Light Chain Amyloidosis-Induced Autophagy Is Mediated by the Foxo3a/Beclin-1 Pathway in Cardiomyocytes.

Cardiac amyloidosis is a disease in which the extracellular space of the heart is deposited with and infiltrated by amyloid fibrillar material, and light chain (LC) amyloidosis (AL) is the most serious form of the disease. AL is caused by the overproduction and aggregation of monoclonal immunoglobulin LCs produced by bone marrow plasma cells. Studies have shown that the initial response at a subcellular level to the toxicity of AL is lysosomal dysfunction with impaired autophagy, elevated reactive oxygen species, cellular dysfunction, and cellular death. Therefore, we speculate that the multiple myeloma complicated by cardiac amyloidosis is due to the deposition of λ LC fibrils in cardiomyocytes, leading to dysregulation of autophagy and cell death. We constructed BACN1 siRNA or FOXO3A siRNA and transfected them into H9c2 cells. We detected changes in oxidative stress- and autophagy-related markers. Our results show that monoclonal immunoglobulin λ LCs can form amyloid aggregates, which are cytotoxic to cardiomyocytes. λ LC fibrils deposit on the cell surface, causing oxidative stress and excessive autophagy by increasing Beclin-1 expression and the LC3 II/LC3 I ratio and decreasing p62 expression, ultimately inducing cell death. Beclin-1 knockdown reversed the increase in the LC3 II/LC3 I ratio and the decrease in p62 induced by LC fibrils, while suppressing overactivated autophagy and oxidative stress. Furthermore, LCs reduce the expression of p-Foxo3a (Ser253) (inactive) and promote Foxo3a translocation into the nucleus to perform transcriptional activity, which induces autophagy-related gene overexpression. Silencing Foxo3a can suppress excessive autophagy induced by LC fibrils and protect cells from death. In summary, the results showed that the cytotoxicity of amyloid fibrils formed by λ LCs on cardiomyocytes is triggered by excessive autophagy and is mediated through the Foxo3a/Beclin-1 pathway.

A Novel Bromophenol Compound from Leathesia nana Inhibits Breast Cancer in a Direct Tumor Killing and Immunotherapy Manner.

Considering the resistance and toxicity of traditional chemotherapeutic drugs, seeking potential candidate for treating breast cancer effectively is a clinical problem that should be solved urgently. Natural products have attracted extensive attention, owing to their multi-target advantages and low toxicity. In the current study, the effects of XK-81, a novel bromophenol compound extracted from Leathesia nana, on breast cancer, and its underlying mechanisms, were explored. Firstly, data from in vitro experiments indicated that 4T-1, one of common mouse breast cancer cell lines, was a XK-81-susceptible cell line, and ferroptosis was the major death manner in response to XK-81 treatment, which was evidenced by increasing intracellular Fe2+ and ROS level with condensed mitochondrial membrane densities, as well as decreasing the protein expressions of SLC7A11 and GPX4. In vivo, XK-81 suppressed the growth of 4T-1 breast-tumor in both BALB/C mice and zebrafish. Obviously, XK-81 decreased the protein expression of SLC7A11 and GPX4 in tumor tissues, hinting at the occurrence of ferroptosis. Moreover, XK-81 increased CD8+ T cells and NK cells numbers and regulated M1/M2 macrophage ratio in tumor tissues, indicating XK-81's immunotherapeutic effect. Additionally, the secretions of immune-related cytokines, including TNF-α, IL-1ß, and IL-12, were elevated with XK-81 stimulation in RAW 264.7 cells. Intriguingly, compared with doxorubicin-induced heart damage, XK-81 demonstrated the therapeutic advantage of little cardiotoxicity on the heart. XK-81 demonstrated potential antitumor advantage by both directly inducing ferroptosis-mediated death of tumor cells and immunization.

Melatonin may suppress lung adenocarcinoma progression via regulation of the circular noncoding RNA hsa_circ_0017109/miR-135b-3p/TOX3 axis.

Melatonin is a hormone synthesized in the pineal gland and has widespread physiological and pharmacological functions. Moreover, it can activate protective receptor-dependent processes. These processes can prevent tissue carcinogenesis and inhibit malignant tumor progression and metastasis. Therefore, we investigated the regulatory effects of melatonin on dysregulated circular RNAs in human lung adenocarcinoma (LUAD) cells. In this study, we treated LUAD cells with melatonin and measured the expression of hsa_circ_0017109, miR-135b-3p, and TOX3 by quantitative reverse transcription polymerase chain reaction. Colony formation and cell counting kit-8 assays were used to determine cell proliferation. The wound-healing assay and Transwell experiment were carried out to evaluate the migration potential and invasive capacity of LUAD cells. Also, cell apoptosis was detected using a cell apoptosis kit, and protein production was identified by Western blot. It was suggested that melatonin could inhibit LUAD progression in vivo and in vitro, and the role of TOX3 in this process was explored. Additionally, hsa_circ_0017109 was found to sponge miR-135b-3p, a downstream factor of circ_0017109, which was demonstrated to target TOX3 in LUAD cells and could promote the Hippo pathway and epithelial-mesenchymal transition pathway. To summarize, we demonstrated that melatonin decreases the expression of circ_0017109 and suppresses the non-small-cell lung cancer cell migration, invasion, and proliferation through decreasing TOX3 expression via direct activation of miR-135b-3p.

MicroRNA-487a-3p functions as a new tumor suppressor in prostate cancer by targeting CCND1.

Prostate cancer (PCa) is one of the major health problems of the aging male. The roles of dysregulated microRNAs in PCa remain unclear. In this study, we mined the public published data and found that miR-487a-3p was significantly downregulated in 38 pairs of clinical prostate tumor tissues compared with the normal tissues. We further verified this result by in situ hybridization on tissue chip and quantitative real-time polymerase chain reaction (qRT-PCR) in PCa/normal cells. miR-487a-3p targeting of cyclin D1 (CCND1) was identified using bioinformatics, qRT-PCR and western blot analyses. The cellular proliferation, cell cycle, migration, and invasion were assessed by cell counting kit-8, flow cytometry analysis and transwell assay. We discovered that overexpression of miR-487a-3p suppressed PCa cell growth, migration, invasion by directly targeting CCND1. Knockdown of CCND1 in PCa cells showed similar results. Meanwhile, the expression level of CCND1 was significantly upregulated in the PCa tissues and cell lines, which presented negative correlation with the expression of miR-487a-3p. More important, we demonstrated significantly reduced growth of xenograft tumors of stable miR-487a-3p-overexpressed human PCa cells in nude mice. Taken together, for the first time, our results revealed that miR-487a-3p as a tumor suppressor of PCa could target CCND1. Our finding might reveal miR-487a-3p could be potentially contributed to the pathogenesis and a clinical biomarker or the new potential therapeutic target of PCa.

Molecular mechanisms of ferroptosis and its role in cancer therapy.

Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron-dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

Critical role of FOXO3a in carcinogenesis.

FOXO3a is a member of the FOXO subfamily of forkhead transcription factors that mediate a variety of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage and tumorigenesis. It also responds to several cellular stresses such as UV irradiation and oxidative stress. The function of FOXO3a is regulated by a complex network of processes, including post-transcriptional suppression by microRNAs (miRNAs), post-translational modifications (PTMs) and protein-protein interactions. FOXO3a is widely implicated in a variety of diseases, particularly in malignancy of breast, liver, colon, prostate, bladder, and nasopharyngeal cancers. Emerging evidences indicate that FOXO3a acts as a tumor suppressor in cancer. FOXO3a is frequently inactivated in cancer cell lines by mutation of the FOXO3a gene or cytoplasmic sequestration of FOXO3a protein. And its inactivation is associated with the initiation and progression of cancer. In experimental studies, overexpression of FOXO3a inhibits the proliferation, tumorigenic potential, and invasiveness of cancer cells, while silencing of FOXO3a results in marked attenuation in protection against tumorigenesis. The role of FOXO3a in both normal physiology as well as in cancer development have presented a great challenge to formulating an effective therapeutic strategy for cancer. In this review, we summarize the recent findings and overview of the current understanding of the influence of FOXO3a in cancer development and progression.

Application of engineered antibodies (scFvs and nanobodies) targeting pathological protein aggregates in Alzheimer's disease.

INTRODUCTION: The misfolding and aggregation of proteins are associated with various neurodegenerative diseases, such as Alzheimer's disease (AD). The small-molecule engineered antibodies, such as single-chain fragment variable (scFv) antibodies and nanobodies (Nbs), have gained attention in recent years due to their strong conformational specificity, ability to cross the blood-brain barrier (BBB), low immunogenicity, and enhanced proximity to active sites within aggregates. AREAS COVERED: We have reviewed recent advances in therapies involving scFvs and Nbs that efficiently and specifically target pathological protein aggregates. Relevant publications were searched for in MEDLINE, GOOGLE SCHOLAR, Elsevier ScienceDirect and Wiley Online Library. EXPERT OPINION: We reviewed the recent and specific targeting of pathological protein aggregates by scFvs and Nbs. These engineered antibodies can inhibit the aggregation or promote the disassembly of misfolded proteins by recognizing antigenic epitopes or through conformational specificity. Additionally, we discuss strategies for improving the effective application of engineered antibodies in treating AD. These technological strategies will lay the foundation for the clinical application of small-molecule antibody drugs in developing effective treatments for neurological diseases. Through rational application strategies, small-molecule engineered antibodies are expected to have significant potential in targeted therapy for neurological disorders.

Nanozyme-based visual diagnosis and therapeutics for myocardial infarction: The application and strategy.

BACKGROUND: Myocardial infarction (MI) is a heart injury caused by ischemia and low oxygen conditions. The occurrence of MI lead to the activation of a large number of neutrophils and macrophages, inducing severe inflammatory injury. Meanwhile, the inflammatory response produces much more free radicals, further exacerbating the inflammatory response and tissue damage. Efforts are being dedicated to developing antioxidants and enzymes, as well as small molecule drugs, for treating myocardial ischemia. However, poor pharmacokinetics and potential side effects limit the clinical application of these drugs. Recent advances in nanotechnology have paved new pathways in biomedical and healthcare environments. Nanozymes exhibit the advantages of biological enzymes and nanomaterials, including with higher catalytic activity and stability than natural enzymes. Thus, nanozymes provide new possibilities for the diagnosis and treatment of oxidative stress and inflammation-related diseases. AIM OF REVIEW: We describe the application of nanozymes in the diagnosis and therapy of MI, aiming to bridge the gap between the diagnostic and therapeutic needs of MI. KEY SCIENTIFIC CONCEPTS OF REVIEW: We describe the application of nanozymes in the diagnosis and therapy of MI, and discuss the new strategies for improving the diagnosis and treatment of MI. We review in detail the applications of nanozymes to achieve highly sensitive detection of biomarkers of MI. Due to their unique enzyme catalytic capabilities, nanozymes have the ability to sensitively detect biomolecules through colorimetric, fluorescent, and electrochemical assays. In addition, nanozymes exhibit excellent antioxidase-mimicking activity to treat MI by modulating reduction/oxidation (REDOX) homeostasis. Nanozymes can also passively or actively target MI tissue sites, thereby protecting ischemic myocardial tissue and reducing the infarct area. These innovative applications of nanozymes in the field of biomedicine have shown promising results in the diagnosis and treatment of MI, offering a novel therapeutic strategy.

Nanozymes targeting mitochondrial repair in disease treatment.

Mitochondria are crucial sites for biological oxidation and substance metabolism and plays a vital role in maintaining intracellular homeostasis. When mitochondria undergo oxidative damage or dysfunction, they can harm the organism, leading to various reactive oxygen species (ROS)-related diseases. Therefore, therapies targeting mitochondria are a strategy for treating multiple diseases. Many nanozymes can mimic antioxidant enzymes, which enables them to eliminate ROS to mitigate mitochondrial dysfunction. The therapeutic approaches and drugs targeting the mitochondrial electron transport chain (ETC) have emerged as effective treatments for oxidative stress-related diseases resulting from mitochondrial respiratory chain disorders. Therefore, nanozymes that can regulate homeostasis in the mitochondrial ETC have emerged as effective therapeutic agents for treating oxidative stress-related diseases. In addition, benefit from the controllability and modifiability of nanozymes, their modification with TPP, SS-31 peptide, and mitochondrial permeability membrane peptide to eliminate ROS and repair mitochondrial function. The nanozymes that specifically target mitochondria are powerful tools for the treatment of ROS-associated disorders. We discussed the design strategies pertaining to mitochondrion-targeted nanozymes to treat various diseases to develop more efficacious nanozyme tools for the treatment of ROS-related diseases in the future.

PROTAC-biomacromolecule conjugates for precise protein degradation in cancer therapy: A review.

Proteolysis targeting chimera (PROTAC) technology is a promising new mode of targeted protein degradation with significant transformative implications for the clinical treatment of different diseases. Nevertheless, while this technology offers numerous advantages, on-target off-tumour toxicity in healthy cells remains a major challenge for clinical application in cancer therapy. Strategies are presently being explored to optimize degradation activity with cellular selectivity to minimize undesirable side effects. PROTAC-antibody conjugates and PROTAC-aptamer conjugates are unique innovations that combine PROTACs and biomacromolecules. These novel PROTAC-biomacromolecule conjugates (PBCs) can enhance the targetability of PROTACs and reduce their off-target side-effects. The combination of potent PROTACs and highly safe biomacromolecules will pioneer an emerging trend in targeted protein degradation. In our review, we have summarized recent advances in PBCs, discussed current challenges, and outlooked opportunities for future research in the field.

Clinical advances in TNC delivery vectors and their conjugate agents.

Tenascin C (TNC), a glycoprotein that is abundant in the tumor extracellular matrix (ECM), is strongly overexpressed in tumor tissues but virtually undetectable in most normal tissues. Many TNC antibodies, peptides, aptamers, and nanobodies have been investigated as delivery vectors, including 20A1, α-A2, α-A3, α-IIIB, α-D, BC-2, BC-4 BC-8, 81C6, ch81C6, F16, FHK, Ft, Ft-NP, G11, G11-iRGD, GBI-10, 19H12, J1/TN1, J1/TN2, J1/TN3, J1/TN4, J1/TN5, NJT3, NJT4, NJT6, P12, PL1, PL3, R6N, SMART, ST2146, ST2485, TN11, TN12, TNFnA1A2-Fc, TNfnA1D-Fc, TNfnBD-Fc, TNFnCD-Fc, TNfnD6-Fc, TNfn78-Fc, TTA1, TTA1.1, and TTA1.2. In particular, BC-2, BC-4, 81C6, ch81C6, F16, FHK, G11, PL1, PL3, R6N, ST2146, TN11, and TN12 have been tested in human tissues. G11-iRGD and simultaneous multiple aptamers and arginine-glycine-aspartic acid (RGD) targeting (SMART) may be assessed in clinical trials because G11, iRGD and AS1411 (SMART components) are already in clinical trials. Many TNC-conjugate agents, including antibody-drug conjugates (ADCs), antibody fragment-drug conjugates (FDCs), immune-stimulating antibody conjugates (ISACs), and radionuclide-drug conjugates (RDCs), have been investigated in preclinical and clinical trials. RDCs investigated in clinical trials include 111In-DTPA-BC-2, 131I-BC-2, 131I-BC-4, 90Y-BC4, 131I81C6, 131I-ch81C6, 211At-ch81C6, F16124I, 131I-tenatumomab, ST2146biot, FDC 131I-F16S1PF(ab')2, and ISAC F16IL2. ADCs (including FHK-SSL-Nav, FHK-NB-DOX, Ft-NP-PTX, and F16*-MMAE) and ISACs (IL12-R6N and 125I-G11-IL2) may enter clinical trials because they contain components of marketed treatments or agents that were investigated in previous clinical studies. This comprehensive review presents historical perspectives on clinical advances in TNC-conjugate agents to provide timely information to facilitate tumor-targeting drug development using TNC.

The applications of nanozymes in cancer therapy: based on regulating pyroptosis, ferroptosis and autophagy of tumor cells.

Nanozymes are nanomaterials with catalytic properties similar to those of natural enzymes, and they have recently been collectively identified as a class of innovative artificial enzymes. Nanozymes are widely used in various fields, such as biomedicine, due to their high catalytic activity and stability. Nanozymes can trigger changes in reactive oxygen species (ROS) levels in cells and the activation of inflammasomes, leading to the programmed cell death (PCD), including the pyroptosis, ferroptosis, and autophagy, of tumor cells. In addition, some nanozymes consume glucose, starving cancer cells and thus accelerating tumor cell death. In addition, the electric charge of the structure and the catalytic activity of nanozymes are sensitive to external factors such as light and electric and magnetic fields. Therefore, nanozymes can be used with different therapeutic methods, such as chemodynamic therapy (CDT), photodynamic therapy (PDT) and sonodynamic therapy (SDT), to achieve highly efficient antitumor effects. Many cancer therapies induce tumor cell death via the pyroptosis, ferroptosis, and autophagy of tumor cells mediated by nanozymes. We review the mechanisms of pyroptosis, ferroptosis, and autophagy in tumor development, as well as the potential application of nanozymes to regulate pyroptosis, ferroptosis, and autophagy in tumor cells.

Doxorubicin prodrug-based nanomedicines for the treatment of cancer.

The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.

Nanozyme-assisted amplification-free CRISPR/Cas system realizes visual detection.

The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR associated) system has proven to be a powerful tool for nucleic acid detection due to its inherent advantages of effective nucleic acid identification and editing capabilities, and is therefore known as the next-generation of molecular diagnostic technology. However, the detection technologies based on CRISPR/Cas systems require preamplification of target analytes; that is, target gene amplification steps through isothermal amplification or PCR before detection to increase target analyte concentrations. This creates a number of testing limitations, such as extended testing time and the need for more sophisticated testing instruments. To overcome the above limitations, various amplification-free assay strategies based on CRISPR/Cas systems have been explored as alternatives, which omit the preamplification step to increase the concentrations of the target analytes. Nanozymes play a pivotal role in enhancing the sensitivity of CRISPR-based detection, enabling visual and rapid CRISPR assays. The utilization of nanozyme exceptional enzyme-like catalytic activity holds great promise for signal amplification in both electrochemical and optical domains, encompassing strategies for electrochemical signal sensors and colorimetric signal sensors. Rather than relying on converting a single detection target analyte into multiple analytes, these methods focus on signal amplification, the main mechanism of which involves the ability to form a large number of reporter molecules or to improve the performance of the sensor. This exploitation of nanozymes for signal amplification results in the heightened sensitivity and accuracy of detection outcomes. In addition to the strategies that improve sensor performance through the application of nanozymes, additional methods are needed to achieve visual signal amplification strategies without preamplification processes. Herein, we review the strategies for improving CRISPR/Cas systems that do not require preamplification, providing a simple, intuitive and preamplification-free CRISPR/Cas system detection platform by improving in-system one-step amplification programs, or enhancing nanozyme-mediated signal amplification strategies.

Molecular mechanisms of bladder outlet obstruction in transgenic male mice overexpressing aromatase (Cyp19a1).

We investigated the etiology and molecular mechanisms of bladder outlet obstruction (BOO). Transgenic (Tg) male mice overexpressing aromatase (Cyp19a1) under the ubiquitin C promoter in the estrogen-susceptible C57Bl/6J genetic background (AROM+/6J) developed inguinal hernia by 2 months and severe BOO by 9 to 10 months, with 100% penetrance. These mice gradually developed uremia, renal failure, renal retention, and finally died. The BOO bladders were threefold larger than in age-matched wild-type (WT) males and were filled with urine on necropsy. Hypotrophic smooth muscle cells formed the thin detrusor urinae muscle, and collagen III accumulation contributed to the reduced compliance of the bladder. p-AKT and ERα expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ERα in the intradetrusor fibroblasts suggests a specific role of this estrogen receptor form in urothelial proliferation. Inactivation of Pten, which in turn activated the p-AKT pathway, was strictly related to the activation of the ERα pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ERα and decreased expression of PTEN in severe human BOO samples, compared with subnormal to mild samples. These findings clarify the involvement of estrogen excess and/or imbalance of the androgen/estrogen ratio in the molecular pathogenetic mechanisms of BOO and provide a novel lead into potential treatment strategies for BOO.

Construction of lncRNA-ceRNA networks to reveal the potential role of Lfng/Notch1 signaling pathway in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) develops through a complex pathological process, in which many genes play a synergistic or antagonistic role. LncRNAs represent a kind of non-coding RNA, which can regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels. Multiple lncRNAs have been found to have important regulatory functions in AD. Thus, their expression patterns, targets and functions should be explored as therapeutic targets. METHODS: We used deep RNA-seq analysis to detect the dysregulated lncRNAs in the hippocampus of APP/PS1 mice. We performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to predict the biological roles and potential signaling pathways of dysregulated lncRNAs. Finally, we constructed lncRNA-miRNA-mRNA and lncRNA-mRNA co-expression networks to reveal the potential regulator roles in AD pathogenesis. RESULTS: Our findings revealed 110 significantly dysregulated lncRNAs. GO and KEGG annotations showed the dysregulated lncRNAs to be closely related to the functions of axon and protein digestion and absorption. The lncRNA-mRNA network showed that 19 lncRNAs regulated App, Prnp, Fgf10 and Il33, while 5 lncRNAs regulated Lfng via the lncRNA-miR-3102-3p-Lfng axis. Furthermore, we preliminarily demonstrated the important regulatory role of the Lfng/Notch1 signaling pathway through lncRNA-ceRNA networks in AD. CONCLUSION: We revealed the important regulatory roles of dysregulated lncRNAs in the etiopathogenesis of AD through lncRNA expression profiling. Our results showed that the mechanism involves the regulation of the Lfng/Notch1 signaling pathway.

The Interaction of Polyphenols and the Gut Microbiota in Neurodegenerative Diseases.

Polyphenols are secondary metabolites of plants and play a potential role in the prevention and treatment of neurodegenerative diseases (NND) such as Alzheimer's disease (AD) and Parkinson's disease (PD) due to their unique physiological functions such as acting as antioxidants, being anti-inflammatory, being neuroprotective, and promoting intestinal health. Since dietary polyphenols exist in plant foods in the form of glycosylation or esterification or are combined with polymers, they need to undergo extensive metabolism through phase I and phase II biotransformations by various intestinal enzymes, as well as metabolism by the intestinal microbiota before they can be fully absorbed. Polyphenols improve intestinal microbiota disorders by influencing the structure and function of intestinal microbiota, inducing beneficial bacteria to produce a variety of metabolites such as short-chain fatty acids (SCFAs), promoting the secretion of hormones and neurotransmitters, and playing an important role in the prevention and treatment of NND by affecting the microbe-gut-brain axis. We review the ways in which some polyphenols can change the composition of the intestinal microbiota and their metabolites in AD or PD animal models to exert the role of slowing down the progression of NND, aiming to provide evidence for the role of polyphenols in slowing the progression of NND via the microbiota-gut-brain (MGB) axis.

Biogenesis, functions, and clinical implications of circular RNAs in non-small cell lung cancer.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide, with high morbidity and mortality. Non-small cell lung cancer (NSCLC) is a major pathological type of LC and accounts for more than 80% of all cases. Circular RNAs (circRNAs) are a large class of non-coding RNAs (ncRNAs) with covalently closed-loop structures, a high abundance, and tissue-specific expression patterns. They participate in various pathophysiological processes by regulating complex gene networks involved in proliferation, apoptosis, migration, and epithelial-to-mesenchymal transition (EMT), as well as metastasis. A growing number of studies have revealed that the dysregulation of circRNAs contributes to many aspects of cancer progression, such as its occurrence, metastasis, and recurrence, suggesting their great potential as efficient and specific biomarkers in the diagnosis, prognosis, and therapeutic targeting of NSCLC. In this review, we systematically elucidate the characteristics, biogenesis, and functions of circRNAs and focus on their molecular mechanisms in NSCLC progression. Moreover, we highlight their clinical implications in NSCLC treatment.

Interplay between Gut Microbiota and NLRP3 Inflammasome in Intracerebral Hemorrhage.

The pathophysiological process of intracerebral hemorrhage (ICH) is very complex, involving various mechanisms such as apoptosis, oxidative stress and inflammation. As one of the key factors, the inflammatory response is responsible for the pathological process of acute brain injury and is associated with the prognosis of patients. Abnormal or dysregulated inflammatory responses after ICH can aggravate cell damage in the injured brain tissue. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex distributed in the cytosol, which can be triggered by multiple signals. The NLRP3 inflammasome is activated after ICH, thus promoting neuroinflammation and aggravating brain edema. In addition, there is evidence that the gut microbiota is crucial in the activation of the NLRP3 inflammasome. The gut microbiota plays a key role in a variety of CNS disorders. Changes in the diversity and species of the gut microbiota affect neuroinflammation through the activation of the NLRP3 inflammasome and the release of inflammatory cytokines. In turn, the gut microbiota composition can be influenced by the activation of the NLRP3 inflammasome. Thereby, the regulation of the microbe-gut-brain axis via the NLRP3 inflammasome may serve as a novel idea for protecting against secondary brain injury (SBI) in ICH patients. Here, we review the recent evidence on the functions of the NLRP3 inflammasome and the gut microbiota in ICH, as well as their interactions, during the pathological process of ICH.

Regulation of nuclear factor erythroid-2-related factor 2 as a potential therapeutic target in intracerebral hemorrhage.

Hemorrhagic stroke can be categorized into several subtypes. The most common is intracerebral hemorrhage (ICH), which exhibits significant morbidity and mortality, affecting the lives of millions of people worldwide every year. Brain injury after ICH includes the primary injury that results from direct compression as well as stimulation by the hematoma and secondary brain injury (SBI) that is due to ischemia and hypoxia in the penumbra around the hematoma. A number of recent studies have analyzed the mechanisms producing the oxidative stress and inflammation that develop following hematoma formation and are associated with the ICH induced by the SBI as well as the resulting neurological dysfunction. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a critical component in mediating oxidative stress and anti-inflammatory response. We summarize the pathological mechanisms of ICH focusing on oxidative stress and the regulatory role of Nrf2, and review the mechanisms regulating Nrf2 at the transcriptional and post-transcriptional levels by influencing gene expression levels, protein stability, subcellular localization, and synergistic effects with other transcription factors. We further reviewing the efficacy of several Nrf2 activators in the treatment of ICH in experimental ICH models. Activation of Nrf2 might produce antioxidant, anti-inflammatory, and neuron-protection effects, which could potentially be a focus for developing future treatments and prevention of ICH.