactory therapeutic outcomes is currently the greatest challenge in treating brain diseases. The main challenges are the structural peculiarities of the brain and the inability to transport drugs across the blood–brain barrier. Biomimetic nanodelivery systems (BNDSs) applied to the brain have been extensively developed in the preclinical phase to surmount these challenges. Considering the inherent properties of BNDSs, the substantially enhanced ability of BNDS to carry therapeutic agents and their higher selectivity toward lesions offer new opportunities for developing safe and effective therapies. This review summarizes brain-targeting nanotherapies, particularly advanced therapies with biomimetic nano-assistance. Prospects for developing BNDSs and the challenges of their clinical translation are discussed. Understanding and implementing biomimetic nanotherapies may facilitate the development of new targeted strategies for brain disorders. Using different bionanomaterials to treat brain disorders. Use of different bionanomaterials for the treatment of brain diseases, e.g., cell membranes, exosomes, viral vectors, and receptor-mediated biomimetic approaches [Display omitted] • Advanced biomimetic nano-delivery systems for the treatment of brain diseases have been illustrated. • Highlighted pathological mechanisms of BBB in different brain diseases and biomimetic strategies to cope with it. • The perspectives and challenges for accelerating the clinical translation of biomimetic nano-delivery systems are highlighted. [ABSTRACT FROM AUTHOR]

The advent of nanotechnology has opened new possibilities for bioimaging. Metal nanoparticles (such as gold, silver, iron, copper, etc.) hold tremendous potential and offer enormous opportunities for imaging and diagnostics due to their broad optical characteristics, ease of manufacturing technique, and simple surface modification. The arginine-glycine-aspartate (RGD) peptide is a three-amino acid sequence that seems to have a considerably greater ability to adhere to integrin adhesion molecules that exclusively express on tumour cells. RGD peptides act as the efficient tailoring ligand with a variety of benefits including non-toxicity, greater precision, rapid clearance, etc. This review focuses on the possibility of non-invasive cancer imaging using metal nanoparticles with RGD assistance. [ABSTRACT FROM AUTHOR]

The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non‐muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co‐immunoprecipitation, GST pull‐down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non‐muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin‐specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co‐expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10‐MYH9‐snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival rate for pediatric cancers has improved significantly over the last decades. Conventional chemotherapies play a vital role in pediatric cancer treatment, especially in low- and middle-income countries, and the roster of chemo drugs for use in children has expanded. However, patients suffer from chemotherapy as a result of its countless side effects. Furthermore, multidrug resistance (MDR) continues to be an insurmountable obstacle that limits survival for a considerable number of patients. In this review, we discuss severe side effects in pediatric chemotherapies such as doxorubicin-induced cardiotoxicity (DIC) and vincristine-induced peripheral neuropathy (VIPN). Here, MDR mechanisms in chemotherapy are elucidated with the aim of improving survival, while also reducing the intensity and toxicity of chemotherapy. Furthermore, we focus on various drug transporters in common types of pediatric tumors, which could provide different therapeutic strategies. The survival rate for pediatric cancers has remarkably improved in recent years. Conventional chemotherapy plays a crucial role in treating pediatric cancers, especially in low- and middle-income countries where access to advanced treatments may be limited. The Food and Drug Administration (FDA) approved chemotherapy drugs that can be used in children have expanded, but patients still face numerous side effects from the treatment. In addition, multidrug resistance (MDR) continues to pose a major challenge in improving the survival rates for a significant number of patients. This review focuses on the severe side effects of pediatric chemotherapy, including doxorubicin-induced cardiotoxicity (DIC) and vincristine-induced peripheral neuropathy (VIPN). We also delve into the mechanisms of MDR in chemotherapy to the improve survival and reduce the toxicity of treatment. Additionally, the review focuses on various drug transporters found in common types of pediatric tumors, which could offer different therapeutic options. [ABSTRACT FROM AUTHOR]

Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt‐9, potently reduced ALK levels through Hsp70 and the ubiquitin−proteasome system (UPS) in vitro without compensatory upregulation of ALK. Furthermore, Hyt‐9 exhibited a significant tumor‐inhibiting effect in vivo with moderate oral bioavailability. More importantly, norbornene can also be used to degrade the intractable enhancer of zeste homolog 2 (EZH2) when tagged with the EZH2 inhibitor tazemetostat. Thus, the discovery of novel hydrophobic norbornene tags shows promise for the future development of TPD technology. [ABSTRACT FROM AUTHOR]

Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt‐9, potently reduced ALK levels through Hsp70 and the ubiquitin−proteasome system (UPS) in vitro without compensatory upregulation of ALK. Furthermore, Hyt‐9 exhibited a significant tumor‐inhibiting effect in vivo with moderate oral bioavailability. More importantly, norbornene can also be used to degrade the intractable enhancer of zeste homolog 2 (EZH2) when tagged with the EZH2 inhibitor tazemetostat. Thus, the discovery of novel hydrophobic norbornene tags shows promise for the future development of TPD technology. [ABSTRACT FROM AUTHOR]

Distant metastasis remains the major cause of morbidity for breast cancer. Individuals with liver or brain metastasis have an extremely poor prognosis and low response rates to anti‐PD‐1/L1 immune checkpoint therapy compared to those with metastasis at other sites. Therefore, it is urgent to investigate the underlying mechanism of anti‐PD‐1/L1 resistance and develop more effective immunotherapy strategies for these patients. Using single‐cell RNA sequencing, a high‐resolution map of the entire tumor ecosystem based on 44 473 cells from breast cancer liver and brain metastases is depicted. Identified by canonical markers and confirmed by multiplex immunofluorescent staining, the metastatic ecosystem features remarkable reprogramming of immunosuppressive cells such as FOXP3+ regulatory T cells, LAMP3+ tolerogenic dendritic cells, CCL18+ M2‐like macrophages, RGS5+ cancer‐associated fibroblasts, and LGALS1+ microglial cells. In addition, PD‐1 and PD‐L1/2 are barely expressed in CD8+ T cells and cancer/immune/stromal cells, respectively. Interactions of the immune checkpoint molecules LAG3‐LGALS3 and TIGIT‐NECTIN2 between CD8+ T cells and cancer/immune/stromal cells are found to play dominant roles in the immune escape. In summary, this study dissects the intratumoral heterogeneity and immunosuppressive microenvironment in liver and brain metastases of breast cancer for the first time, providing insights into the most appropriate immunotherapy strategies for these patients. [ABSTRACT FROM AUTHOR]

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive type of cancer. Its current first‐line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage‐inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA‐damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin‐proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood‐brain barrier to exert anti‐GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA‐damaging treatments. [ABSTRACT FROM AUTHOR]

Skin cancer has emerged as the fifth most commonly reported cancer in the world, causing a burden on global health and the economy. The enormously rising environmental changes, industrialization, and genetic modification have further exacerbated skin cancer statistics. Current treatment modalities such as surgery, radiotherapy, conventional chemotherapy, targeted therapy, and immunotherapy are facing several issues related to cost, toxicity, and bioavailability thereby leading to declined anti-skin cancer therapeutic efficacy and poor patient compliance. In the context of overcoming this limitation, several nanotechnological advancements have been witnessed so far. Among various nanomaterials, nanoparticles have endowed exorbitant advantages by acting as both therapeutic agents and drug carriers for the remarkable treatment of skin cancer. The small size and large surface area to volume ratio of nanoparticles escalate the skin tumor uptake through their leaky vasculature resulting in enhanced therapeutic efficacy. In this context, the present review provides up to date information about different types and pathology of skin cancer, followed by their current treatment modalities and associated drawbacks. Furthermore, it meticulously discusses the role of numerous inorganic, polymer, and lipid-based nanoparticles in skin cancer therapy with subsequent descriptions of their patents and clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the availability of numerous therapeutic approaches, pancreatic ductal adenocarcinoma still stands as one of the most fatal cancers worldwide. Nanoliposomes could potentially be helpful in improving the pharmacokinetic and anticancer efficacy of drug molecules. Gemcitabine is the first line of therapy, but due to its hydrophilic nature, entrapment within nanoliposomes is very limited. To overcome this problem, we explored the lipophilic form of gemcitabine, i.e., Gemcitabine Elaidate. The present study is aimed towards investigating the antitumor activity of Gemcitabine Elaidate and further designing an appropriate nano-liposomal formulation in combination with Palmitoyl-DL-carnitine chloride as a Protein kinase C (PKC) inhibitor. Our combination therapy in a nano-liposomal carrier resulted in enhanced cellular uptake, inhibition of angiogenesis potential and augmented anticancer potency in both 2D and 3D in vitro models of pancreatic tumors. The promising results indicate the successful development of a nano-liposomal carrier incorporating Gemcitabine Elaidate and Palmitoyl-DL-carnitine chloride as a more effective approach for the treatment of pancreatic cancer by overcoming the key drawbacks of the current first-line therapy. Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC. [ABSTRACT FROM AUTHOR]

Background: As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure–activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods: We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1–6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method to screen inhibitors among them. We further analyze the three-dimensional quantitative structure–activity relationship (3D-QSAR) for those inhibitors. Results: The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin: (1), 2-Oʹʹrhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 μM). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds 1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion: 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4ʹ and C7 in the characteristic compounds. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell‐derived nanosized vesicles that mediate cell‐to‐cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial‐mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed. [ABSTRACT FROM AUTHOR]

The present work was aimed at developing an optimized and modified nanostructured lipid carrier of BRD4 protein degrading Proteolysis Targeting Chimera (PROTAC) against non-small cell lung carcinoma. PROTACs are an emerging class of anticancer molecules with nanomolar activity but associated with significant solubility challenges. Lipid-based colloidal systems like nanostructured lipid carriers are widely explored for such highly lipophilic molecules. ARV-825, a cereblon-based PROTAC was investigated for its anticancer efficacy in vitro in 2D and 3D lung cancer models. ARV-825 loaded PEGylated nanostructured lipid carriers (AP-NLC) was prepared using melt emulsification technique. ARV-825 was stabilized using Precirol® ATO5 and Captex® 300 EP/NF as the solid and liquid lipid, respectively. However, hydrophobic ion-pairing with medium chain fatty acid was required to improve drug loading and stability. A hydrodynamic diameter and polydispersity index of 56.33 ± 0.42 nm and 0.16 respectively with zeta potential of -21 ± 1.24 mV was observed. In vitro migration and colony formation assay confirmed the anticancer activity of ARV-825 alone and AP-NLC. Nearly 38% and 50% apoptotic cell population were observed after ARV-825 and AP-NLC treatment. Immunoblotting assay showed complete suppression of BRD4 and c-Myc protein expression for AP-NLC. Most importantly, significant reduction in the growth of multicellular 3D spheroid of A549 cells confirmed the effectiveness of BRD4 PROTAC and its lipid nanoparticle in non-small cell lung cancer (NSCLC). AP-NLC. Higher amount of red fluorescence throughout the spheroid surface further confirmed superior efficacy of AP-NLC in tumor penetration and cell killing. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an increasingly prevalent disease that is associated with high and continually rising mortality rates. Lipid metabolism holds a crucial role in the pathogenesis of HCC, in which abnormalities pertaining to the delicate balance of lipid synthesis, breakdown, and storage, predispose for the pathogenesis of the nonalcoholic fatty liver disease (NAFLD), a disease precursor to HCC. If caught early enough, HCC treatment may be curative. In later stages, treatment is only halting the inevitable outcome of death, boldly prompting for novel drug discovery to provide a fighting chance for this patient population. In this review, we begin by providing a summary of current local and systemic treatments against HCC. From such we discuss hepatic lipid metabolism and highlight novel targets that are ripe for anti-cancer drug discovery. Lastly, we provide a targeted summary of current known risk factors for HCC pathogenesis, providing key insights that will be essential for rationalizing future development of anti-HCC therapeutics. • Dysregulation of lipid metabolism can promote cancer cell proliferation and metastasis. • Inhibition of sterol regulatory element binding protein-1 (SREBP-1) can directly reduce fatty acid synthesis and hepatic triglyceride levels, thereby reducing the risk of non-alcoholic fatty liver disease developing into HCC. • Stearoyl-coa desaturase (SCD), fatty acid synthase (FASN), acetyl-coa carboxylase (ACC), and ATP citrate lyase (ACLY) are novel targets for anti-HCC drug discovery. • Viral hepatitis, genetic disorders such as hemochromatosis, nonalcoholic fatty liver disease (NAFLD), advanced nonalcoholic steatohepatitis (NASH), and chronic alcohol use can induce liver cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • We review the molecular mechanism of resistance to lenvatinib in hepatocellular carcinoma cells. • We summarize the use of combination therapy to overcome lenvatinib resistance. • We discuss future directions for overcoming resistance to lenvatinib in hepatocellular carcinoma. Lenvatinib is a multikinase inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor α (PDGFRα), as well as the proto-oncogenes RET and KIT. Lenvatinib has been approved by the US Food and Drug Administration (FDA) for the first-line treatment of hepatocellular carcinoma (HCC) due to its superior efficacy when compared to sorafenib. Unfortunately, the development of drug resistance to lenvatinib is becoming increasingly common. Thus, there is an urgent need to identify the factors that lead to drug resistance and ways to mitigate it. We summarize the molecular mechanisms that lead to lenvatinib resistance (LR) in HCC, which involve programmed cell death (PCD), translocation processes, and changes in the tumor microenvironment (TME), and provide strategies to reverse resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs), expressed at low levels on tumor-infiltrating lymphocytes (TILs), and can be expressed on other tumor cells. • VISTA maintains naïve T cell and myeloid quiescence, which inhibits T cell activation and cytokine production. • VISTA exerts its immunomodulatory functions as a ligand and receptor by binding to PSGL-1 or VSIG3. • VISTA has a potential role as a prognostic indicator in some cancers, but conflicting results have been reported. • This review outlines the limitations of conventional immune checkpoint inhibitors (ICIs) and explores the promising prospects for the use of VISTA as a novel ICI. V-domain Ig suppressor of T cell activation (VISTA) is a recently identified member of the B7 family of immunoregulatory proteins. It is pivotal for maintaining T cell quiescence and exerts a significant regulatory influence on the immune response to tumors. Accumulating clinical evidence suggests that the influence of VISTA on tumor immunity is more nuanced than initially postulated. Although these revelations add layers of complexity to our understanding of the function of VISTA, they also offer novel avenues for scientific inquiry and potential therapeutic targets. In this review, we scrutinize the current literature pertaining to the expression of VISTA in various of malignancies, aiming to elucidate its intricate roles within the tumor microenvironment and in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the clonal expansion and differentiation arrest of leukemic cells in peripheral blood and bone marrow. Though the treatment using cytarabine-based protocol for AML patients with t (8; 21) translocation has improved the 5-year overall survival rate, drug resistance continues to be the principal limiting factor for the cure of the disease. In addition, very few AML patients with mixed lineage leukemia gene rearrangements (MLLr) have a desirable outcome. This study evaluated the cell differentiation effect of a potent HDAC (histone deacetylase) inhibitor, I3, and its possible mechanism on the AML cells with t (8; 21) translocation or MLLr and leukemic stem-like cells (Kasumi-1, KG-1, MOLM-13, and THP-1). I3 exhibited efficient anti-proliferative activity on these cells via promoting cell differentiation, accompanied by the cell cycle exit at G0/G1. Importantly, I3 showed the properties of HDAC inhibition, as assessed by the acetylation of histones H3 and H4, which resulted in blocking the activation of the VEGF (vascular endothelial growth factor)-MAPK (mitogen-activated protein kinase) signaling pathway in the Kasumi-1 cell line. These data demonstrate that I3 could be a potent chromatin-remodeling agent to surmount the differentiation block in AML patients, including those with t (8; 21) translocation or MLLr, and could be a potent and selective agent for AML treatment. [ABSTRACT FROM AUTHOR]

Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs' role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment. [ABSTRACT FROM AUTHOR]

A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3′-azido-3′-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic β -elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07–278.8 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3 , 4 , 8 , and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143B and the thymidine kinase-deficient 143B/TK − cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly. [ABSTRACT FROM AUTHOR]

Background: PIK3CA mutation and PTEN suppression lead to tumorigenesis and drug resistance in colorectal cancer (CRC). There is no research on the role of circular RNAs (circRNAs) in regulating PIK3CA mutation and MEK inhibitor resistance in CRC. Methods: The expression of circLHFPL2 in PIK3CA-mutant and wild-type cells and tissues was quantified by RNA-sequencing and qRT-PCR. CCK-8 assay and colony formation assay were used to evaluate cell viability. Annexin V/PI staining was implemented to assess cell apoptosis. Luciferase assay, biotin-coupled microRNA capture, and RIP assay were used to validate the interaction among potential targets. Western blotting and qRT-PCR assays were used to evaluate the expression of involved targets. Xenograft tumor in a nude mouse model was used to explore the role of circRNAs in vivo. Results: RNA sequencing defined downregulated expression of circLHFPL2 in both PIK3CAH1047R (HCT116) and PIK3CAE545K (DLD1) cells. CircLHFPL2 was also downregulated in PIK3CA-mutant CRC primary cells and tissues, which was correlated with poor prognosis. CircLHFPL2 was mainly localized in the cytoplasm and its downregulation was attributed to the PI3K/AKT signaling pathway activated by phosphorylating Foxo3a. CircLHFPL2 inhibited PI3KCA-Mut CRC progression both in vitro and in vivo. Furthermore, our work indicated that circLHFPL2 acts as a ceRNA to sponge miR-556-5p and miR-1322 in CRC cells and in turn modulate the expression of PTEN. Importantly, circLHFPL2 was able to overcome PIK3CA-mediated MEK inhibitor resistance in CRC cells. Conclusions: Downregulation of circLHFPL2 sustains the activation of the PI3K/AKT signaling pathway via a positive feedback loop in PIK3CA-mutant CRC. In addition, downregulation of circLHFPL2 leads to MEK inhibitor resistance in CRC. Therefore, targeting circLHFPL2 could be an effective approach for the treatment of CRC patients harboring oncogenic PIK3CA mutations. [ABSTRACT FROM AUTHOR]

Photonics has spurred a myriad of diagnostic and therapeutic applications for defeating cancer owing to its superiority in spatiotemporal maneuverability and minimal harm. The limits of light penetration depth and elusiveness of photosensitizer utilization, however, impede the implementation of the photodiagnostic and ‐therapy for determining and annihilating the deep‐situated tumor. Herein, a promising strategy that harnesses functional optical fibers is developed and demonstrated to realize an in vivo endoscopic cancer sensing and therapy ensemble. Tumor detection is investigated using hypoxia‐sensitive fluorescent fibers to realize fast and accurate tumor recognition and diagnosis. The tumor treatment is further performed by exploiting the endogenous photothermal effect of rare‐earth‐doped optical fibers. The eradication of orthotopic and subcutaneous xenografts significantly validates the availability of tumoricidal fibers. The strategy opens horizons to inspire the design of optical fiber‐mediated "plug and play" precise tumor theranostics with high safety, which may intrigue broader fields, such as fiber optics, materials, chemistry, medicine, and clinics. [ABSTRACT FROM AUTHOR]

Background: Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro. Methods: Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178. Results: We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan–Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters. Conclusions: Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown. Methods: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis. Results: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110β, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110β deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110β. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110β level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice. Conclusions: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency. [ABSTRACT FROM AUTHOR]

Early diagnosis and treatment of gastric precancerous lesions (GPL) are key factors for reducing the incidence and morbidity of gastric cancer. The study is aimed at examining GPL in mice induced by N-methyl-N-nitroso-urea (MNU) and to illustrate the underlying mechanisms of tumorigenesis. In this study, we utilized an in vivo MNU-induced GPL mouse model, and histopathological changes of the gastric mucosa were observed by hematoxylin and eosin (H&E-stain) and alcian blue (AB-PAS-stain). The level of miR-194-5p in the gastric mucosa was determined by real-time polymerase chain reaction. We used transmission electron microscopy to observe the effects of MNU on gastric chief cells and parietal cells. We performed immunohistochemical detection of HIF-1α, vWF, Ki-67, and P53, while the changes in the protein expression of key genes in LKB1-AMPK and AKT-FoxO3 signaling pathways were detected by western blot analysis. We demonstrated that the miR-194-5p expression was upregulated under hypoxia in GPL gastric tissues, and that a high miR-194-5p expression level closely related with tumorigenesis. Mechanistically, miR-194-5p exerted the acceleration of activities related to metabolic reprogramming through LKB1-AMPK and AKT-FoxO3 pathways. Furthermore, similar to miR-194-5p, high expression levels of AMPK and AKT were also related to the metabolic reprogramming of GPL. Moreover, we revealed the correlation between the expression levels of miR-194-5p, p-AMPKα, p-AKT, and FoxO3a. These findings suggest that miR-194-5p/FoxO3 pathway is important for the reversal of metabolic reprogramming in GPL. Thus, exploring strategies to regulate the miR-194-5p/FoxO3a pathway may provide an efficient strategy for the prevention and treatment of GPL. [ABSTRACT FROM AUTHOR]

Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease. [Display omitted] • The role of autophagy and neuroinflammation in the pathophysiology of depression. • The latest findings of anti-depressants small moleculars through regulating neuroinflammation and autophagy. • A novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat depression. [ABSTRACT FROM AUTHOR]

[Display omitted] • This review summarizes the complex regulatory networks and pathways involved in the process of ferroptosis in retinal cells. • Ferroptosis plays a pivotal role in the progression of age-related macular degeneration (AMD), making it a potential target for targeted therapeutic interventions. • The review provides an overview of potential iron chelators and antioxidants that target ferroptosis to protect retinal cells for the treatment of AMD. • We discuss the challenges and opportunities in basic research on ferroptosis and in using ferroptosis as a therapeutic target for clinical applications. Cell death plays a crucial part in the process of age-related macular degeneration (AMD), but its mechanisms remain elusive. Accumulating evidence suggests that ferroptosis, a novel form of regulatory cell death characterized by iron-dependent accumulation of lipid hydroperoxides, has a crucial role in the pathogenesis of AMD. Numerous studies have suggested that ferroptosis participates in the degradation of retinal cells and accelerates the progression of AMD. Furthermore, inhibitors of ferroptosis exhibit notable protective effects in AMD, underscoring the significance of ferroptosis as a pivotal mechanism in the death of retinal cells during the process of AMD. This review aims to summarize the molecular mechanisms of ferroptosis in AMD, enumerate potential inhibitors and discuss the challenges and future opportunities associated with targeting ferroptosis as a therapeutic strategy, providing important information references and insights for the prevention and treatment of AMD. [ABSTRACT FROM AUTHOR]

The article titled "Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function" has been retracted by the Biomolecules Editorial Office. Concerns were raised about partial figure duplications within the article, and an investigation confirmed the overlap of panels and Western blots representing different experimental conditions. Due to the extent and impact of these duplications on the validity of the findings, the article has been retracted in accordance with MDPI's retraction policy and the Committee on Publication Ethics retraction guidelines. The retraction was approved by the Editor-in-Chief of the journal Biomolecules, and the authors agreed to the retraction. [Extracted from the article]

Alterations in DNAs could not reveal what happened in proteins. The accumulated alterations of DNAs would change the manifestation of proteins. Therefore, as is the case in cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information in real-time throughout all stages of cancer progression. However, due to the great complexity of proteomes in liquid biopsy samples and the limitations of proteomic technologies compared to high-plex sequencing technologies, proteomic discoveries have yet lagged behind their counterpart, genomic technologies. Therefore, novel protein technologies are in urgent demand to fulfill the goals set out for biomarker discovery in cancer liquid biopsies. Notably, conventional and innovative technologies are being rapidly developed for proteomic analysis in cancer liquid biopsies. These advances have greatly facilitated early detection, diagnosis, prognosis, and monitoring of cancer evolution, adapted or adopted in response to therapeutic interventions. In this paper, we review the high-plex proteomics technologies that are capable of measuring at least hundreds of proteins simultaneously from liquid biopsy samples, ranging from traditional technologies based on mass spectrometry (MS) and antibody/antigen arrays to innovative technologies based on aptamer, proximity extension assay (PEA), and reverse phase protein arrays (RPPA). [ABSTRACT FROM AUTHOR]

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future. [ABSTRACT FROM AUTHOR]

Background: Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance. Methods: METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance. Results: Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo. Conclusions: This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients. [ABSTRACT FROM AUTHOR]

Highlights: ABCB1 overexpression significantly desensitized both drug-selected and gene-transfected cells, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by verapamil, a known ABCB1 inhibitor. Consistently, a similar trend was observed in tumor-bearing mice. OTS964 stimulated ATPase activity of ABCB1 and upregulated expression levels of ABCB1, resulting in induced resistance to other ABCB1 substrate-drugs, such as paclitaxel. OTS964 received a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein. [ABSTRACT FROM AUTHOR]

Purpose: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. Experimental design: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. Results: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). Conclusions: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer. [ABSTRACT FROM AUTHOR]

Background: More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. Methods: Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Results: Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. Conclusions: Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention. [ABSTRACT FROM AUTHOR]

Background: Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods: The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results: We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion: Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients. [ABSTRACT FROM AUTHOR]

• Better understanding of the cell receptors and ligands involved in HSV infection. • Illustrating the process of HSV infection. • The value of drugs targeting HSV entry process is highlighted. • An attempt to curb the elevating risk of HSV for its high prevalence. Human herpes simplex viruses (HSVs) belong to the Herpesviridae family. At present, no vaccine or curative treatment is available for the prevention of HSV infections. Here, we review the cell surface receptors that are recognized by HSV's glycoprotein B, glycoprotein C, glycoprotein D, and the glycoprotein H – glycoprotein L complex to facilitate entry into host cells. These receptors include heparan sulfate (HS), herpesvirus entry mediator (HVEM), and nectin-1/-2, 3- O -sulfated heparan sulfate (3- O S HS). [ABSTRACT FROM AUTHOR]

Abstract: The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with heteroatom substituted pyridyl and phenyl ring systems was synthesized and evaluated against a panel of kinases including c-Kit and KDR. Aminopyridyl derivative 6 was found to be the most active member of the series with 91% and 57% inhibition of c-Kit at 10μM and 1μM, respectively and 88% and 50% inhibition of KDR at 10μM and 1μM, respectively. The target compounds were also tested for their ability to inhibit efflux of mitoxantrone through inhibition of ATP dependent ABCG2 pump. Nitropyridyl derivative 5 and o-nitrophenyl derivative 7 exhibited complete inhibition of the ABCG2 pump with IC50 values of 13.67μM and 16.67μM, respectively. [Copyright &y& Elsevier]

Background: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. Methods: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer. [ABSTRACT FROM AUTHOR]