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In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment. [ABSTRACT FROM AUTHOR]

The increasing prevalence of orthopedic‐related diseases necessitates the development of effective orthopedic implants. Conventional metal scaffolds used in orthopedic devices have limitations such as poor biocompatibility and the need for a second surgery to remove the scaffold. Degradable metal‐based scaffolds, including metal‐based scaffolds and multifunctional scaffolds doped with metal elements, are a rapidly developing tissue engineering strategy aimed at utilizing the mechanical and biological properties of metal elements to create a support structure that matches the complex bone regeneration environment. Repairing bone defects involves the regeneration of various tissues, and incomplete repair can negatively affect bone function and overall recovery. Therefore, combining metal‐based degradable materials with other active components has great potential for enhancing the versatility and clinical applications of scaffolds. Multifunctional scaffolds doped with metal elements have better biocompatibility, osteoinductivity, biodegradability, matching mechanical, and microenvironmental adjustment capabilities. Moreover, these metal‐doped scaffolds possess the advantages of controlled release of metal ions, multifunctionality, and faster degradation. This review focuses on the materials and techniques used for constructing degradable metal‐based scaffolds. Furthermore, this study discussed the potential for designing and constructing multifunctional biodegradable metal‐based scaffolds doped with metal elements by integrating multiple strategies. [ABSTRACT FROM AUTHOR]

The development of primary liver cancer (PLC) is associated with chronic liver inflammation and the loss of associated tumor suppressor genes, which characterizes inflammation-related tumors. In this study, we aimed to explore the effect of saikosaponin-b2 (SS-b2) on the development of PLC and its effect of the STK4 expression and IRAK1/NF-κB signaling axis. In vitro and in vivo experiments showed that SS-b2 exerted potent anti-inflammatory and antitumor effects. A PLC model was induced in vivo by treating male BALB/c mice with diethylnitrosamine, while an inflammatory model was induced in vitro by exposing RAW 264.7 macrophages to lipopolysaccharides (LPS). After treating cancer mice with SS-b2, the serum levels of alpha-fetoprotein, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly reduced. Ki67 expression also decreased. The carcinomatous lesions of the liver were attenuated. Similar results were observed in liver tissue and RAW 264.7 macrophages, where SS-b2 significantly elevated serine/threonine protein kinase 4 (STK4) expression and decreased the expression of interleukin-1 receptor–associated kinase 1 (IRAK1), nuclear factor-kappaB (NF-κB), and downstream inflammatory cytokines, thus exerting anti-cancer and anti-inflammatory effects. Moreover, we employed siRNA to silence the STK4 expression in HepG2 to investigate the anti-tumor effect of SS-b2 in vitro. The STK4 knockdown would upregulate IRAK1 and thus the activation of NF-κB activity revealed by the increase in the levels of proinflammatory cytokines, consequently impairing SS-b2-induced inhibition of liver cancer development. Consequently, SS-b2 effectively inhibited PLC by upregulating STK4 to suppress the IRAK1/NF-κB signaling axis and is a promising agent for treating this disease. [ABSTRACT FROM AUTHOR]

Objectives: 3D‐printing scaffold with specifically customized and biomimetic structures gained significant recent attention in tissue engineering for the regeneration of damaged bone tissues. However, constructed scaffolds that simultaneously promote bone regeneration and in situ inhibit bacterial proliferation remains a great challenge. This study aimed to design a bone repair scaffold with in situ antibacterial functions. Materials and Methods: Herein, a general strategy is developed by using epigallocatechin‐3‐gallate (EGCG), a major green tea polyphenol, firmly anchored in the nano‐hydroxyapatite (HA) and coating the 3D printed polymerization of caprolactone and lactide (PCLA) scaffold. Then, we evaluated the stability, mechanical properties, water absorption, biocompatibility, and in vitro antibacterial and osteocyte inductive ability of the scaffolds. Results: The coated scaffold exhibit excellent activity in simultaneously stimulating osteogenic differentiation and in situ resisting methicillin‐resistant Staphylococcus aureus colonization in a bone repair environment without antibiotics. Meanwhile, the prepared 3D scaffold has certain mechanical properties (39.3 ± 3.2 MPa), and the applied coating provides the scaffold with remarkable cell adhesion and osteogenic conductivity. Conclusion: This study demonstrates that EGCG self‐assembled HA coating on PCLA surface could effectively enhance the scaffold's water absorption, osteogenic induction, and antibacterial properties in situ. It provides a new strategy to construct superior performance 3D printed scaffold to promote bone tissue regeneration and combat postoperative infection in situ. [ABSTRACT FROM AUTHOR]

Vitamin K epoxide reductases (VKORs) are a large family of integral membrane enzymes found from bacteria to humans. Human VKOR, specific target of warfarin, has both the epoxide and quinone reductase activity to maintain the vitamin K cycle. Bacterial VKOR homologs, however, are insensitive to warfarin inhibition and are quinone reductases incapable of epoxide reduction. What affords the epoxide reductase activity in human VKOR remains unknown. Here, we show that a representative bacterial VKOR homolog can be converted to an epoxide reductase that is also inhibitable by warfarin. To generate this new activity, we first substituted several regions surrounding the active site of bacterial VKOR by those from human VKOR based on comparison of their crystal structures. Subsequent systematic substitutions narrowed down to merely eight residues, with the addition of a membrane anchor domain, that are responsible for the epoxide reductase activity. Substitutions corresponding to N80 and Y139 in human VKOR provide strong hydrogen bonding interactions to facilitate the epoxide reduction. The rest of six substitutions increase the size and change the shape of the substrate‐binding pocket, and the membrane anchor domain stabilizes this pocket while allowing certain flexibility for optimal binding of the epoxide substrate. Overall, our study reveals the structural features of the epoxide reductase activity carried out by a subset of VKOR family in the membrane environment. [ABSTRACT FROM AUTHOR]

The global physiological function of specifically expressed genes of mitoxantrone (MTX)‐resistant prostate cancer (PCa) is unclear. In this study, gene expression pattern from microarray data was investigated for identifying differentially expressed genes (DEGs) in MTX‐resistant PCa xenografts. Human PCa cell lines DU145 and PC3 were cultured in vitro and xenografted into severe combined immunodeficiency (SCID) mice, treated with MTX intragastrically, three times a week until all mice relapsed. Gene expression profiles of the xenografts from castrated mice were performed with Affymetrix human whole genomic oligonucleotide microarray. The Cytoscape software was used to investigate the relationship between proteins and the signalling transduction network. A total of 355 overlapping genes were differentially expressed in MTX‐resistant DU145R and PC3R xenografts. Of these, 16 genes were selected to be validated by quantitative real‐time PCR (qRT‐PCR) in these xenografts, and further tested in a set of formalin‐fixed, paraffin‐embedded and optimal cutting temperature (OCT) clinical tumour samples. Functional and pathway enrichment analyses revealed that these DEGs were closely related to cellular activity, androgen synthesis, DNA damage and repair, also involved in the ERK/MAPK, PI3K/serine‐threonine protein kinase, also known as protein kinase B, PKB (AKT) and apoptosis signalling pathways. This exploratory analysis provides information about potential candidate genes and may bring new insights into the molecular cascade involvement in MTX‐resistant PCa. [ABSTRACT FROM AUTHOR]

Manganese superoxide dismutase (MnSOD) plays a critical role in the defense against reactive oxygen species. The association between MnSOD Val16Ala polymorphism and cancer risk has been widely studied, but the results are contradictory. To obtain more precision on the association, we performed the current meta-analysis with 33,098 cases and 37,831 controls from 88 studies retrieved from PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association. We found that the polymorphism was associated with an increased overall cancer risk (homozygous: OR=1.09, 95% CI = 1.00–1.19; heterozygous: OR=1.07, 95% CI = 1.02–1.12; dominant: OR=1.08, 95% CI = 1.02–1.14; and allele comparison: OR=1.06, 95% CI = 1.02–1.11). Stratification analysis further showed an increased risk for prostate cancer, Asians, Caucasians, population-based studies, hospital-based studies, low quality and high quality studies. However, the increased risk for MnSOD Val16Ala polymorphism among Asians needs further validation based on the false-positive report probability (FPRP) test. To summarize, this meta-analysis suggests that the MnSOD Val16Ala polymorphism is associated with significantly increased cancer risk, which needs further validation in single large studies. [ABSTRACT FROM AUTHOR]

Domoic acid (DA) is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are involved in DA-induced cognitive functional impairment. Therefore, therapeutics targeted to improve mitochondrial function and increase oxidative stress defence could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuroprotective effects and anti-oxidative ability, but its preventive effects on DA-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. In this study, we evaluated the effects of quercetin on DA-induced cognitive deficits in mice and explored its potential mechanism. Our results showed that the oral administration of quercetin to DA-treated mice significantly improved their behavioural performance in a novel objective recognition task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of PPARγ coactivator 1α-mediated mitochondrial biogenesis signalling and an amelioration of mitochondrial dysfunction. Moreover, quercetin activated nuclear factorerythroid-2-related factor-2 (Nrf2)-mediated phase II enzymes and decreased reactive oxygen species and protein carbonylation. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated group. Taken together, these findings suggest that a reduction in mitochondrial dysfunction through the increase of AMPK activity, coupled with an increase in Nrf2 pathway mediated oxidative defence, may be one of the mechanisms by which quercetin improves cognitive impairment induced by DA in mice. [ABSTRACT FROM AUTHOR]

Background: Despite initial indications that the transcription factor Twist could be used as a breast cancer prognostic marker, there still exists some controversy about its reliability. Thus, the aim of the present study was to assess the relationship between Twist expression and prognosis in breast carcinoma. Materials and methods: We identified eligible studies that reported an association between Twist expression and breast cancer prognosis by searching the literature in PubMed, Embase, the Cochrane Library, and Web of Science databases, through June 5, 2017. Studies investigating Twist protein or mRNA expression as well as reporting survival data in breast cancer were included. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (95% CI) were used to estimate associations. Results: A total of 2,671 patients from seven included studies were assessed, and the data indicated that increased Twist expression significantly correlated with poor overall survival (OS) (HR, 1.15; 95% CI, 1.00–1.33; P = 0.04) in breast cancer. In addition, we also observed a significant correlation of elevated Twist expression with larger tumor size (OR, 1.92; 95% CI, 1.31–2.81; P = 0.0009), lymph node involvement (OR, 3.81; 95% CI, 1.16–12.54; P = 0.03), higher nuclear grade (OR, 1.45; 95% CI, 1.06–2.00; P = 0.02), and positive human epidermal growth factor receptor 2 (HER2) status (OR, 1.49; 95% CI, 1.06–2.09; P = 0.02). However, no correlation between Twist expression and disease-free survival (DFS), age, estrogen receptor (ER) status, and progesterone receptor (PR) status was observed. Conclusions: Our results demonstrate that Twist over-expression is a statistically significant indicator of OS in breast cancer. In addition, our meta-analysis shows that increased Twist expression is significantly associated with larger tumor size, lymph node involvement, higher nuclear grade, and positive HER2 status. [ABSTRACT FROM AUTHOR]

The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

The mouse double minute 2 (MDM2) gene encodes a negative regulator for p53, and the polymorphism SNP285 in the promoter region of MDM2 gene has been implicated in cancer risk, but individual published studies had inconclusive results. Therefore, we performed this meta-analysis to obtain a more precise estimation between MDM2 SNP285 polymorphism and risk of cancer. A systematic literature search was performed using the PubMed, Embase, and Chinese Biomedical (CBM) databases. Ultimately, 16 published studies comprising 14,573 cases and 9,115 controls were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of associations. Overall, MDM2 SNP285 polymorphism was significantly associated with a decreased overall cancer risk with the heterozygous model (OR = 0.89, 95% CI = 0.79–0.99), and reduced ORs were observed with other genetic models (dominant: OR = 0.90, 95% CI = 0.79–1.01 and allele comparison: OR = 0.91, 95% CI = 0.80–1.03) but not reaching statistical significance. Stratification analysis indicated a decreased risk for ovarian cancer, Caucasians, and studies with relatively large sample size. Despite some limitations, this meta-analysis indicated that the MDM2 SNP285 polymorphism was associated with a decreased cancer risk, which warrants further validation in large and well-designed studies. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy has become the fist-line treatment of metastatic prostate cancer; however, progression to castrate resistance disease occurs in the majority of patients. Thus, there is an urgent need for improvements in therapy for castration-resistant prostate cancer. The aims of the present study were to determine the efficacy somatostatin analogue octreotide (OCT) combined with a low dose of docetaxel (DTX) using castration resistant prostate cancer cells and to investigate the involved molecular mechanisms in vitro. The anti-proliferative and synergism potential effects were determined by MTT assay. Induction of apoptosis was analyzed employing annexing V and propidium iodide staining and flow cytometry. VEGFA, CASP9, CASP3 and ABCB1 gene expression was evaluated by RT-PCR and Q-RT-PCR analysis. OCT in combination with DTX treatments on DU145 cell migration was also evaluated. Investigation revealed that combined administration of DTX and OCT had significant, synergistically greater cytotoxicity than DTX or OCT treatment alone. The combination of the two drugs caused a more marked increase in apoptosis and resulted in greater suppression of invasive potential than either individual agent. There was obvious increase in caspase 3 expression in the OCT alone and two-drug combined treatment groups, however, VEGFA expression was markedly suppressed in them. These results support the conclusion that somatostatin analogues combined with docetaxel may enhance the chemotherapy efficacies through multiple mechanisms in castration-resistant PCa cell line. This work provides a preclinical rationale for the therapeutic strategies to improve the treatment in castrate resistance disease. [ABSTRACT FROM AUTHOR]

The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl4-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment. [ABSTRACT FROM AUTHOR]

Paeoniflorin (PF) is a natural monoterpene glycoside in Paeonia lactiflora pall with anti-diabetic, antioxidant, anti-inflammatory, and neuro-protective properties. This study was designed to investigate the neuroprotective effects of PF against cognitive deficits induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in mice. STZ was injected twice intracerebroventrically (3 mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with PF (10 mg/kg per day, intraperitoneally) starting from the first dose of STZ for 21 days showed an improvement in ICV-STZ induced cognitive deficits as assessed by novel object recognition and Morris water maze (MWM) test. PF significantly attenuated STZ induced mitochondrial dysfunction manifested by dramatically elevated cytochrome c oxidase activity and ATP synthesis, and restoration of the mitochondrial membrane potential (MMP), and oxidative stress in hippocampus and in the cortex compared to control. Moreover, PF treatment also markedly increased synaptic density in the CA1 region of the hippocampus compared to control. Furthermore, PF ameliorated defective insulin signaling by up-regulating p-PI3K and p-Akt protein expression while downregulating p-IRS-1 protein expression. Taken together, the outcomes of the current study suggest the therapeutic potential of PF in the cognitive deficits induced by ICV-STZ. [ABSTRACT FROM AUTHOR]

Increasing evidence has shown that diabetes-associated cognitive impairment is correlated with mitochondrial dysfunction and resultant synaptic injury as well as brain insulin resistance. Cardiotrophin-1 (CT-1), a regulator of energy metabolism, has been shown to exhibit impressive neuroprotective effects. In this study, we evaluated the effects of CT-1 on brain pathological features in intracerebroventrical-streptozotocin (ICV-STZ)-treated mouse model, and explored its potential mechanisms. STZ was injected twice (3 mg/kg, ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with CT-1 (1 μg/day, ICV) starting from the first dose of STZ for 14 days showed that CT-1 significantly improved learning and memory deficits, alleviated mitochondrial dysfunction, and increased synaptic density in the CA1 region of the hippocampus in ICV-STZ-treated mice. Moreover, CT-1 significantly enhanced insulin signaling pathway in the hippocampus of ICV-STZ-treated mice when compared with the control. However, all the protective effects including biochemistry, pathological changes and cognitive function could be blocked by an ICV injection of Compound C, a specific AMPK inhibitor. Taken together, these results suggested that CT-1 improves pathological changes and cognitive impairments via AMPK activation in ICV-STZ mice. [ABSTRACT FROM AUTHOR]

A novel ratiometric electrochemical aptasensor was constructed for the detection of carcinoembryonic antigen (CEA) based on a hairpin DNA (hpDNA) probe and exonuclease Ⅰ (Exo Ⅰ)-assisted target recycling amplification strategy. A thiolated methylene blue (MB)-labeled hpDNA as the internal control element was fixed on the surface of the gold nanoparticles (AuNPs)-modified gold electrode (AuE) through Au–S bonds. A ferrocene (Fc)-modified aptamer DNA (Fc-Apt) was partially hybridized with hpDNA to form a Fc-Apt/hpDNA duplex. Due to the specific recognition of Fc-Apt to CEA, the presence of CEA caused dissociation of Fc-Apt from the duplex, and further triggered the degradation process of Exo Ⅰ and recycling of CEA. Hence, the Fc tags were released from the electrode surface and the oxidation peak current of Fc (I Fc) decreased while that of MB (I MB) remained stable owing to the distance between MB tags and the electrode unchanged. A linear relationship was observed between I Fc /I MB and the logarithm of CEA concentration from 10 pg mL−1 to 100 ng mL−1 with a detection limit of 1.9 pg mL−1. Moreover, the developed aptasensor had been applied to detect CEA in diluted human serum with satisfactory results, indicating its great potential in practical applications. [Display omitted] • A novel ratiometric electrochemical aptasensor was developed for CEA detection. • Methylene blue (MB)-labeled hairpin DNA was used as control probe. • Ferrocene (Fc)-modified aptamer DNA was used as signal probe. • The strategy showed a limit of detection of 1.9 pg mL−1. [ABSTRACT FROM AUTHOR]

Based on the structure of the anti-HIV drug cabotegravir, we introduced 1,2,3-triazole groups with different substituents to obtain 19 cabotegravir derivatives and tested their activity against HepG2 cells. The proliferation of HepG2 cells was examined following treatment with derivatives. Most of the compounds demonstrated significant inhibitory effects, particularly compounds KJ-5 and KJ-12 with IC 50 values of 4.29 ± 0.10 and 4.07 ± 0.09 μM, respectively. Furthermore, both compounds 5 and 12 significantly caused cell apoptosis, G2/M arrest, and DNA damage, and suppressed invasion and migration in a concentration-dependent manner. In addition, KJ-5 and KJ-12 could trigger apoptosis via the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating cleaved caspase-9, cleaved caspase-3, and cleaved PARP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xie, Mao, Fan, Wu, Wang, Hou, Wang, Wang, Liu and Li.)

In pursuit of discovering novel anticancer agents, we designed and synthesized a series of novel 1,2,3-triazole hybrids based on cabotegravir analogues. These compounds were subjected to initial biological evaluations to assess their anticancer activities against non-small-cell lung cancer (NSCLC). Our findings indicated that some of these compounds exhibited promising antitumor abilities against H460 cells, while demonstrated less efficacy against H1299 cells. Notably, compound 5i emerged as the most potent, displaying an IC 50 value of 6.06 μM. Furthermore, our investigations into cell apoptosis and reactive oxygen species (ROS) production revealed that compound 5i significantly induced apoptosis and triggered ROS generation. Additionally, Western blot analysis revealed the pronounced elevation of LC3 expression in H460 cells and γ-H2AX expression in H1299 cells subsequent to treatment with compound 5i. These molecular responses potentially contribute to the observed cell death phenomenon. These findings highlight the potential of compound 5i as a promising candidate for further development as an anticancer agent especially lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guo, Sang, Guo, Wang, Xu, Wang, Hou, Mao, Li and Li.)

Poly(rC)-binding proteins (PCBPs), a defined subfamily of RNA binding proteins, are characterized by their high affinity and sequence-specific interaction with poly-cytosine (poly-C). The PCBP family comprises five members, including hnRNP K and PCBP1-4. These proteins share a relatively similar structure motif, with triple hnRNP K homology (KH) domains responsible for recognizing and combining C-rich regions of mRNA and single- and double-stranded DNA. Numerous studies have indicated that PCBPs play a prominent role in hematopoietic cell growth, differentiation, and tumorigenesis at multiple levels of regulation. Herein, we summarized the currently available literature regarding the structural and functional divergence of various PCBP family members. Furthermore, we focused on their roles in normal hematopoiesis, particularly in erythropoiesis. More importantly, we also discussed and highlighted their involvement in carcinogenesis, including leukemia and lymphoma, aiming to clarify the pleiotropic roles and molecular mechanisms in the hematopoietic compartment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Wei, Shen, Chen, Hao, Li and Wang.)

Exosomes are representative of a promising vehicle for delivery of biomolecules. Despite their discovery nearly 40 years, knowledge of exosomes and extracellular vesicles (EVs) and the role they play in etiology of disease and normal cellular physiology remains in its infancy. EVs are produced in almost all cells, containing nucleic acids, lipids, and proteins delivered from donor cells to recipient cells. Consequently, they act as mediators of intercellular communication and molecular transfer. Recent studies have shown that, exosomes are associated with numerous physiological and pathological processes as a small subset of EVs, and they play a significant role in disease progression and treatment. In this review, we discuss several key questions: what are exosomes, why do they matter, and how do we repurpose them in their strategies and applications in drug delivery systems. In addition, opportunities and challenges of exosome-based theranostics are also described and directions for future research are presented.

Geraniin has been reported to possess potent anti-inflammatory properties and to modulate the macrophage polarization. This study sought to evaluate the protective effects and underlying mechanisms of geraniin on lipopolysaccharide (LPS)-induced neuroinflammation and neurobiological alternations as well as cognitive impairment. Daily intragastrical administration with geraniin (20 mg kg -1 day -1 ) for 14 days significantly prolonged the duration in the target quadrant (26.53 ± 2.03 versus 37.09 ± 3.27%; p < 0.05) and increased crossing-target number (1.93 ± 0.22 versus 3.08 ± 0.17; p < 0.01) in the probe test of LPS-treated mice. Geraniin also ameliorated LPS-elicited neural/synaptic impairments and decreased levels of LPS-induced Aβ generation ( p < 0.05), amyloid precursor protein (APP) ( p < 0.05) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) ( p < 0.05). Furthermore, geraniin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) (9.85 ± 0.58 versus 5.20 ± 0.52 pg/mg of protein; p < 0.01), interleukin (IL)-1β (16.31 ± 0.67 versus 8.62 ± 0.46 pg/mg of protein; p < 0.01), and IL-6 (12.12 ± 0.45 versus 7.43 ± 0.32 pg/mg of protein; p < 0.05), and inhibited glial cell activation. Moreover, geraniin effectively polarized the microglia toward an anti-inflammatory M2 phenotype. Further study revealed that geraniin targeted toll-like receptor 4 (TLR4)-mediated signaling and decreased the production of pro-inflammatory cytokines in BV-2 microglial cells. These results indicate that geraniin mitigates LPS-elicited neural/synaptic neurodegeneration, amyloidogenesis, neuroinflammation, and cognitive impairment and suggest geraniin as a therapeutic option for neuroinflammation-associated neurological disorders, such as Alzheimer's disease.

The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl 4 -induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl 4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.

Numerous studies have examined the associations of three promoter polymorphisms (-1082A/G, -819T/C and -592A/C) in IL-10 gene with cancer susceptibility in the Chinese population, but the results remain inconclusive. To gain a more precise estimation of this potential association, we conducted the current meta-analysis based on 53 articles, including 26 studies with 4,901 cases and 6,426 controls for the -1082A/G polymorphism, 33 studies with 6,717 cases and 8,550 controls for the -819T/C polymorphism, and 42 studies with 9,934 cases and 13,169 controls for the -592A/C polymorphism. Pooled results indicated that the three promoter polymorphisms in IL-10 gene were significantly associated with an increased overall cancer risk in the Chinese population. Stratification analysis showed that the association was more pronounced for hepatocellular carcinoma and low quality studies for the -1082A/G polymorphism, lung cancer and oral cancer for the -819T/C polymorphism. However, the -592A/C polymorphism was associated with a statistically significant increased risk for lung cancer, oral cancer, hospital-based studies and low quality studies, but a decreased risk for colorectal cancer. We further investigated the significant results using the false-positive report probability (FPRP) test. Interestingly, FPRP test results revealed that only IL-10 -1082A/G polymorphism was truly associated with an increased overall cancer risk. In the subgroup analysis, only the low quality studies, lung cancer and colorectal cancer remained significant at the prior level of 0.1. Although this association needs further confirmation by considering large studies, this meta-analysis suggested an association between IL-10 gene polymorphisms and cancer risk in the Chinese population., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Methionine synthase reductase (MTRR) is a key regulatory enzyme involved in the folate metabolic pathway. Previous studies investigating the association of MTRR A66G polymorphism with cancer susceptibility reported inconclusive results. We performed the current meta-analysis to obtain a more precise estimation of the possible association. Published literatures were identified from PubMed, Embase and CBM databases up to October 2016. The strength of the association between the MTRR A66G polymorphism and cancer susceptibility was assessed using odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Eighty five published studies with 32,272 cases and 37,427 controls were included in this meta-analysis. Pooled results indicated that the MTRR A66G polymorphism was associated with an increased overall cancer risk (homozygous model: OR = 1.08, 95% CI = 1.02-1.15, P = 0.009; recessive model: OR = 1.06, 95% CI = 1.00-1.12, P < 0.001 and allele comparison: OR = 1.03, 95% CI = 1.00-1.06, P < 0.001). Stratification analysis further indicated significant associations in head and neck cancer, Caucasians, Africans, and high quality studies. However, to avoid the "false-positive report", the significant findings were assessed by the false-positive report probability (FPRP) test. Interestingly, the results of FPRP test revealed that the increased risk for MTRR A66G polymorphism among Africans need further validation due to the high probabilities of false-positive results. This meta-analysis suggests that the MTRR A66G polymorphism is associated with significantly increased cancer risk, a finding that needs to be confirmed in single large studies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD.

In order to probe into the patho-physiology semicarbazide-sensitive amine oxidase (SSAO), we determined the variation of its activity in the days of 3T3-F442A cells' differentiation into adipocytes in vitro. The differentiated 3T3-F442A cells were collected in various days and disrupted by ultrasonication. Then we studied the SSAO activity of the collected cells by oxidase-linked spectrophotometric assay. In the course of 3T3-F442A cells' differentiation, SSAO expression was shown by a curve graph. There was no SSAO detected in 3T3-F442A preadipocyte, and only a little of SSAO was detected in the cells on the 3rd day of differentiation. Since then, SSAO significantly increased and reached to a maximum level six or seven days after the cells' differentiation.