Hazards of microplastics exposure to liver function in fishes: A systematic review and meta-analysis.

Microplastics (5 mm - 1 µm) have become one of the major pollutants in the environment. Numerous studies have shown that microplastics can have negative impacts on aquatic organisms, affecting their liver function levels. However, the extent of these effects and their potential toxicological mechanisms are largely unknown. In this study, a meta-analysis and systematic review were conducted to assess the effects of microplastics on fish liver function and summarize the potential toxicological mechanisms of microplastic-induced liver toxicity. The meta-analysis results indicate that compared to the control group, exposure to microplastics significantly affects fish liver indicators: aspartate aminotransferase (AST) (p < 0.001), alanine aminotransferase (ALT) (p < 0.001), alkaline phosphatase (ALP) (p < 0.001), total protein (TP) (p < 0.001), and lactate dehydrogenase (LDH) (p < 0.001), including oxidative stress indicators: superoxide dismutase (SOD) (p < 0.001), glutathione S-transferase (GST) (p < 0.001), glutathione (GSH) (p < 0.001), and malondialdehyde (MDA) (p < 0.001) in fish liver. For fish living in different environments, the potential toxicological mechanisms of microplastics exposure on fish liver may exhibit some differences. For freshwater fish, the mechanism may be that microplastics exposure causes overproduction of reactive oxygen species (ROS) in fish hepatocyte mitochondria. ROS promotes the expression of toll-like receptor 2 (TLR2) and activates downstream molecules myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) of the TLR2 signaling pathway, leading to phosphorylation of NF-κB p65. This leads to the release of inflammatory factors and oxidative stress and inflammation in fish liver. In addition, for seawater fish, the mechanism may be that microplastics exposure can cause damage or death of fish hepatocytes, leading to continuous pathological changes, inflammation, lipid and energy metabolism disorders, thereby causing significant changes in liver function indexes.

Extraction, structural characterization and biological activities of polysaccharides from mulberry leaves: A review.

In recent years, plant polysaccharides have garnered attention for their impressive biological activity. Mulberry leaves have a long history of medicinal and edible use in China, polysaccharide is one of the main active components of mulberry leaves, mainly consist of xylose, arabinose, fructose, galactose, glucose and mannose, etc. The extraction methods of mulberry leaves polysaccharides (MLPs) mainly include hot water extraction, microwave-assisted extraction, ultrasonic extraction, enzyme-assisted extraction, and co-extraction. The separation and purification of MLPs involve core steps such as decolorization, protein removal, and chromatographic separation. In terms of pharmacological effects, MLPs exhibit excellent activity in reducing blood glucose, anti-oxidation, immune regulation, anti-tumor, antibacterial, anti-coagulation, and regulation of gut microbiota. Currently, there is a considerable amount of research on MLPs, however, there is a lack of systematic summarization. This review summarizes the research progress on the extraction, structural characterization, and pharmacological activities of MLPs, and points out existing shortcomings and suggests reference solutions, aiming to provide a basis for further research and development of MLPs.

Discovery of small molecule c-Maf inhibitors using molecular docking-based virtual screening, molecular dynamics simulation, and biological evaluation.

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c-Maf in most MM patients, targeting c-Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA-approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI-8226 cell line. Moreover, both compounds simultaneously downregulated c-Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c-Maf inhibitors in the future.

The role of lncRNAs and exosomal lncRNAs in cancer metastasis.

Tumor metastasis is the main reason for cancer-related death, but there is still a lack of effective therapeutic to inhibit tumor metastasis. Therefore, the discovery and study of new tumor metastasis regulators is a prominent measure for cancer diagnosis and treatment. Long non-coding RNA (lncRNA) is a type of non-coding RNAs over 200 bp in length. It has been shown that the abnormally expressed lncRNAs promote tumor metastasis by participating in the epithelial-to-mesenchymal transition (EMT) process, altering the metastatic tumor microenvironment, or changing the extracellular matrix. It is,thus, critical to explore the regulation of lncRNAs expression in cells and the molecular mechanism of lncRNA-mediated cancer metastasis. Simultaneously, it has been shown that lncRNA is one kind of the main components of exosomes, which protects lncRNAs from being rapidly degraded. Meanwhile, the components of exosomes are parent-specific, making exosomal lncRNAs to be potential tumor metastasis markers and therapeutic targets. In view of this, we also summarized the aberrant enrichment of lncRNAs in exosomes and their role in metastatic cancer. The aberrant lncRNAs and exosomal lncRNAs gradually become biomarkers and therapeutic targets for tumor metastatic, and the potential of lncRNAs in therapeutics are studied here. Besides, the lncRNA-related databases, which could greatly facilitate in the study of lncRNAs and exosomal lncRNAs in metastatic of cancer are included in this review.

Design, synthesis and biological evaluation of nitric oxide-releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives.

In this study, a series of nitric oxide (NO) -releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives were designed and synthesized. In the in vitro biological evaluation, compound 24l exhibited optimal antiproliferative activity against MGC-803 cells with the IC50 value of 0.95 µM, significantly better than that of the positive control 5-FU. In addition, preliminary mechanistic studies indicated that 24l inhibited colony formation and blocked MGC-803 cells in the G0/G1 phase. DAPI staining, reactive oxygen species and apoptosis assays demonstrated that 24l induced apoptosis of MGC-803 cells. Particularly, the most potent compound 24l produced the highest level of NO, and the antiproliferative activity was significantly reduced after preincubation with NO scavengers. In conclusion, compound 24l may be considered as a potential candidate antitumor agent.

Annual review of KRAS inhibitors in 2022.

Kirsten rat sarcoma viral (KRAS) oncogene is the most commonly mutated isoform of RAS, accounting for 85% of RAS-driven human cancers. KRAS functioning as a signaling hub participates in multiple cellular signaling pathways and regulates a variety of critical processes such as cell proliferation, differentiation, growth, metabolism and migration. Over the past decades, KRAS oncoprotein has been considered as an "undruggable" target due to its smooth surface and high GTP/GDP affinity. The breakthrough in directly targeting G12C mutated-KRAS and recently approved covalent KRASG12C inhibitors sotorasib and adagrasib broke the myth of KRAS undruggable and confirmed the directly targeting KRAS as one of the most promising strategies for the treatment of cancers. Targeting KRASG12C successfully enriched the understanding of KRAS and brought opportunities for the development of inhibitors to directly target other KRAS mutations. With the stage now set for a new era in the treatment of KRAS-driven cancers, the development of KRAS inhibitors also enters a booming epoch. In this review, we overviewed the research progress of KRAS inhibitors with the potential to treat cancers covering articles published in 2022. The design strategies, discovery processes, structure-activity relationship (SAR) studies, cocrystal structure analysis as well as in vitro and in vivo activity were highlighted with the aim of providing updated sight to accelerate the further development of more potent inhibitors targeting various mutated-KRAS with favorable drug-like properties.

The overview of Mitogen-activated extracellular signal-regulated kinase (MEK)-based dual inhibitor in the treatment of cancers.

Mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1/2) are the critical components of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) signaling pathway which is one of the well-characterized kinase cascades regulating cell proliferation, differentiation, growth, metabolism, survival and mobility both in normal and cancer cells. The aberrant activation of MAPK/ERK1/2 pathway is a hallmark of numerous human cancers, therefore targeting the components of this pathway to inhibit its dysregulation is a promising strategy for cancer treatment. Enormous efforts have been done in the development of MEK1/2 inhibitors and encouraging advancements have been made, including four inhibitors approved for clinical use. However, due to the multifactorial property of cancer and rapidly arising drug resistance, the clinical efficacy of these MEK1/2 inhibitors as monotherapy are far from ideal. Several alternative strategies have been developed to improve the limited clinical efficacy, including the dual inhibitor which is a single drug molecule able to simultaneously inhibit two targets. In this review, we first introduced the activation and function of the MAPK/ERK1/2 components and discussed the advantages of MEK1/2-based dual inhibitors compared with the single inhibitors and combination therapy in the treatment of cancers. Then, we overviewed the MEK1/2-based dual inhibitors for the treatment of cancers and highlighted the theoretical basis of concurrent inhibition of MEK1/2 and other targets for development of these dual inhibitors. Besides, the status and results of these dual inhibitors in both preclinical and clinical studies were also the focus of this review.

[Effect of Dimethyl Fumarate (DMF) on T-cell Acute Lymphoblastic Leukemia].

OBJECTIVE: To explore the effect and possible mechanism of dimethyl fumarate (DMF) on T-cell acute lymphoblastic leukemia (T-ALL), and provide experimental and theoretical basis for the clinical treatment of T-ALL. METHODS: Jurkat cells were treated with different concentrations of DMF for 24 hours, and then the proportion and absolute count of Ki67-positive Jurkat cells were analyzed by flow cytometry. Meanwhile, the protein levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and E3 ubiquitin ligase HACE1 in Jurkat cells treated with DMF for 24 hours were evaluated by Western blot. Nrf2 proteins were co-immunoprecipitated in Jurkat cells, and then HACE1 protein was assessed by Western blot. Plasmids of Flag-Nrf2 and different gradients of Flag-HACE1 were transfected into HEK293T cells, and the levels of Flag-Nrf2 were detected by Western blot after 48 hours. RESULTS: DMF could significantly inhibit the proportion and absolute count of Ki67-positive Jurkat cells, and DMF inhibited the proliferation of Jurkat cells in a dose-dependent manner (r=0.9595, r=0.9054). DMF could significantly up-regulate the protein levels of Nrf2 and E3 ubiquitin ligase HACE1 in Jurkat cells (P<0.01, P<0.01). HACE1 physically interacted with Nrf2 in Jurkat cells. Overexpression of Flag-HACE1 significantly increased the protein level of Flag-Nrf2 in a dose-dependent manner (r=0.9771). CONCLUSION: DMF inhibits the proliferation of T-cell acute lymphoblastic leukemia cell. The mechanism may be that, DMF significantly up-regulates the protein levels of Nrf2 and E3 ubiquitin ligase HACE1, and HACE1 interacts with Nrf2 and positively regulates Nrf2 protein level.

Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy.

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

Design, synthesis and antitumor activity evaluation of trifluoromethyl-substituted pyrimidine derivatives.

In order to find efficient new antitumor drugs, a series of novel trifluoromethyl-substituted pyrimidine derivatives were designed and synthesized, and the bioactivity against four human tumor cells (PC-3, MGC-803, MCF-7 and H1975) was evaluated by MTT assay. Compound 17v displayed potent anti-proliferative activity on H1975 (IC50 = 2.27 µΜ), which was better than the positive control 5-FU (IC50 = 9.37 µΜ). Further biological evaluation studies showed that compound 17v induced apoptosis of H1975 cells and arrested the cell cycle at G2/M phase. Furthermore, compound 17v induced H1975 cells apoptosis through increasing the expression of pro-apoptotic proteins Bax and p53 and down-regulating the anti-apoptotic protein Bcl-2. In addition, compound 17v was able to be tightly embedded in the active pocket of EGFR. In summary, these results demonstrated that compound 17v has a potential as a lead compound for further investigation.

Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway.

In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.

Biotransformation of androst-4-ene-3,17-dione by three fungal species Fusarium solani BH1031, Aspergillus awamori MH18 and Mucor circinelloides W12.

The microbial transformation of androst-4-ene-3,17-dione (4-AD; I) by three fungal species, involved Fusarium solani BH1031, Aspergillus awamori MH18 and Mucor circinelloides W12, has been studied. The latter two fungi were studied for the first time on biotransformation of 4-AD. The main product obtained by Fusarium solani BH1031 was 17α-oxa-D-homo-androst-1,4-diene-3,17-dione (testolactone; IV), which can be used as an anticancer agent. The main derivative yielded by Aspergillus awamori MH18 was 11α-hydroxyandrost-4-ene-3,17-dione (11α-OH-4-AD; VI), which was an important intermediate to produce Eplerenone. Meanwhile, the microbial transformation of 4-AD by Mucor circinelloides W12 produced three derivatives. Possible metabolic pathway of 4-AD via Fusarium solani BH1031 was proposed. Furthermore, the optimization for the production of 11α-OH-4-AD was carried out and the conversion rate reached to 84.0%. In this process, the dextrin and corn flour showed significant effects by response surface analysis.

The design, synthesis and anti-tumor mechanism study of new androgen receptor degrader.

Targeted protein degradation using small molecules is a novel strategy for drug development. In order to solve the problem of drug resistance in the treatment of prostate cancer, proteolysis-targeting chimeras (PROTAC) was introduced into the design of anti-prostate cancer derivatives. In this work, we synthesized two series of selective androgen receptor degraders (SARDs) containing the hydrophobic degrons with different linker, and then investigated the structure-activity relationships of these hybrid compounds. Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Among them, compound A9 displayed potent inhibitory activity against LNCaP prostate cancer cell line with IC50 values of 1.75 µM, as well as excellent AR degradation activity. Primary mechanism studies elucidated compound A9 arrested cell cycle at G0/G1 phase and induced a mild apoptotic response in LNCaP cells. Further study indicated that the degradation of AR was mediated through proteasome-mediated process. For all these reasons, compound A9 held promising potential as anti-proliferative agent for the development of highly efficient SARDs for drug-resistance prostate cancer therapies.

Association between increased mutation rates in DNMT3A and FLT3-ITD and poor prognosis of patients with acute myeloid leukemia.

A total of 133 patients with acute myeloid leukemia (AML) were enrolled in the current study and were subdivided into 4 groups: 34 harboring DNA methyltransferase 3 α (DNMT3A) + fms related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations, 37 harboring only FLT3-ITD mutation, 32 harboring only DNMT3A mutation and 30 harboring no mutations in DNMT3A and FLT3-ITD (control). Patients in all groups were administered daunorubicin and cytarabine chemotherapy regimens. The rates of complete remission (CR), 1-year relapse (RR) and 3-year overall survival (OS) were compared. Patients in the DNMT3A + FLT3-ITD mutation group exhibited higher proportions of peripheral white blood cells (WBCs) and myeloid progenitor cells compared with those in DNMT3A mutation only, FLT3-ITD mutation only and control groups (P<0.05). The rates of CD15+ and HLA-DR+ in the DNMT3A + FLT3-ITD mutation and DNMT3A mutation only groups were significantly higher than those in the FLT3-ITD mutation only and control groups (P<0.05); in addition, the rate of CD38+ in the DNMT3A + FLT3-ITD mutation and FLT3-ITD mutation only groups was significantly higher compared with that in the DNMT3A mutation only and control groups (P<0.05). The overall chemotherapy effectiveness rate, CR, 1-year RR and the 3-year OS rates of patients in the DNMT3A + FLT3-ITD mutation group were significantly worse compared with FLT3-ITD mutation only, DNMT3A mutation only and control groups (P<0.05). The results of this study indicated that increased mutation rates in DNMT3A and FLT3-ITD may be associated with increased WBC and myeloid progenitor cell counts, an inferior chemotherapy efficacy and prognosis, a lower CR rate, and higher 1-year RR and mortality rate.

2,4-Disubstituted quinazolines targeting breast cancer cells via EGFR-PI3K.

A series of novel 2,4-disubstituted quinazolines were synthesized and evaluated for their anti-tumor activity against five human cancer cells (MDA-MB-231, MCF-7, PC-3, HGC-27 and MGC-803) using MTT assay. Among them, compound 9n showed the most potent cytotoxicity against breast cancer cells. Compound 9n also significantly inhibited the colony formation and migration of MDA-MB-231 and MCF-7 cells. Meanwhile, compound 9n induced cell cycle arrest at G1 phase and cell apoptosis, as well as increased accumulation of intracellular ROS. Furthermore, compound 9n exerted anti-tumor effects in vitro via decreasing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 9n markedly decreased p-EGFR and p-PI3K expression, which revealed that compound 9n targeted breast cancer cells via interfering with EGFR-PI3K signaling pathway. Molecular docking suggested that compound 9n could indeed bind into the active pocket of EGFR. All the findings suggest that compound 9n might be a valuable lead compound for anti-tumor agents targeting breast cancer cells.

Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives.

Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 µM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.

Synthesis and biological evaluation of novel pyrimidine-benzimidazol hybrids as potential anticancer agents.

A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 µM and 1.06 to 12.89 µM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.

Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine-benzimidazol combinations.

A series of novel 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl)methyl] thio}-6-methylpyrimidine derivatives were designed, synthesized and evaluated for their cytotoxic activities against four human cancer cell lines and inhibitory activities against five type culture strains in vitro. Some of synthetic pyrimidine-benzimidazol combinations showed good inhibitory activities against Stenotrophomonas maltophilia, especially compounds 7b and 7c. Compounds 7a and 7d exhibited enhanced activities against MGC-803 in vitro, when compared to 5-Fu.

Synthesis and biological evaluation of 2,6-dichloropurine bicyclonucleosides containing a triazolyl-carbohydrate moiety.

A series of bicyclic nucleosides containing a triazolyl-carbohydrate moiety were synthesized and their antitumor activity in vitro for human cancer cell lines was also tested. Compound 11 was synthesized efficiently with 3,6-anhydro sugar 7 as raw material, while compound 7 was prepared from 1,2;5,6-di-O-isopropylidene-α-d-glucose. Compounds 12a-e were synthesized by treating compound 11 with alkynes, catalyzed by copper(I). After removal of the acetyl protecting groups, the target compounds 5a-e showed significant inhibitory activity against EC109, PC-3, MGC-803, and HGC-7 cell lines.