The enhancing effects of selenomethionine on harmine in attenuating pathological cardiac hypertrophy via glycolysis metabolism.

Pathological cardiac hypertrophy, a common feature in various cardiovascular diseases, can be more effectively managed through combination therapies using natural compounds. Harmine, a ß-carboline alkaloid found in plants, possesses numerous pharmacological functions, including alleviating cardiac hypertrophy. Similarly, Selenomethionine (SE), a primary organic selenium source, has been shown to mitigate cardiac autophagy and alleviate injury. To explores the therapeutic potential of combining Harmine with SE to treat cardiac hypertrophy. The synergistic effects of SE and harmine against cardiac hypertrophy were assessed in vitro with angiotensin II (AngII)-induced hypertrophy and in vivo using a Myh6R404Q mouse model. Co-administration of SE and harmine significantly reduced hypertrophy-related markers, outperforming monotherapies. Transcriptomic and metabolic profiling revealed substantial alterations in key metabolic and signalling pathways, particularly those involved in energy metabolism. Notably, the combination therapy led to a marked reduction in the activity of key glycolytic enzymes. Importantly, the addition of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) did not further potentiate these effects, suggesting that the antihypertrophic action is predominantly mediated through glycolytic inhibition. These findings highlight the potential of SE and harmine as a promising combination therapy for the treatment of cardiac hypertrophy.

Aculeaquamides B and C, two new paraherquamides from the co-culture of Aspergillus aculeatinus WHUF0198 and Penicillium sp. DM27.

Two new paraherquamides (PHQs) namely aculeaquamides B and C (1 and 2), along with four known PHQs (3-6), were isolated from the co-culture of marine fungus Aspergillus aculeatinus WHUF0198 and mangrove-associated fungus Penicillium sp. DM27. Compound 1 represents the first PHQ derivative featuring an uncommon 7/6/5/5/6/5 hexacyclic system. The structures of the isolated compounds were elucidated based on exhaustive NMR spectroscopy measurement and HRESIMS data. The absolute configurations of new compounds were determined by TDDFT-ECD calculations. Compound 3 demonstrated suppression of AngII-induced cardiac hypertrophy while exhibiting relatively low cardiomyocyte toxicity.

Glutamine supplementation improves the activity and immunosuppressive action of induced regulatory T cells in vitro and in vivo.

BACKGROUND: Glutamine is crucial for the activation and efficacy of T cells, and may play a role in regulating the immune environment. This study aimed to investigate the potential role of glutamine in the activation and proliferation of induced regulatory T cells (iTregs). METHODS: CD4+CD45RA+T cells were sorted from peripheral blood mononuclear cells and cultured to analyze iTreg differentiation. Glutamine was then added to the culture system to evaluate the effects of glutamine on iTregs by determining oxidative phosphorylation (OXPHOS), apoptosis, and cytokine secretion. Additionally, a humanized murine graft-versus-host disease (GVHD) model was constructed to confirm the efficacy of glutamine-treated iTregs in vivo. RESULTS: After being cultured in vitro, glutamine significantly enhanced the levels of Foxp3, CTLA-4, CD39, CD69, IL-10, TGF-ß, and Ki67 (CTLA-4, IL-10, TGF-ß are immunosuppressive markers of iTregs) compared with that of the control iTregs (P < 0.05). Furthermore, the growth curve showed that the proliferative ability of glutamine-treated iTregs was better than that of the control iTregs (P < 0.01). Compared with the control iTregs, glutamine supplementation significantly increased oxygen consumption rates and ATP production (P < 0.05), significantly downregulated Annexin V and Caspase 3, and upregulated BCL2 (P < 0.05). However, GPNA significantly reversed the effects of glutamine (P < 0.05). Finally, a xeno-GVHD mouse model was successfully established to confirm that glutamine-treated iTregs increased the mice survival rate, delayed weight loss, and alleviated colon injury. CONCLUSION: Glutamine supplementation can improve the activity and immunosuppressive action of iTregs, and the possible mechanisms by which this occurs are related to cell proliferation, apoptosis, and OXPHOS.

Application of Laennec extrathecal blockade combined with indocyanine green fluorescence imaging in laparoscopic anatomic hepatectomy.

OBJECTIVE: To investigate the safety and application value of combining Laennec extracapsular occlusion with ICG fluorescence imaging in laparoscopic anatomic hepatectomy. METHODS: Complete laparoscopic dissection was performed outside the Laennec sheath, blocking Glisson's pedicle of the corresponding liver segment or lobe. An appropriate amount of indocyanine green (ICG) dye was intravenously injected, and the boundary line between the pre-cut liver segment and liver lobe was identified using fluorescence laparoscopy. Complete resection of the liver segment or lobe was performed based on anatomical markers. Clinical data, including operation time, intraoperative blood loss, postoperative hospital stay, and postoperative complications, were collected. RESULTS: A total of 14 cases were included in the study, including seven cases of primary liver cancer, three cases of metastatic liver cancer, three cases of intrahepatic bile duct calculi, and one case of hepatic hemangioma. All 14 patients underwent anatomic hepatectomy under fluorescent laparoscopy, with four cases involving the right liver, seven cases involving the left liver, two cases involving the right anterior lobe, and one case involving the right posterior lobe. CONCLUSION: Combining laparoscopic follow-up of the Laennec membrane with Glisson outer sheath block and intraoperative ICG fluorescence imaging provides real-time guidance for locating the resection boundaries during anatomic hepatectomy. This approach helps in controlling intraoperative bleeding, reducing operation time, and ensuring high safety. It holds significant value in clinical application.

Recent discoveries of the role of histone modifications and related inhibitors in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is a common response of the heart to various pathological stimuli. In recent years, various histone modifications, including acetylation, methylation, phosphorylation and ubiquitination, have been identified to have crucial roles in regulating chromatin remodeling and cardiac hypertrophy. Novel drugs targeting these epigenetic changes have emerged as potential treatments for pathological cardiac hypertrophy. In this review, we provide a comprehensive summary of the roles of histone modifications in regulating the development of pathological cardiac hypertrophy, and discuss potential therapeutic targets that could be utilized for its treatment.

Pyroptosis in neurodegenerative diseases: from bench to bedside.

The central nervous system regulates all aspects of physiology to some extent. Neurodegenerative diseases (NDDs) lead to the progressive loss and dysfunction of neurons, which are particularly evident in Alzheimer's disease, Parkinson's disease, and many other conditions. NDDs are multifactorial diseases with complex pathogeneses, and there has been a rapid increase in the prevalence of NDDs. However, none of these diseases can be cured, making the development of novel treatment strategies an urgent necessity. Numerous studies have indicated how pyroptosis induces inflammation and affects many aspects of NDD. Therefore, components related to pyroptosis are potential therapeutic candidates and are attracting increasing attention. Here, we review the role of pyroptosis in the pathogenesis of NDDs and potential treatment options. Additionally, several of the current drugs and relevant inhibitors are discussed. Through this article, we provide theoretical support for exploring new therapeutic targets and updating clinical treatment strategies for NDDs. Notably, pyroptosis, a recently widely studied mode of cell death, is still under-researched compared to other traditional forms of cell death. Moreover, the focus of research has been on the onset and progression of NDDs, and the lack of organ-specific target discovery and drug development is a common problem for many basic studies. This urgent problem requires scientists and companies worldwide to collaborate in order to develop more effective drugs against NDDs.

Regulatory T cells (Tregs) in liver fibrosis.

The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2-dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.

Association between per- and polyfluoroalkyl substances exposure and risk of diabetes: a systematic review and meta-analysis.

BACKGROUND: Emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the etiology of diabetes. OBJECTIVES: This study aimed to systematically review the epidemiological evidence on the associations of PFAS with mortality and morbidity of diabetes and to quantitatively evaluate the summary effect estimates of the existing literature. METHODS: We searched three electronic databases for epidemiological studies concerning PFAS and diabetes published before April 1, 2022. Summary odds ratio (OR), hazard ratio (HR), or ß and their 95% confidence intervals (CIs) were respectively calculated to evaluate the association between PFAS and diabetes using random-effects model by the exposure type, and dose-response meta-analyses were also performed when possible. We also assessed the risk of bias of the studies included and the confidence in the body of evidence. RESULTS: An initial literature search identified 1969 studies, of which 22 studies were eventually included. The meta-analyses indicated that the observed statistically significant PFAS-T2DM associations were consistent in cohort studies, while the associations were almost non-significant in case-control and cross-sectional studies. Dose-response meta-analysis showed a "parabolic-shaped" association between perfluorooctanoate acid (PFOA) exposure and T2DM risk. Available evidence was rated with "low" risk of bias, and the level of evidence for PFAS and incident T2DM was considered "moderate". CONCLUSIONS: Our findings suggest that PFAS exposure may increase the risk of incident T2DM, and that PFOA may exert non-monotonic dose-response effect on T2DM risk. Considering the widespread exposure, persistence, and potential for adverse health effects of PFAS, further cohort studies with improvements in expanding the sample size, adjusting the covariates, and considering different types of PFAS exposure at various doses, are needed to elucidate the putative causal associations and potential mode of action of different PFAS on diabetes. IMPACT STATEMENT: A growing body of evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the development of diabetes. However, epidemiological evidence on the associations of PFAS and diabetes is inconsistent. We performed this comprehensive systematic review and meta-analysis to quantitatively synthesize the evidence. The findings of this study suggest that exposure to PFAS may increase diabetes risk among the general population. Reduced exposure to these "forever and everywhere chemicals" may be an important preventative approach to reducing the risk of diabetes across the population.

Hominibacterium faecale gen. nov., sp. nov., an anaerobic L-arginine-degrading bacterium isolated from human feces.

Two anaerobic, mesophilic bacteria SF3T and ASD5510 were isolated from human feces in two different countries. Strain SF3T shared 99.9% of 16S rRNA gene sequence similarity with strain ASD5510, and 92.8% similarity with the most similar strain Aminipila butyrica DSM 103574T. Strain SF3T was an anaerobic, Gram-stain-positive bacterium. Cells of strain SF3T were short rods with 0.3-0.4 µm in width × 2.0-2.4 µm in length and occurred mostly in pairs or short chains. Spore formation was not observed. The strain grew optimally at 35 °C (range from 20 to 45 °C), pH 7.5 (pH 6.0-8.5) and without NaCl addition (range from 0 to 20 g l-1 NaCl). Yeast extract was an essential growth factor for strain SF3T, L-arginine and γ-aminobutyrate were utilized as substrates for growth. The major cellular fatty acids were iso-C15:0 and C16:0 DMA. The main polar lipids were aminophospholipid (APL), diphosphatidylglycerol (DPG) and phosphatidylethanolamine (PE). The G + C content of the genomic DNA of the strain SF3T was 47.38 mol %. The paired genomic average amino acid identity (AAI) and percentage of conserved proteins (POCP) values showed relatedness of less than 61.0 and 39.4% with type strains of order Eubacteriales. On the basis of phenotypic, phylogenetic and phylogenomic evidence strain SF3T constitutes a novel species in a novel genus, for which the name Hominibacterium faecale gen. nov., sp. nov. is proposed. The type strain is SF3T (= CCAM 730T = JCM 34755T = KCTC 25324T).

The Hepatoprotective Effect of Leonurine Hydrochloride Against Alcoholic Liver Disease Based on Transcriptomic and Metabolomic Analysis.

Excessive alcohol consumption can eventually progress to alcoholic liver disease (ALD). The underlying mechanism of ALD toxicity is primarily associated with oxidative damage. Many alkaloids have been reported to possess potential antioxidative efficacy, while the mechanism of their hepatoprotective activity against ALD is still not clear. In this study, eight alkaloids were selected from a monomer library of Traditional Chinese Medicine and evaluated for their antioxidant activity against ALD by the evaluation of Glutathione (GSH) and Malondialdehyde (MDA). The result suggested that Leonurine hydrochloride (LH) was a potent antioxidant that could reduce alcoholic liver damage. To further investigate the underlying mechanism of LH against ALD, the molecular pathway induced by LH was identified by RNA-seq analyses. Transcriptome data revealed the principal mechanism for the protective effect of LH against ALD might be attributed to the differentially expressed genes (DEGs) of PI3K-AKT, AMPK, and HIF-1 signaling pathways involved in the lipid metabolism. Given the hepatoprotective mechanism of LH is involved in lipid metabolism, the lipid metabolism induced by LH was further analyzed by UHPLC-MS/MS. Metabolome analysis indicated that LH significantly regulated glycerophospholipid metabolism including phosphatidylcholine, 1-acyl-sn-glycero-3-phosphocholine, phosphatidylethanolamine and 1-acyl-sn-glycero-3-phosphoethanolamine in the liver. Overall, this study revealed that the hepatoprotective mechanism of LH against alcoholic liver damage might be associated with the genes involved in glycerophospholipid metabolism.

Association Between Exposure to Per- and Polyfluoroalkyl Substances and Birth Outcomes: A Systematic Review and Meta-Analysis.

Background: A large body of emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) affect birth outcomes in various pathways, but the evidence is inconsistent. Therefore, this study aimed to systematically review the epidemiological evidence on PFAS exposure and birth outcomes. Methods: Three electronic databases were searched for epidemiological studies through February 13, 2021. We used random-effects meta-analysis for eight birth outcome indicators to calculate summary effect estimates for various exposure types. The risk of bias and the overall quality and level of evidence for each exposure-outcome pair were assessed. Results: The initial search identified 58 potentially eligible studies, of which 46 were ultimately included. Many PFAS were found to have previously unrecognized statistically significant associations with birth outcomes. Specifically, birth weight (BW) was associated with PFAS, with effect sizes ranging from -181.209 g (95% confidence interval (CI) = -360.620 to -1.798) per 1 ng/ml increase in perfluoroheptanesulfonate (PFHpS) to -24.252 g (95% CI = -38.574 to -9.930) per 1 ln (ng/ml) increase in perfluorodecaoic acid (PFDA). Similar patterns were observed between other PFAS and birth outcomes: perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with birth length (BL) and ponderal index (PI), PFOS and perfluorododecanoic acid (PFDoDA) with head circumference (HC), PFHpS with gestational age (GA), and perfluorononanoic acid (PFNA) and PFHpS with preterm birth (PTB). Additionally, PFDA showed a statistically significant association with small for gestational age (SGA). The level of the combined evidence for each exposure-outcome pair was considered to be "moderate". Conclusion: This study showed that PFAS exposure was significantly associated with increased risks of various adverse birth outcomes and that different birth outcome indicators had different degrees of sensitivity to PFAS. Further studies are needed to confirm our results by expanding the sample size, clarifying the effects of different types or doses of PFAS and the time of blood collection on birth outcomes, and fully considering the possible confounders.

Traffic noise and adiposity: a systematic review and meta-analysis of epidemiological studies.

Traffic noise has attracted much attention as a significant and intractable public health threat. This study was designed as a systematical review to explore the association of traffic noise with different indicators of obesity, thus providing updated quantitative estimates for the pooled effect estimates of the existing literature. We conducted an extensive search for epidemiological studies that investigated the association of traffic noise with obesity in three electronic databases till February 23, 2021. We used random-effects meta-analysis to calculate the summary effect estimates for each 10-dB(A) increase in noise and compared the highest with the lowest category of noise in relation to seven obesity indicators. Meanwhile, we assessed the risk of bias and the overall quality of the evidence of each study as well as the level of evidence for each exposure-outcome pair. The initial search identified 30 studies, 13 of which were ultimately included. The meta-analysis for the highest versus the lowest category of noise exposure was generally associated with higher waist circumfluence (WC) ranging from 0.326 cm (95% confidence interval (CI) = 0.078, 0.574) to 0.705 cm (95% CI = 0.071, 1.340) and higher odds of central obesity ranging from 1.055 (95% CI = 1.000, 1.109) to 1.167 (95% CI = 1.037, 1.298). When the continuous exposure (each 10 dB(A) increase in noise) was introduced, similar results were found. This study indicated positive associations of traffic noise with WC and central obesity. However, in consideration of some limitations, there is an urgent need for future studies to increase the sample size, discriminate the etiological differences in different noise and obesity indicators, and thoroughly consider socioeconomic status.

Effects and Mechanism of Ganoderma lucidum Polysaccharides in the Treatment of Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats.

Ganoderma lucidum polysaccharides (GLP) have renal protection effect but there was no study on the diabetic nephropathy. This study was designed to investigate its effect and mechanism using a diabetic rat model induced by streptozotocin (50 mg/kg, i.p.). The diabetic rats were treated with GLP (300 mg/kg/day) for 10 weeks. The blood glucose, glycated hemoglobin, body weight, and the levels of blood creatinine, urea nitrogen, and urine protein were assessed. And renal pathologies were assessed by the tissue sections stained with hematoxylin-eosin, Masson's trichome, and periodic acid-Schiff. The expression of phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR), the autophagy proteins beclin-1, LC3-II, LC3-I, and P62; the apoptosis-related proteins caspase-3 and caspase-9; and the inflammation markers IL-6, IL-1ß, and TNF-ɑ were assessed. Results showed that GLP alleviated the impairment of renal function by reducing urinary protein excretion and the blood creatinine level and ameliorated diabetic nephropathy. The expression of p-PI3K, p-Akt, and p-mTOR in the diabetic kidney were significantly reduced in the GLP treatment group compared to the without treatment group. GLP treatment activated the autophagy indicators of beclin-1 and the ratio of LC3-II/LC3-I but reduced p62 and also inhibited the expression of caspase-3, caspase-9 and IL-6, IL-1ß, and TNF-ɑ. In conclusion, the effect of GLP amelioration diabetic nephropathy may be via the PI3k/Akt/mTOR signaling pathway by inhibition of the apoptosis and inflammation and activation of the autophagy process.

Treatment of hepatic venous system hemorrhage and carbon dioxide gas embolization during laparoscopic hepatectomy via hepatic vein approach.

With the improvement of laparoscopic surgery, the feasibility and safety of laparoscopic hepatectomy have been affirmed, but intraoperative hepatic venous system hemorrhage and carbon dioxide gas embolism are the difficulties in laparoscopic hepatectomy. The incidence of preoperative hemorrhage and carbon dioxide gas embolism could be reduced through preoperative imaging evaluation, reasonable liver blood flow blocking method, appropriate liver-breaking device, controlled low-center venous pressure technology, and fine-precision precision operation. In the case of blood vessel rupture bleeding in the liver vein system, after controlling and reducing bleeding, confirm the type and severity of vascular damage in the liver and venous system, take appropriate measures to stop the bleeding quickly and effectively, and, if necessary, transfer the abdominal treatment in time. In addition, to strengthen the understanding, prevention and emergency treatment of severe CO2 gas embolism in laparoscopic hepatectomy is also the key to the success of surgery. This study aims to investigate the methods to deal with hepatic venous system hemorrhage and carbon dioxide gas embolization based on author's institutional experience and relevant literature. We retrospectively analyzed the data of 60 patients who received laparoscopic anatomical hepatectomy of hepatic vein approach for HCC. For patients with intraoperative complications, corresponding treatments were given to cope with different complications. After the operation, combined with clinical experience and literature, we summarized and discussed the good treatment methods in the face of such situations so that minimize the harm to patients as much as possible.

Thermosynergistes pyruvativorans gen. nov., sp. nov., an anaerobic, pyruvate-degrading bacterium from Shengli oilfield, and proposal of Thermosynergistaceae fam. nov. in the phylum Synergistetes.

A strictly anaerobic, thermophilic, Gram-stain-negative bacterium, named as strain S15T, was isolated from oily sludge of Shengli oilfield in PR China. Cells of strain S15T were straight or slightly curved rods with 0.4-0.8 µm width × 1.4-3 µm length and occurred mostly in pairs or short chains. Endospore-formation was not observed. The strain grew optimally at 55 °C (range from 30-65 °C), pH 6.5 (pH 6.0-8.5) and 0-30 g l-1 NaCl (optimum with 10 g l-1 NaCl). Yeast extract was an essential growth factor for strain S15T. The major cellular fatty acid was iso-C15 : 0 (58.2 %), and the main polar lipids were amino phospholipid (APL), glycolipids (GLs) and phosphatidylethanolamine (PE). The G+C content of DNA of strain S15T was 52.2 mol%. Strain S15T shared 89.8 % 16S rRNA gene similarity with the most related organism Acetomicrobium hydrogeniformans DSM 22491T in the phylum Synergistetes. The paired genomic average amino acid identity (AAI) and percentage of conserved proteins (POCP) values showed relatedness of less than 58.0 and 39.7 % with type strains of the species in the phylum Synergistetes. On the basis of phenotypic, phylogenetic and phylogenomic evidences, strain S15T constitutes a novel species in a novel genus, for the name Thermosynergistes pyruvativorans gen. nov., sp. nov. is proposed. The type strain is S15T (=CCAM 583T=JCM 33159T). Thermosynergistaceae fam. nov. is also proposed.

IGF2BP1/UHRF2 Axis Mediated by miR-98-5p to Promote the Proliferation of and Inhibit the Apoptosis of Esophageal Squamous Cell Carcinoma.

OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor worldwide. Its five-year survival rate has decreased significantly in recent years. This study was aimed at exploring the roles of the IGF2BP1/UHRF2 axis and miR-98-5p in the progression of esophageal squamous cell carcinoma. METHODS: The ESCC tissues and paracancerous tissues were collected from the 40 patients with ESCC after surgical resection at the First Affiliated Hospital of Chongqing Medical University (Chongqing, China) from January 2019 to January 2020. The clinicopathological characteristics of these patients were analyzed. Gene expression in all specimens was tested to detect miR-98-5p expression. The function of miR-98-5p on ESCC cell proliferation and apoptosis was performed in vitro. The relationship between UHRF2, IGF2BP1, and miR-98-5p was analyzed by IP assay, bioinformatics methods, and Western bolt. RESULTS: The expression of miR-98-5p decreased in 32/40 (80.0%) of the ESCC patient samples. Kaplan-Meier survival analysis of the TCGA cohort grouped by miR-98-5p levels produced significant differences in overall survival (log rank p=0.027). miR-98-5p suppressed ESCC progression. IGF2BP1 and UHRF2 promoted ESCC invasion and proliferation, and they inhibited apoptosis through miR-98-5p mediation. CONCLUSION: miR-98-5p and the IGF2BP1/UHRF2 axis might have the biological functions of regulating cell proliferation and apoptosis in the progression of ESCC, which might provide potential novel targets, such as miR-98-5p, in the treatment of esophageal squamous cell carcinoma.

Ubiquitination Regulators Discovered by Virtual Screening for the Treatment of Cancer.

The ubiquitin-proteasome system oversees cellular protein degradation in order to regulate various critical processes, such as cell cycle control and DNA repair. Ubiquitination can serve as a marker for mutation, chemical damage, transcriptional or translational errors, and heat-induced denaturation. However, aberrant ubiquitination and degradation of tumor suppressor proteins may result in the growth and metastasis of cancer. Hence, targeting the ubiquitination cascade reaction has become a potential strategy for treating malignant diseases. Meanwhile, computer-aided methods have become widely accepted as fast and efficient techniques for early stage drug discovery. This review summarizes ubiquitination regulators that have been discovered via virtual screening and their applications for cancer treatment.

Simultaneous blocking of the pan-RAF and S100B pathways as a synergistic therapeutic strategy against malignant melanoma.

Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five-year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF-selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan-RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan-RAF and S100B pathways.

Time-Resolved Luminescent High-Throughput Screening Platform for Lysosomotropic Compounds in Living Cells.

Lysosomes are membrane-bound organelles that regulate protein degradation and cellular organelle recycling. Homeostatic alteration by lysosomotropic compounds has been suggested as a potential approach for the treatment of cancer. However, because of the high false-negative rate resulting from strong fluorescent background noise, few luminescent high-throughput screening methods for lysosomotropic compounds have been developed for cancer therapy. Imidazole is a five-membered heterocycle that can act within the acidic interior of lysosomes. To develop an efficient lysosomotropic compound screening system, we introduced an imidazole group to iridium-based complexes and designed a long-lifetime lysosomal probe to monitor lysosomal activity in living cells. By integrating time-resolved emission spectroscopy (TRES) with the novel iridium-based lysosomal probe, a high-throughput screening platform capable of overcoming background fluorescent interference in living cells was developed for discovering lysosomotropic drugs. As a proof-of-concept, 400 FDA/EMA-approved drugs were screened using the TRES system, revealing five compounds as potential lysosomotropic agents. Significantly, the most promising potent lysosomotropic compound (mitoxantrone) identified in this work would have showed less activity if screened using a commercial lysosomal probe because of interference from the intrinsic fluorescence of mitoxantrone. We anticipate that this TRES-based high-throughput screening system could facilitate the development of more lysosomotropic drugs by avoiding false results arising from the intrinsic fluorescence of both bioactive compounds and/or the cell background.

Recent Progress and Development of G-Quadruplex-Based Luminescent Assays for Ochratoxin A Detection.

Ochratoxin A (OTA) is a mycotoxin that is widespread throughout the world. It contaminates foods such as vegetables, fruits, and rice. It harms human health and has potential carcinogenic effects. The G-quadruplex (G4) is a tetraplexed DNA structure generated from guanine-rich DNA that has found emerging use in aptamer-based sensing systems. This review outlines the status of OTA contamination and conventional detection methods for OTA. Various G4-based methods to detect OTA developed in recent years are summarized along with their advantages and disadvantages compared to existing approaches.