UNASSIGNED: Chemotherapy-induced peripheral neuropathy (CIPN) not only affects the tolerability of chemotherapy, but also causes intolerable and prolonged neuropathic pain in cancer patients. Currently, duloxetine is the only drug used to treat CIPN. However, the clinical use of this drug still faces several challenges. Therefore, we focused on traditional Chinese medicine (TCM) to find an effective and safe alternative medicine. Huangqi Guizhi Wuwu Decoction (HGWD) is a traditional Chinese medicine that has been clinically used for treating nerve pain for thousands of years. This study aimed to investigate the neuroprotective effect of HGWD on cisplatin-induced nerve injury in PC12 cells and to elucidate its potential mechanism of action.
UNASSIGNED: HGWD-containing serum and blank serum were prepared from a rat model. The protective effects of HGWD on cisplatin (10 µmol/L)-induced PC12 cell injury were assessed by a Cell Counting Kit-8 (CCK-8) assay. RNA expression in HGWD-protected PC12 cells was analyzed using RNA-seq, and subsequently, differentially expressed genes (DEGs) were further analyzed using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA).
UNASSIGNED: The CCK-8 results showed that pretreatment of PC12 cells with HGWD-containing serum (5%, 10%, 15%) significantly increased cells\' viability to 10 µmol/L cisplatin-induced cell death. RNA-seq analysis revealed 843 DEGs in the CIPN group and 249 in the HGWD group. The GSEA results in this study suggest that HGWD may treat CIPN by enhancing axon guidance.
UNASSIGNED: This study provides valuable evidence for using HGWD in treating CIPN, partially achieved by improving axon guidance pathways.

Fungal secondary metabolites have a long history of contributing to pharmaceuticals, notably in the development of antibiotics and immunosuppressants. Harnessing their potent bioactivities, these compounds are now being explored for cancer therapy, by targeting and disrupting the genes that induce cancer progression. The current study explores the anticancer potential of gliotoxin, a fungal secondary metabolite, which encompasses a multi-faceted approach integrating computational predictions, molecular dynamics simulations, and comprehensive experimental validations. In-silico studies have identified potential gliotoxin targets, including MAPK1, NFKB1, HIF1A, TDP1, TRIM24, and CTSD which are involved in critical pathways in cancer such as the NF-κB signaling pathway, MAPK/ERK signaling pathway, hypoxia signaling pathway, Wnt/β-catenin pathway, and other essential cellular processes. The gene expression analysis results indicated all the identified targets are overexpressed in various breast cancer subtypes. Subsequent molecular docking and dynamics simulations have revealed stable binding of gliotoxin with TDP1 and HIF1A. Cell viability assays exhibited a dose-dependent decreasing pattern with its remarkable IC50 values of 0.32, 0.14, and 0.53 μM for MDA-MB-231, MDA-MB-468, and MCF-7 cells, respectively. Likewise, in 3D tumor spheroids, gliotoxin exhibited a notable decrease in viability indicating its effectiveness against solid tumors. Furthermore, gene expression studies using Real-time PCR revealed a reduction of expression of cancer-inducing genes, MAPK1, HIF1A, TDP1, and TRIM24 upon gliotoxin treatment. These findings collectively underscore the promising anticancer potential of gliotoxin through multi-targeting cancer-promoting genes, positioning it as a promising therapeutic option for breast cancer.

Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

Angiogenesis is the process by which blood vessels are generated from preexisting ones. Synthetic cannabinoids represent new psychoactive substances that bind to the cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) and simulate similar effects of tetrahydrocannabinol, the primary component found in cannabis. In the present study, we used the synthetic cannabinoid EMB-FUBINACA to study its impact on brain angiogenesis. Human brain microvascular endothelial cells (HBMECs) were cultivated in DMEM media before being subjected to different concentrations of EMB-FUBINACA and the control. Cell viability and the migration rates of HBMECs were evaluated using the viability and wound healing assays, respectively. An in vitro Matrigel Tube Formation Assay was carried out to measure the angiogenic capacity of endothelial cells. Angiopoietin-1 (ANG-1), Angiopoietin-2 (ANG-2), and vascular endothelial growth factor (VEGF) mRNA expression were detected using Real-Time PCR. The released VEGF, ANG-1, and ANG-2 concentrations were detected using ELISA. Western blotting was performed to measure the levels of phosphorylated GSK-3β, VEGF, ANG-1, and ANG-2. EMB-FUBINACA stimulated endothelial cell proliferation, migration, and capillary tube-like formation and promoted the expression of proangiogenic factors on RNA and protein levels. This study points out that the synthetic cannabinoid EMB-FUBINACA is a potential candidate for further investigations to confirm its potential as an inducer of brain angiogenesis. This could encourage researchers to create a new therapeutic approach for angiogenesis-related diseases.

BACKGROUND: The present study aimed to evaluate the viability of human dental pulp stem cells (hDPSCs) exposed to boric acid (BA) and injectable platelet-rich fibrin (I-PRF).
METHODS: hDPSCs were isolated from impacted third molars. Nine milliliters of whole blood was transferred to I-PRF tubes and centrifuged at 700 rpm for 3 minutes. A BA solution was prepared by dissolving BA in a 0.1 g/ml stock solution. The cells were divided into four groups: control, I-PRF, BA, and BA + I-PRF. Cell viability was evaluated using flow cytometry. Mineralized calcium nodules were observed using Alizarin Red staining. The data were analyzed using two-way analysis of variance and Tukey\'s HSD test (p<0.05).
RESULTS: The highest percentage of viable cells was in the I-PRF group, and the lowest percentage of viable cells was in the BA group at all times. Larger calcium nodules were observed in the BA group compared to the other groups.
CONCLUSIONS: The use of I-PRF with or without BA had a positive effect on cell viability. BA and I-PRF affected the formation of mineralized calcium nodules. I-PRF and BA may be used in combination because these substances minimally reduce cell viability and promote mineralized nodule formation.

3D bioprinting with cell-laden materials is an emerging technique for fabricating functional tissue constructs. However, current cell-laden bioinks often lack sufficient cytocompatibility with commonly used UV-light sources. In this study, green to red photoinduced hydrogel crosslinking was obtained by introducing synthesized biosafety photoinitiators and used in light-based direct ink writing (DIW) 3D printing for enabling cell encapsulation successfully. The novel type II photointiators contain iodonium (ONI) and synthesized cyanine dyes CZBIN, TDPABIN, Col-SH-CZ, and Col-SH-TD with strong absorption in the range of 400-600 nm. Collagen-based macromolecule dyes Col-SH-CZ and Col-SH-TD showed excellent cytocompatibility. The photochemistry of these photoinitiators revealed an efficient photoinduced electron transfer (PET) process from the singlet excited states of the dyes to iodonium (ONI), facilitating the crosslinking of the biogels. L929 cells were encapsulated in Gel-MA hydrogels containing various photoinitiating systems and exposed to near-ultraviolet, green, or red LED irradiation. DIW-type 3D printing of Gel-MA bioink with L929 cells was also evaluated. The cell viability achieved with green light encapsulation reached 90 %. This novel approach offers promising prospects for bioprinting functional tissues with enhanced cytocompatibility under visible light conditions.

The aim of our study was to investigate the effects of cyanobacterial metabolites: microcystin-LR (MC-LR) anabaenopeptin-A (ANA-A), cylindrospermopsin (CYL), their binary and ternary mixtures on rainbow trout (Oncorhynchus mykiss) gill (RTgill-W1) cell line. We determined the following cell parameters: Hoechst and propidium iodide (PI) double staining, intracellular ATP level with luminometric assay, glutathione level with ThiolTracker Violet®- glutathione detection reagent and cytoskeletal F-actin fluorescence. The results showed that although reduction of Hoechst fluorescence was observed in both binary and ternary combinations of cyanobacterial metabolites, the mixture of MC-LR+ANA-A+CYL was the most potent inhibitor (EC50=148 nM). PI fluorescence and ATP levels were more increased in the cells exposed to the mixtures than those exposed to the individual metabolites with synergistic toxic changes suggesting apoptosis as the mechanism of cell death. Reduced glutathione level was also decreased in cells exposed both to single metabolites and their mixtures with the highest decrease and synergistic effects at 334 nM MC-LR+334 nM ANA-A+ 334 nM CYL suggesting induction oxidative stress by the tested compounds. Reduction of F-actin fluorescence was found in the cells from all of the groups exposed to individual metabolites and their mixtures, however the highest level of inhibition showed the binary MC-LR+CYL and the ternary MC-LR+ANA-A+CYL with synergistic interactions. The study suggests that in natural conditions fish gill cells may be very sensitive to individual cyanobacterial metabolites and more prone to their binary and ternary mixtures.

Microbial remediation is a viable and eco-friendly approach for decontaminating pollution. However, its effectiveness can be limited by the microorganisms\' survival and growth in changing environments. Hydrochar materials have been utilized in this study to increase the growth and atrazine degradation capabilities of Paenarthrobacter sp. KN0901, a strain capable of atrazine biodegradation. Acid-modified hydrochars exhibited a higher carbonation rate, specific surface area, and number of defect sites compared to raw hydrochar. Following three days of incubation at 15 °C, the atrazine degradation rate increased from 90.7 % to 98.2 % when utilizing H3PO4-modified hydrochar (PHC). Additionally, the addition of PHC resulted in an increase in both bacterial concentration and cell viability of strain KN0901, by 1.6 and 1.4 times, respectively. Under various conditions, including temperatures of 4 ºC and 35 ºC, as well as pH levels of 5 and 9, and dd·H2O media, PHC exhibited a significant enhancement in atrazine degradation and cell viability of strain KN0901. Furthermore, PHC demonstrated the ability to sustain high proliferation and viability of strain KN0901 over five cycles, indicating its remarkable stability and biocompatibility. This study offers a new perspective on the development and application of bioremediation approaches in restoring atrazine-polluted environments, even under challenging conditions.

Previous studies have shown that modified citrus pectin (MCP) is an anti-tumor material of food grade. In this study, two enzymatically modified Ougan (Citrus Suavissima Hort. ex Tanaka) peel pectins (EMP1 and EMP2, the ones extracted by alkali and enzymatic methods) were used to investigate their differential effects on viability and physiology of Hela cells. The results showed that EMP1 and EMP2 had 88.00 % and 81.01 % galacturonic acid, 21.31 % and 20.25 % esterification degree, 10,417 g/mol and 6416 g/mol molecular weight (Mw), 82.86 % and 50.62 % RG-I, and 8.91 % and 15.70 % HG, respectively. EMP2 had higher intensities of absorption peaks than EMP1. They were irregularly shaped, with more holes on EMP1 but more wrinkles on EMP2. Both could inhibit the growth, proliferation, migration, and invasion of HeLa cells in a concentration-dependent manner, with better efficiency in EMP2. Meanwhile, EMP2 was more efficient than EMP1 in blocking the cell cycle in S phase, resulting in apoptosis. In conclusion, the variations caused by extraction resulted in differences in anti-tumor activity of MCP and EMP2 with lower Mw and higher HG exhibited better anti-tumor effects. This study would provide an experimental basis and reference for the research and development of anti-tumor supplements from citrus pectin.

BACKGROUND: - Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia.
METHODS: - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8 h, 37 °C) or 75 mM ethanol (EtOH; 4 days, 37 °C) alone or in the presence of GET73 (1-30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay).
RESULTS: - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10-30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1-30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability.
CONCLUSIONS: - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders.