Stress/cell death pathways, neuroinflammation, and neuropathic pain.

Neuropathic pain is a common and debilitating modality of chronic pain induced by a lesion or disease of the somatosensory nervous system. Albeit the elucidation of numerous pathophysiological mechanisms and the development of potential treatment compounds, safe and reliable therapies of neuropathic pain remain poor. Multiple stress/cell death pathways have been shown to be implicated in neuroinflammation during neuropathic pain. Here, we summarize the current knowledge of stress/cell death pathways and present an overview of the roles and molecular mechanisms of stress/cell death pathways in neuroinflammation during neuropathic pain, covering intrinsic and extrinsic apoptosis, autophagy, mitophagy, ferroptosis, pyroptosis, necroptosis, and phagoptosis. Small molecule compounds that modulate stress/cell death pathways in alleviating neuropathic pain are discussed mainly based on preclinical neuropathic pain models. These findings will contribute to in-depth understanding of the pathological processes during neuropathic pain as well as bridge the gap between basic and translational research to uncover new neuroprotective interventions.

Peroxymonosulfate activation by walnut shell activated carbon supported nano zero-valent iron for the degradation of tetracycline: Performance, degradation pathway and mechanism.

In this study, activated carbon (WS-AC) was prepared from walnut shell. Nano-zero-valent iron (nZVI) was loaded on walnut shell activated carbon by liquid phase reduction method and used as catalyst (WS-AC/nZVI) to activate peroxymonosulfate (PMS) to efficiently degrade tetracycline (TC) in solution. The composite material with a mass ratio of WS-AC to nZVI of 1:1 has the highest catalytic performance for activating PMS to degrade TC. The results showed that under the conditions of TC concentration of 100 ppm, PMS dosage of 0.2 mM and WS-AC/nZVI dosage of 0.1 g/L, the removal efficiency of TC could reach 81%. Based on quenching experiments and electron spin resonance (EPR), it was verified that •OH, SO4•- and 1O2 bound on the catalyst surface were the main reactive oxygen species during the reaction. The intermediate products of TC were identified by liquid chromatography-mass spectrometry (HPLC-MS) and DFT calculation, and the possible degradation pathway of TC was proposed. The catalyst still maintained high removal efficiency of TC after four cycles of experiments, and the minimal iron loss on the surface of the catalyst indicated that it had good stability. The efficient and stable WS-AC/nZVI activated PMS showed great potential in the degradation of antibiotics.

Continuous-Flow Microreactor Accelerates Molecular Collisions for Lignin Depolymerization to Phenolic Monomers and Oligomers.

Effective depolymerization of lignin is the most important step for its comprehensive utilization. So far, most of the studies on depolymerization of lignin focused on batch processing, whereas only a few studies relied on the microreactor. In this study, we developed a continuous-flow microreactor for depolymerization of lignin into monomeric and oligomeric compounds. The yields of monomers and oligomers can be adjusted by varying the temperature, pressure, residence time, NaOH dosage, and solvent. Under optimized conditions, the lignin conversion rate was 77.73 wt %, and the monomer yield was 13.26 wt %, with 77.81% being phenolic compounds. In addition, comparative characterizations on the raw lignin and products demonstrated that the oil products were mainly composed of phenolic tetramers and trimers, and the effective cleavage of the ß-O-4 linkage of S-type lignin was responsible for the high yield of 2,6-dimethoxyphenol. It indicated that raw lignin could be effectively depolymerized continuously using the continuous-flow microreactor, and it will be a new strategy for comprehensive utilization of lignin to produce fine-chemical intermediates.

Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review.

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.

A meta-analysis comparing the effects of cemented and uncemented prostheses on wound infection and pain in patients with femoral neck fractures.

To providing evidence-based recommendations for surgery in patients with femoral neck fractures, a meta-analysis was conducted to comprehensively evaluate the effects of cemented and uncemented prostheses on postoperative surgical site wound infection and pain in these patients. Relevant studies on the use of cemented prostheses in femoral neck fractures were retrieved from PubMed, EMBASE, Cochrane Library, Ovid, CNKI, and Wanfang databases from the time of their establishment until March 2023. Two authors independently screened and extracted data from the included and excluded literature according to predetermined criteria. Review Manager 5.4 software was used to perform meta-analyses on the collected data. A total of 27 articles comprising 34 210 patients (24 646 cases in the cemented group and 9564 cases in the uncemented group) were included in the final analysis. The results of the meta-analysis showed that, compared with the uncemented group, cemented prostheses significantly reduced the incidence of surgical site wound infections (odds ratio [OR]: 0.75, 95% confidence interval [CI]: 0.64-0.88, p < 0.001) and relieved surgical site wound pain (standardised mean difference: -0.76, 95% CI: -1.12-0.40, p < 0.001), but did not reduce the incidence of pressure ulcers after surgery (OR: 0.50, 95% CI: 0.20-1.26, p = 0.140). Therefore, existing evidence suggests that the use of cemented prostheses in femoral neck fracture surgery can significantly reduce the incidence of surgical site wound infections and relieve surgical site wound pain, which is worthy of clinical recommendation.

Double-Interpenetrating-Network Lignin-based Epoxy Resin Adhesives for Resistance to Extreme Environment.

The gradually depleting fossil resources and the biosafety of bisphenol A have always restricted the green development of the traditional epoxy resin field. In this Article, biomass macromolecule lignin sulfonates are selected as the raw material instead of traditional bisphenol A to prepare lignin-based epoxy resin adhesives. Lignin sulfonates are chemically modified and combined with a cross-linking agent to form lignin-based epoxy resin adhesives with double-interpenetrating-network structures. The resulting lignin-based epoxy adhesive exhibits a maximum tensile shear strength of 11.29 MPa, which is 213% higher than the strength before chemical modification. The tensile shear strength of the adhesive is still 10.13 MPa after 12 h of immersion in water (20 °C), and its tensile shear strength is 9.30 MPa after 12 h of immersion in boiling water (100 °C). The high-temperature and high-humidity environment has no significant effect on the properties of the resulting lignin-based epoxy adhesive.

Preoperative insomnia and its association with psychological factors, pain and anxiety in Chinese colorectal cancer patients.

PURPOSE: Sleep disturbances are common in cancer patients, but little is known about preoperative insomnia and its associated factors in colorectal cancer (CRC) patients. The aim of this study was to clarify the relationship between preoperative insomnia and its associated factors (i.e., pain, anxiety, self-esteem, and coping styles) in CRC patients. METHODS: A cross-sectional study was conducted in consecutive CRC inpatients (N = 434), who were required to complete the questionnaires about insomnia, pain, anxiety, self-esteem, and coping styles (acceptance/resignation, confrontation, avoidance) before the day of surgery. Hierarchical regression analyses were conducted to explore the relationships between preoperative anxiety and its associated factors. RESULTS: Based on the cutoff value of Athens Insomnia Scale (scores ≥ 6) in Chinese cancer patients, the prevalence of insomnia was 38.2% before surgery. Pain (ß = 0.087, p = 0.015) and anxiety (ß = 0.372, p < 0.001) were positively associated with preoperative insomnia, while self-esteem (ß = - 0.479, p < 0.001) and confrontation coping (ß = - 0.124, p = 0.003) showed protective effects on preoperative insomnia when putting them together into hierarchical regression. The associated factors together accounted for an additional variance of preoperative insomnia (47.6%). CONCLUSIONS: In line with previous findings, the detrimental effects of pain and anxiety on preoperative insomnia were also observed in our study. More importantly, our main new findings were that self-esteem and confrontation coping played important roles in alleviating preoperative insomnia among CRC patients. Clinicians should take these results into account when developing cancer care management to relieve preoperative insomnia.

Identification of a five-gene signature with prognostic value in colorectal cancer.

Colorectal cancer (CRC) ranks as one of the most commonly diagnosed malignancies worldwide. Although mortality rates have been decreasing, the prognosis of CRC patients is still highly dependent on the individual. Therefore, identifying and understanding novel biomarkers for CRC prognosis remains crucial. The gene expression profiles of five-gene expression omnibus (GEO) data sets of CRC were first downloaded. A total of 352 consistent differentially expressed genes (DEGs) were identified for CRC and paired with normal tissues. Functional analysis including gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment revealed that these DEGs were related to metabolic pathways, tight junctions, and the cell cycle. Ten hub DEGs were identified based on the search tool for the retrieval of interacting genes database and protein-protein interaction networks. By using univariate Cox proportional hazard regression analysis, we found 11 survival-related genes among these DEGs. We finally established a five-gene signature (kinesin family member 15, N-acetyltransferase 2, glutathione peroxidase 3, secretogranin II, and chloride channel accessory 1) with prognostic value in CRC by step multivariate Cox regression analysis. Based on this risk scoring system, patients in the high-risk group had significantly poorer survival results compared with those in the low-risk group (log-rank test, p < 0.0001). Finally, we validated our gene signature scoring system in two independent GEO cohorts (GSE17536 and GSE33113). We found all five of the signature genes to be DEGs in The Cancer Genome Atlas database. In conclusion, our findings suggest that our five DEG-based signature can provide a novel biomarker with useful applications in CRC prognosis.

Identification of differentially expressed genes and biological characteristics of colorectal cancer by integrated bioinformatics analysis.

Colorectal cancer (CRC) ranks as one of the most common malignant tumors worldwide. Its mortality rate has remained high in recent years. Therefore, the aim of this study was to identify significant differentially expressed genes (DEGs) involved in its pathogenesis, which may be used as novel biomarkers or potential therapeutic targets for CRC. The gene expression profiles of GSE21510, GSE32323, GSE89076, and GSE113513 were downloaded from the Gene Expression Omnibus (GEO) database. After screening DEGs in each GEO data set, we further used the robust rank aggregation method to identify 494 significant DEGs including 212 upregulated and 282 downregulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by DAVID and the KOBAS online database, respectively. These DEGs were shown to be significantly enriched in different cancer-related functions and pathways. Then, the STRING database was used to construct the protein-protein interaction network. The module analysis was performed by the MCODE plug-in of Cytoscape based on the whole network. We finally filtered out seven hub genes by the cytoHubba plug-in, including PPBP, CCL28, CXCL12, INSL5, CXCL3, CXCL10, and CXCL11. The expression validation and survival analysis of these hub genes were analyzed based on The Cancer Genome Atlas database. In conclusion, the robust DEGs associated with the carcinogenesis of CRC were screened through the GEO database, and integrated bioinformatics analysis was conducted. Our study provides reliable molecular biomarkers for screening and diagnosis, prognosis as well as novel therapeutic targets for CRC.

Impact of the preoperative prognostic nutritional index on postoperative and survival outcomes in colorectal cancer patients who underwent primary tumor resection: a systematic review and meta-analysis.

PURPOSE: We aimed to explore whether the preoperative prognostic nutritional index (PNI) could be an indicator of prognostic outcomes in colorectal cancer (CRC) patients. METHODS: A systematic review and meta-analysis was conducted using the PubMed, Embase, and Web of Science databases. All original comparative studies published in English that were related to a high PNI versus a low PNI in CRC patients were included. RESULTS: A total of 10 studies involving 6372 patients were included in our meta-analysis. Our overall analysis indicated that the low-PNI group had a significantly reduced overall survival (OS) (HR = 1.87, 95% CI = 1.45-2.42, P < 0.01), cancer-specific survival (HR = 1.53, 95% CI = 1.07-2.19, P = 0.02), and disease-free survival (HR = 1.67, 95% CI = 1.23-2.26, P < 0.01) compared with the high-PNI group. Furthermore, our subgroup results indicated that a high PNI could be a significant indicator of improved OS in TNM stage II (HR = 1.93, 95% CI = 1.29-2.90, P < 0.01) and III (HR = 1.71, 95% CI = 1.25-2.34, P < 0.01), and a similar trend in TNM stage I or IV could also be observed though without statistical significance. Regarding postoperative complications, our pooled results indicated that the low-PNI group had a significantly increased incidence of total and severe postoperative complications. CONCLUSIONS: Our findings indicated that CRC patients with a preoperative high PNI had a significantly improved OS. However, almost only Asian CRC patients were included based on current issue.

Telephone-based reminiscence therapy for colorectal cancer patients undergoing postoperative chemotherapy complicated with depression: a three-arm randomised controlled trial.

BACKGROUND: Colorectal cancer patients undergoing postoperative chemotherapy often exhibit symptoms of depression that in turn may negatively affect outcome. The aim of this study was to assess the efficacy of telephone-based reminiscence therapy on the depression, anxiety, subjective well-being, and social support of colorectal cancer patients undergoing postoperative chemotherapy complicated with depression. METHODS: Patients were divided randomly into a control group (CON, n = 45), telephone support group (TS, n = 45), and telephone-based reminiscence therapy group (TBR, n = 45). Patients in TS and TBR groups received six 20-40-min telephone intervention sessions conducted weekly. Patients were assessed at baseline and at 6 weeks. The primary outcomes were changes on the Self-Rating Depression Scale (SDS) and Hamilton Depression Scale (HAMD), which were used to evaluate depression symptoms. Secondary outcomes were changes in Self-Rating Anxiety Scale (SAS), Hamilton Anxiety Scale (HAMA), Memorial University of Newfoundland Scale of Happiness (MUNSH), and Perceived Social Support Scale (PSSS) scores, which were used to evaluate anxiety symptoms, subjective well-being, and social support, respectively. RESULTS: After 6 weeks, SDS and HAMD scores were significantly lower than pre-intervention baseline in the TBR group but not in the CON and TS groups (P < 0.05). Both SAS and HAMA scores were significantly reduced in TBR and TS groups but not the CON group (P < 0.05) following intervention; however, there was no significant difference in post-intervention scores between TS and TBR groups (P > 0.05). Neither telephone support nor telephone-based reminiscence therapy improved subjective well-being or social support (P > 0.05). CONCLUSIONS: These findings suggest that telephone-based reminiscence therapy can reduce depression symptoms in colorectal cancer patients undergoing postoperative chemotherapy. Telephone-based reminiscence therapy may also improve anxiety, but no better than telephone support. Alternatively, telephone-based reminiscence therapy did not improve subjective well-being or social support. We suggest that clinicians provide appropriate telephone-based reminiscence therapy in long-term care institutions based on patient mental health status.

Factor Xa Inhibitors and Direct Thrombin Inhibitors Versus Low-Molecular-Weight Heparin for Thromboprophylaxis After Total Hip or Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: The purpose of this study is to perform a meta-analysis to compare outcomes of venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) vs other anticoagulants in patients who received total knee (TKA) or total hip arthroplasty (THA). METHODS: MEDLINE, Cochrane, EMBASE, and Google Scholar databases were searched until June 30, 2017 for eligible randomized controlled studies. RESULTS: Thirty-two randomized controlled studies were included. LMWH provided better protection against VTE than placebo. In both TKA and THA patients, the rates of VTE were lower with factor Xa inhibitors than LMWH. In THA patients, the rate of deep vein thrombosis (DVT) was lower with factor Xa inhibitors than LMWH. In TKA patients, the rates of VTE and DVT were similar between LMWH and direct thrombin inhibitors. In THA patients, the rate of VTE was lower with direct thrombin inhibitors than with LMWH, while the DVT rates were similar. The pulmonary embolism rates were similar between all 3 classes of drugs in TKA and THR patients, as were the major bleeding rates. Nonmajor and minor bleeding rates were also similar between the 3 drug classes. CONCLUSION: LMWH is associated with a higher rate of VTE than factor Xa inhibitors in TKA and THA patients. Direct thrombin inhibitors are associated with a lower rate of VTE in THA patients, but their effectiveness with respect to DVT and pulmonary embolism prophylaxis is similar to that of LMWH in TKA and THA patients.

Can sarcopenia be a predictor of prognosis for patients with non-metastatic colorectal cancer? A systematic review and meta-analysis.

PURPOSE: We aimed to explore whether sarcopenia diagnosed with the third lumbar vertebra skeletal muscle index (L3 SMI) can be a predictor of prognosis for colorectal cancer (CRC) patients. METHODS: A systematic review and meta-analysis was conducted using PubMed, Embase, and the Web of Science databases. All original comparative studies published in English that were related to sarcopenia versus non-sarcopenia in non-metastatic CRC patients based on postoperative and survival outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. RESULTS: A total of 12 studies including 5337 patients were included in our meta-analysis. In our overall analyses of postoperative outcomes, we indicated that CRC patients with sarcopenia would have longer hospital stays, higher incidence of total postoperative morbidity (OR = 1.70, 95% CI = 1.07-2.70, P < 0.01), mortality (OR = 3.45, 95% CI = 1.69-7.02, P < 0.01), and infection (OR = 2.21, 95% CI = 1.50-3.25, P < 0.01) but not anastomosis leakage or intestinal obstruction when compared to non-sarcopenia patients. Regarding survival outcomes, our results showed that sarcopenia predicted a decreased overall survival (HR = 1.63, 95% CI = 1.24-2.14, P < 0.01), disease-free survival, and cancer-specific survival for non-metastatic CRC patients. Moreover, our subgroup analyses showed similar tendency with our overall analyzed results. CONCLUSIONS: Sarcopenia diagnosed with L3 SMI can be a negative predictor of postoperative and survival outcomes for non-metastatic CRC patients. Prospective studies with a uniform definition of sarcopenia are needed to update our findings.

Effects of gelling bath on the physical properties of alginate gel beads and the biological characteristics of entrapped HepG2 cells.

Optimizing alginate gel beads is necessary to support the survival, proliferation, and function of entrapped hepatocytes. In this study, gelling bath was modified by decreasing calcium ion concentration and increasing sodium ion concentration. Alginate gel beads (using 36% G sodium alginate) prepared in the modified gelling bath had more homogeneous structure and better mass transfer properties compared with the traditional gelling bath that contains only calcium ions. Moreover, alginate gel beads generated in the modified gelling bath could significantly promote the HepG2 cell proliferation and the growth of cell spheroids, and maintain the albumin secretion ability similar to alginate gel beads prepared in the traditional gelling bath with only calcium ions. The mass transfer properties and cell proliferation were similar in ALG beads with different M/G ratio (36% G and 55% G) generated in the modified gelling bath, whereas they were significantly increased compared with alginate gel beads (55% G) in traditional gelling bath. These results indicated that adjusting the gelling bath was a simple and convenient method to enhance the mass transfer properties of alginate gel beads for 3D hepatocyte culture, which might provide more hepatocytes for the bioartificial liver support system.

Engineering islet for improved performance by optimized reaggregation in alginate gel beads.

After islet isolation, diffusion has become the main mechanism to transport oxygen and nutrients into the core of islets. However, diffusion has limitations, by which nutrients cannot effectively reach the core of large islets and can eventually cause core cell death and islet loss. This problem can be resolved by dispersing islets into single islet cells, but single islet cells do not exhibit insulin release function in in vitro culture. In this study, we intended to establish a new islet engineering approach by forming islet cell clusters to improve islet survival and function. Therefore, alginate gels were used to encapsulate islet cells to form artificial islets after dispersion of islets into single cells. The shape of the islet cell clusters was similar to native islets, and the size of the islet cell clusters was limited to a maximum diameter of 100 µm. By limiting the diameter of this engineered islet cell cluster, cell viability was nearly 100%, a significant improvement over natural islets. Importantly, islet cell clusters express the genes of islets, including Isl-1, Gcg, and insulin-1, and insulin secretion ability was maintained in vitro.

Mesenchymal stem cells enhance the metastasis of 3D-cultured hepatocellular carcinoma cells.

BACKGROUND: Accumulating evidences have demonstrated that mesenchymal stem cells (MSC) could be recruited to the tumor microenvironment. Umbilical cord mesenchymal stem cells (UCMSC) were attractive vehicles for delivering therapeutic agents against cancer. Nevertheless, the safety of UCMSC in the treatment of tumors including hepatocellular carcinoma (HCC) was still undetermined. METHODS: In this study, an in vitro co-culture system was established to evaluate the effect of UCMSC on the cell growth, cancer stem cell (CSC) characteristics, drug resistance, metastasis of 3D-cultured HCC cells, and the underlying mechanism was also investigated. RESULTS: It was found that after co-cultured with UCMSC, the metastatic ability of 3D-cultured HCC cells was significantly enhanced as indicated by up-regulation of matrix metalloproteinase (MMP), epithelial-mesenchymal transition (EMT)-related genes, and migration ability. However, cell growth, drug resistance and CSC-related gene expression of HCC cells were not affected by UCMSC. Moreover, EMT was reversed, MMP-2 expression was down-regulated, and migration ability of HCC cell was significantly inhibited when TGF-ß receptor inhibitor SB431542 was added into the co-culture system. CONCLUSIONS: Therefore, these data indicated that UCMSC could significantly enhance the tumor cell metastasis, which was due to the EMT of HCC cells induced by TGF-ß.

Potential effect of matrix stiffness on the enrichment of tumor initiating cells under three-dimensional culture conditions.

Cancer stem cell (CSC) or tumor initiating cell (TIC) plays an important role in tumor progression and metastasis. Biophysical forces in tumor microenvironment have an important effect on tumor formation and development. In this study, the potential effect of matrix stiffness on the biological characteristics of human head and neck squamous cell carcinoma (HNSCC) TICs, especially the enrichment of HNSCC TICs, was investigated under three-dimensional (3D) culture conditions by means of alginate gel (ALG) beads with different matrix stiffnesses. ALG beads with soft (21 kPa), moderate (70 kPa) and hard (105 kPa) stiffness were generated by changing alginate concentration. It was found that significant HNSCC TIC enrichment was achieved in the ALG beads with moderate matrix stiffness (70 kPa). The gene expression of stemness markers Oct3/4 and Nanog, TIC markers CD44 and ABCG2 was enhanced in cells under this moderate (70 kPa) stiffness. HNSCC TIC proportion was also highly enriched under moderate matrix stiffness, accompanying with higher tumorigenicity, metastatic ability and drug resistance. And it was also found that the possible molecular mechanism underlying the regulated TIC properties by matrix stiffness under 3D culture conditions was significantly different from 2D culture condition. Therefore, the results achieved in this study indicated that 3D biophysical microenvironment had an important effect on TIC characteristics and alginate-based biomimetic scaffolds could be utilized as a proper platform to investigate the interaction between tumor cells and 3D microenvironment.

Neuroprotective effects of cutamesine, a ligand of the sigma-1 receptor chaperone, against noise-induced hearing loss.

The sigma-1 receptor, which is expressed throughout the brain, provides physiological benefits that include higher brain function. The sigma-1 receptor functions as a chaperone in the endoplasmic reticulum and may control cell death and regeneration within the central nervous system. Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride) is a ligand selective for this receptor and may mediate neuroprotective effects in the context of neurodegenerative disease. We therefore assessed whether cutamesine protects the inner ear from noise-induced or aging-associated hearing loss. Immunohistochemistry and Western blotting revealed that the sigma-1 receptor is present in adult cochlea. We treated mice with 0, 3, or 30 mg/kg cutamesine from 10 days before noise exposure until the end of the study. All subjects were exposed to a 120-dB, 4-kHz octave-band noise for 2 hr. We assessed auditory thresholds by measuring the auditory-evoked brainstem responses at 4, 8, and 16 kHz, prior to and 1 week, 1 month, or 3 months following noise exposure. For the aging study, measurements were made before treatment was initiated and after 3 or 9 months of cutamesine treatment. Damage to fibrocytes within the cochlear spiral limbus was assessed by quantitative histology. Cutamesine significantly reduced threshold shifts and cell death within the spiral limbus in response to intense noise. These effects were not dose or time dependent. Conversely, cutamesine did not prevent aging-associated hearing loss. These results suggest that cutamesine reduces noise-induced hearing loss and cochlear damage during the acute phase that follows exposure to an intense noise.

Role of three-dimensional matrix stiffness in regulating the chemoresistance of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) was the most common primary liver cancer, and its resistance to anti-tumor drugs often caused the death of patients suffering with HCC. Matrix stiffness was reported to be closely related to tumor chemoresistance; however, the relationship between HCC drug resistance and three-dimensional (3D) matrix stiffness is still unclear at present. In this study, alginate gel (ALG) beads with controllable matrix stiffness were used to mimic tumor tissue rigidity, and the role of 3D matrix stiffness in regulating the chemoresistance of HCC cells was investigated by using these ALG beads. It was found that HCC cells in ALG beads with 105 kPa stiffness had highest resistance to paclitaxel, 5-FU, and cisplatin. Although the mechanism was still uncovered, ABC transporters and endoplasmic reticulum stress-related molecules were highly expressed in ALG bead-encapsulated HCC cells compared with two-dimensional-cultured cells, which suggested a very complex mechanism underlying HCC drug resistance in 3D culture conditions. In addition, to mimic the specific stiffness of HCC tumor tissue, or other tumor tissues in vivo, response surface methodology (RSM) was used to build up a prediction mathematical model so that ALG beads with desired matrix stiffness could be prepared by simply changing three factors: molecular weight, G content, and alginate concentration.

Encapsulated human hepatocellular carcinoma cells by alginate gel beads as an in vitro metastasis model.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often forms metastases, which are the most important prognostic factors. For further elucidation of the mechanism underlying the progression and metastasis of HCC, a culture system mimicking the in vivo tumor microenvironment is needed. In this study, we investigated the metastatic ability of HCC cells cultured within alginate gel (ALG) beads. In the culture system, HCC cells formed spheroids by proliferation and maintained in nuclear abnormalities. The gene and protein expression of metastasis-related molecules was increased in ALG beads, compared with the traditional adhesion culture. Furthermore, several gene expression levels in ALG bead culture system were even closer to liver cancer tissues. More importantly, in vitro invasion assay showed that the invasion cells derived from ALG beads was 7.8-fold higher than adhesion cells. Our results indicated that the in vitro three-dimensional (3D) model based on ALG beads increased metastatic ability compared with adhesion culture, even partly mimicked the in vivo tumor tissues. Moreover, due to the controllable preparation conditions, steady characteristics and production at large-scale, the 3D ALG bead model would become an important tool used in the high-throughput screening of anti-metastasis drugs and the metastatic mechanism research.