Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma.

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

The study of Yangyinyiqi mixture anti bleomycin-induced pulmonary fibrosis on rats by intervening matrix metalloproteinase-9 and tissue inhibitors of matrix metallopreoteinases-1 / El estudio de la mezcla Yangyinyiqi en fibrosis pulmonar inducida por anti-bleomicina en ratas por intervención en la matriz metaloproteinasa-9 e inhibidores de tejido de matriz metaloproteinasa-1

To investigate effectsof Yangyinyiqi Mixture on pulmonary fibrosis caused by bleomycin. SD ratswere divided randomly into: model group(distilled water,1 mL·0.1 kg-1), dexamethasone acetate group (dexamethasone acetate, the dosage was reduced gradually), low-dose group (Yangyinyiqi Mixture, 11 g·kg-1), moderate-dose group (Yangyinyiqi Mixture, 22 g·kg-1), high-dose group (Yangyinyiqi Mixture, 44 g·kg-1) and control group (distilled water, 1 mL·0.1 kg-1). Yangyinyiqi Mixture and dexamethasone acetate were intragastrically administrated. Lung tissue was collected for histopathological examination. Compared with control group, collagen markedly increased and HYP content significantly increased on 7th day in model group (p<0.01). On 28th day, collagen was diffusely deposited, alveolar was destroyed, and HYP content significantly increased (p<0.01). Compared with model group, bleomycin-induced suffering injury caused MMP-9 expression levels to rapidly increase (7and 14 days, p<0.01). TIMP-1 markedly increased (7and 14 days, p<0.01) and stayed at a high level to28th day. Yangyinyiqi Mixture exerted an effect against pulmonary fibrosis, which could involved prevention of collagen deposition through inhibitingMMP-9 and TIMP-1 expression.

El trabajo investiga los efectos de la mezcla Yangyinyiqi sobre la fibrosis pulmonary causada por bleomicina. Ratas SD se dividieron aleatoriamente en: grupo modelo (agua destilada, 1 mL·0.1 kg-1), grupo acetate de dexametasona (acetate de dexametasona, la dosis se redujo gradualmente), grupo de dosis baja (mezcla Yangyinyiqi, 11 g·kg-1), grupo de dosis moderada (mezcla Yangyinyiqi, 22 g·kg-1), grupo de dosis alta (mezcla Yangyinyiqi, 44 g·kg-1) y grupo control (agua destilada, 1 Ml·0.1 kg-1). La mezcla de Yangyinyiqi y el acetate de dexametasona se administraron por vía intragástrica. Se recolectó tejido pulmonary para examen histopatológico. En comparación con el grupo control, el colágeno aumentó notablemente y el contenido de HYP aumentó significativamente el séptimo día en el grupo modelo (p<0.01). El día 28, el colágeno se depositó difusamente, se produjo destrucción alveolar y el contenido de HYP aumento significativamente (p<0.01). En comparación con el grupo modelo, la lesión inducida por bleomicina causó que los niveles de expression de MMP-9 aumentaron rápidamente (7 y 14 días, p<0.01). TIMP-1 aumentó notablemente (7 y 14 días, p<0.01) y se mantuvo en un nivel alto hasta el día 28. La mezcla Yangyinyiqi ejerció un efecto contra la fibrosis pulmonary, lo que podría implicar la prevención del deposito de colágenio mediante la inhibición de la expression de MMP-9 y TIMP-1.

Meteorological impact on the COVID-19 pandemic: A study across eight severely affected regions in South America.

The role of meteorological factors in the transmission of the COVID-19 still needs to be determined. In this study, the daily new cases of the eight severely affected regions in four countries of South America and their corresponding meteorological data (average temperature, maximum temperature, minimum temperature, average wind speed, visibility, absolute humidity) were collected. Daily number of confirmed and incubative cases, as well as time-dependent reproductive number (Rt) was calculated to indicate the transmission of the diseases in the population. Spearman's correlation coefficients were assessed to show the correlation between meteorological factors and daily confirmed cases, daily incubative cases, as well as Rt. In particular, the results showed that there was a highly significant correlation between daily incubative cases and absolute humidity throughout the selected regions. Multiple linear regression model further confirmed the negative correlation between absolute humidity and incubative cases. The absolute humidity is predicted to show a decreasing trend in the coming months from the meteorological data of recent three years. Our results suggest the necessity of continuous controlling policy in these areas and some other complementary strategies to mitigate the contagious rate of the COVID-19.

Partial replacement of inorganic phosphorus (P) by organic manure reshapes phosphate mobilizing bacterial community and promotes P bioavailability in a paddy soil.

The optimization of more sustainable fertilization practice to relieve phosphorus (P) resource scarcity and increase P fertilizer utilization, a better understanding of the regulatory roles of microbes in P mobilization is urgently required to reduce P input. The genes phoD and pqqC are responsible for regulating organic and inorganic P mobilization, respectively. Using high-throughput sequencing, the corresponding bacterial communities harbored by these genes were determined. We conducted a 4-year rice-rice-crop rotation to investigate the responses of phoD- and pqqC-harboring bacterial communities to the partial replacement of inorganic P fertilizer by organic manure with reduced P input. The results showed that a combination of organic and inorganic fertilization maintained high rice yield, and also produced a more complex and stable phosphate mobilizing bacterial community, which contributed to phosphatase activities more than their gene abundances in the model analysis. Compared with the conventional mineral fertilization, organic-inorganic fertilization with the reduced P input slightly increased pqqC gene abundance while significantly enhanced the abundance of phoD-harboring bacteria, especially the genera Bradyrhizobium and Methylobacterium known as potential organic P mineralizers which can maintain high rice production. Moreover, the increased pH was the most impactful factor for the phoD- and pqqC-harboring bacterial communities, by promoting microbial P turnover and greatly increasing bioavailable P pools (H2O-Pi and NaHCO3-Pi, NaOH-Pi) in this P-deficient paddy soil. Hence, our study demonstrated that the partial replacement of mineral P with organic manure could reshape the inorganic phosphate solubilizing and alkaline-phosphomonoesterase encoding bacterial communities towards more resilient and effective to the high P utilization and productivity over intense cultivation, providing insights into the potential of soil microbes in the efficient management of agricultural P fertilization.

A modified method by differential adhesion for enrichment of bladder cancer stem cells.

PURPOSE: In a previous study the vaccine was effective against bladder cancer in a mouse model. However, a small portion of tumors regrew because the vaccine could not eliminate bladder cancer stem cells (CSCs). In this study, we showed a modified method for the isolation of bladder CSCs using a combination of differential adhesion method and serum-free culture medium (SFM) method. MATERIALS AND METHODS: Trypsin-resistant cells and trypsin-sensitive cells were isolated from MB49, EJ and 5637 cells by a combination of differential adhesion method and SFM method. The CSCs characterizations of trypsin-resistant cells were verified by the flow cytometry, the western blotting, the quantitative polymerase chain reaction, the resistance to chemotherapy assay, the transwell assay, and the tumor xenograft formation assay. RESULTS: Trypsin-resistant cells were isolated and identified in CSCs characters, with high expression of CSCs markers, higher resistance to chemotherapy, greater migration in vitro, and stronger tumorigenicity in vivo. CONCLUSION: Trypsin-resistant cells displayed specific CSCs properties. Our study showed trypsin-resistant cells were isolated successfully with a modified method using a combination of differential adhesion method and SFM method.

A modified method by differential adhesion for enrichment of bladder cancer stem cells

ABSTRACT Purpose: In a previous study the vaccine was effective against bladder cancer in a mouse model. However, a small portion of tumors regrew because the vaccine could not eliminate bladder cancer stem cells (CSCs). In this study, we showed a modified method for the isolation of bladder CSCs using a combination of differential adhesion method and serum-free culture medium (SFM) method. Materials and Methods: Trypsin-resistant cells and trypsin-sensitive cells were isolated from MB49, EJ and 5637 cells by a combination of differential adhesion method and SFM method. The CSCs characterizations of trypsin-resistant cells were verified by the flow cytometry, the western blotting, the quantitative polymerase chain reaction, the resistance to chemotherapy assay, the transwell assay, and the tumor xenograft formation assay. Results: Trypsin-resistant cells were isolated and identified in CSCs characters, with high expression of CSCs markers, higher resistance to chemotherapy, greater migration in vitro, and stronger tumorigenicity in vivo. Conclusion: Trypsin-resistant cells displayed specific CSCs properties. Our study showed trypsin-resistant cells were isolated successfully with a modified method using a combination of differential adhesion method and SFM method.

External validation and comparison of six prognostic models in a prospective cohort of HBV-ACLF in China.

UNLABELLED:  Background. Acute-on-chronic liver failure has high mortality. Currently, robust models for predicting the outcome of hepatitis B virus (HBV)-associated ACLF are lacking. AIM: To assess and compare the performance of six prevalent models for short- and longterm prognosis in patients with HBV-ACLF. MATERIAL AND METHODS: The model for end-stage liver disease (MELD), MELD sodium (MELD-Na), MELD to sodium ratio (MESO), integrated MELD, Child-Turcotte-Pugh (CTP), and modified CTP (mCTP) were validated in a prospective cohort of 232 HBV-ACLF patients. The six models were evaluated by determining discrimination, calibration and overall performance at 3 months and 5 years. RESULTS: According to the Hosmer-Lemeshow tests and calibration plots, all models could adequately describe the data except CTP at 3 months. Discrimination analysis showed that the iMELD score had the highest AUC of 0.76 with sensitivity of 62.6% and specificity of 80.2% for an optimal cut-off value of 52 at 3 months. It also had the highest AUC of 0.80 with sensitivity of 89.9% and specificity of 48.2% for an optimal cut-off value of 43 at 5 years. The overall performance of iMELD, assessed with Nagelkerke's R2 and the Brier score, was also the best among the six models. CONCLUSION: Integrated MELD may be the best model to predict short- and long-term prognosis in patients with HBV-ACLF.

Cloning, phylogenetic analysis and expression of somatolactin and its receptor in Cichlasoma dimerus: their role in long-term background color acclimation.

Somatolactin (SL) and SL receptor (SLR) belong to the growth hormone and cytokine type I receptor superfamilies, respectively. However, further research is required to define the duplications and functions of SL and its receptors in basal vertebrates including environmental background color adaptation in fish. In the present study, we cloned and sequenced SL and its putative receptor (SLR), classified and compared the sequences phylogenetically, and determined SL and SLR mRNA expression levels during long-term background color exposure in Cichlasoma dimerus, a freshwater South American cichlid. Our results show that C. dimerus SL and SLR share high sequence similarity with homologous from other perciform fish. Phylogenetic analysis indicates that C. dimerus SL belongs to the SLα clade sub-group. C. dimerus SLR is clearly a member of the GHR1 receptor subgroup, which includes the experimentally validated SLR from salmonids. Higher transcript levels of SLα in the pituitary and SLR in the epidermis and dermis cells of fish scales were observed in fish following long-term black background color exposure compared to those exposed to a white background. A higher number of melanophores was also observed in fish exposed for 10days to a black background compared to those exposed to a white background. These changes were concomitant to differences in SL or SLR transcript levels found in fish exposed to these two different background colors. Our results suggest, for the first time, that SLR is expressed in fish scales, and that there is an increase in SL in the pituitary and the putative SLR in likely target cells, i.e., melanophores, in long-term black background exposure in C. dimerus.