Cecal necroptosis triggers lethal cardiac dysfunction in TNF-induced severe SIRS.

Tumor necrosis factor (TNF) induces systemic inflammatory response syndrome (SIRS), and severe SIRS can serve as a model for studying animal death caused by organ failure. Through strategic cecectomy, we demonstrate that necroptosis in the cecum initiates the death process in TNF-treated mice, but it is not the direct cause of death. Instead, we show that it is the cardiac dysfunction downstream of cecum damage that ultimately leads to the death of TNF-treated mice. By in vivo and ex vivo physiological analyses, we reveal that TNF and the damage-associated molecular patterns (DAMPs) released from necroptotic cecal cells jointly target cardiac endothelial cells, triggering caspase-8 activation and subsequent cardiac endothelial damage. Cardiac endothelial damage is a primary cause of the deterioration of diastolic function in the heart of TNF-treated mice. Our research provides insights into the pathophysiological process of TNF-induced lethality.

Fructus choerospondiatis: A comprehensive review of its traditional uses, chemical composition, pharmacological activities, and clinical studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Choerospondiatis is the dried and mature fruit of Choerospondias axillaris (Roxb.) Burtt et Hill. It has been used for a long time in Tibetan and Mongolian medicine, first recorded in the ancient Tibetan medicine book "Medicine Diagnosis of the King of the Moon" in the early 8th century. Fructus Choerospondiatis shows multiple pharmacological activities, especially in treating cardiovascular diseases. AIM OF THIS REVIEW: This paper reviews the progress in research on the botanical characteristics, traditional uses, chemical constituents, pharmacological activity, clinical studies, and quality control of Fructus Choerospondiatis. This review aims to summarize current research and provide a reference for further development and utilization of Fructus Choerospondiatis resources. METHOD: The sources for this review include the Pharmacopeia of the People's Republic of China (2020), theses, and peer-reviewed papers (in both English and Chinese). Theses and papers were downloaded from electronic databases including Web of Science, PubMed, SciFinder, Scholar, Springer, and China National Knowledge Infrastructure.The search terms used were "Choerospondias axillaris", "C. axillaris", "Choerospondias axillaris (Roxb.) Burtt et Hill", "Fructus choerospondiatis", "Guangzao", "Lapsi", and "Lupsi". RESULTS: Fructus Choerospondiatis contains polyphenols, organic acids, amino acids, fatty acids, polysaccharides, and other chemical components. These ingredients contribute to its diverse pharmacological activities such as antioxidant activity, protection against myocardial ischemia-reperfusion injury, anti-myocardial fibrosis, heart rhythm regulation, anti-tumor, liver protection, and immunity enhancement. It also affects the central nervous system, with the ability to repair damaged nerve cells. CONCLUSION: Fructus Choerospondiatis, with its various chemical compositions and pharmacological activities, is a promising medicinal resource. However, it remains under-researched, particularly in pharmacodynamic material basis and quality control. These areas require further exploration by researchers in the future.

Botulinum toxin type A ameliorates adjuvant-arthritis pain by inhibiting microglial activation-mediated neuroinflammation and intracellular molecular signaling.

Chronic inflammatory pain is a serious clinical problem caused by inflammation of the joints and degenerative diseases and greatly affects patients' quality of life. Persistent pain states are thought to result from the central sensitization of nociceptive pathways in the spinal dorsal horn. Spinal microglia-mediated neuroinflammation plays a pivotal role in the development and maintenance of the central sensitization of chronic inflammatory pain. Botulinum toxin type A (BoNT/A) was recently reported to have analgesic and anti-inflammatory effects. However, the precise mechanism underlying its analgesic effect remains unclear. Although several studies have reported that BoNT/A could regulate neuroflammation, the reduction of neuroinflammation regulated by BoNT/A in chronic inflammatory pain in experimentally induced arthritis has not been reported. The aim of this study was to investigate whether BoNT/A could alleviate adjuvant-arthritis pain via modulating microglia-mediated neuroinflammation and intracellular molecular pathway. The pain behavioral tests were performed before and after CFA immunization as well as after BoNT/A injection. Western blotting and immunofluorescence staining were used to assess the changes of microglial activation markers (ionized calcium binding adaptor molecule 1, IBA-1) and phosphorylation of P38MAPK (P-p38MAPK) in the lumbar spinal cord. TNF-αand P2X4R gene expression were studied by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that (1) the activation of spinal microglia can be continued till 21 days after CFA injection, which suggested its role in the development and maintenance of chronic inflammatory pain. (2) The intra-articular administration of a single effective dose of BoNT/A (5U/10 U) on day 21 after CFA injection significantly reduced nociceptive behaviors and decreased protein overexpression and immunoreactivity for IBA-1 and P-p38MAPK in CFA induced rat. Simultaneously, BoNT/A (5 U) also inhibited the increase in TNF-α mRNA and P2X4R mRNA expression induced by CFA injection. These results suggested that BoNT/A is a potential therapeutic agent for relieving the neuroinflammation that occurs in chronic inflammatory pain by inhibiting the activation of microglial cells and the release of microglia-derived TNF-α. This effect is likely mediated by inhibiting the activation of the P2X4R-P38MAPK signaling pathways in spinal microglial cells.

ZBP1 mediates interferon-induced necroptosis.

Interferons (IFNs) play an important role in immunomodulatory and antiviral functions. IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1 (RIPK1), Fas-associated protein with death domain (FADD), or caspase-8, but the mechanism is largely unknown. Here, we report that the DNA-dependent activator of IFN regulatory factors (ZBP1, also known as DAI) is required for both type I (ß) and type II (γ) IFN-induced necroptosis. We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1, FADD, or Caspase-8 was genetically deleted, confirming the antinecroptotic role of these proteins in IFN signaling. We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1, an IFN-stimulated gene (ISG) product, as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells. The N-terminal domain (ND) of ZBP1 is important for ZBP1-ZBP1 homointeraction, and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis. The antinecroptotic function of RIPK1, FADD, and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3, since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated. ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant, as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome (SIRS) induced by TNF + IFN-γ.

HIF-1α promotes the migration and invasion of hepatocellular carcinoma cells via the IL-8-NF-κB axis.

BACKGROUND: Hypoxia plays a critical role in many cancers. Hypoxia inducible factor-1α (HIF-1α) is an important mediator of the hypoxia response. It regulates the expression of various chemokines involved in tumor growth, angiogenesis and metastasis but the associated pathway needs further investigation. METHODS: The expression level of HIF-1α was determined in hepatocellular carcinoma (HCC) cells. The correlation of interleukin-8 (IL-8) and HIF-1α was assessed by knocking down HIF-1α. These cells were also used to assess its influence on HCC cell migration and invasion was checked. Pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB, was used to confirm the associated signaling pathway. RESULTS: HIF-1α was significantly expressed in HCC cells and found to promote HCC cell migration and invasion in an IL-8-dependent manner. NF-κB was confirmed to be involved in the process. CONCLUSIONS: HIF-1α promotes HCC cell migration and invasion by modulating IL-8 via the NF-κB pathway.

Value of CNRIP1 promoter methylation in colorectal cancer screening and prognosis assessment and its influence on the activity of cancer cells.

INTRODUCTION: The aim of the study was to investigate the effect of CNRIP1 promoter methylation on the proliferative, invasive and migration potential of colorectal cancer cells, including its potential use for the early detection and prognostic assessment of colorectal cancer. MATERIAL AND METHODS: Quantitative methylation-specific PCR (qMSP) was used to detect the methylation status of the CNRIP1 promoter region in peripheral blood samples drawn from patients with colorectal adenocarcinoma, benign colorectal adenoma, and matched healthy controls. Putative CpG methylation sites were then pyrosequenced. We subsequently suppressed CNRIP1 methylation within colon cancer cells via treatment with 5-azacytidine and overexpressed colon cancer cells by transfection with a CNRIP1-overexpression pcDNA3.0 plasmid. Thereafter, the CNRIP1 methylation status and mRNA and protein expressions levels were determined. Finally, the proliferative, invasive and migration abilities of cell lines were determined with the CCK-8 and Transwell cell assays. RESULTS: There were differences in the methylation status at loci 2216, 2226, 2231, 2245, and 2254 within the promoter region of CNRIP1 between patients with colorectal adenocarcinoma, colorectal adenoma, and healthy volunteers. The methylation status of CpG sequence 2245 significantly correlated with tumor diameter, invasion depth, TNM stage, grade, and lymph node metastasis (p < 0.05). The proliferative, invasive and migration abilities of colon cancer cells treated with 5-azaC or transfected with a CNRIP1-overexpression plasmid were significantly impaired relative to negative controls (p < 0.05). CONCLUSIONS: The methylation status at locus 2245 within the CNRIP1 promoter region has potential value for the early detection and prognostic evaluation of colorectal cancers. Demethylation of the CNRIP1 promoter or overexpression of CNRIP1 can reduce the proliferative and migration abilities of colon cancer cells.

Clinical observation of docetaxel or gemcitabine combined with cisplatin in the chemotherapy after surgery for stage II-III non-small cell lung cancer.

OBJECTIVE: This study aimed to compare the efficacy and toxicity of docetaxel combined with cisplatin (DP) and gemcitabine combined with cisplatin (GP) in postoperative chemotherapy after surgery of non-small cell lung cancer (NSCLC). METHODS: A total of 92 patients diagnosed with NSCLC after surgery were enrolled, and they were treated with DP (DP group) and GP (GP group). The efficacy and toxicity of the medications were then compared. RESULTS: Approximately 92.4% (85 out of 92) of the patients received chemotherapy for more than three weeks. In DP and GP groups, the incidence rates of grade III-IV thrombocytopenia were 24.4% and 6.38%, respectively, whereas the incidence rates of alopecia were 88.9% and 25.5%, respectively. The difference between the two groups was statistically significant (P < 0.05). Disease-free survival rates in DP group in one and two years were 76.5% and 50.47%, respectively, whereas in GP group were 77.8% and 49.52%, respectively. No significant difference was observed between the two groups (P > 0.05). CONCLUSION: These results showed similar disease-free survival rates of DP and GP therapies in one and two years after surgery for NSCLC. However, DP group exhibited higher incidence of grade III-IV thrombocytopenia and alopecia than GP group. Therefore, we should select a specific treatment for each patient according to individual differences.

High Blood Glucose Levels Correlate with Tumor Malignancy in Colorectal Cancer Patients.

BACKGROUND Research shows that type 2 diabetes mellitus (T2DM) affects the risk and prognosis of colorectal cancer (CRC). Here, we conducted a retrospective study to investigate whether the clinicopathological features of CRC patients correlate with their blood glucose levels. MATERIAL AND METHODS We enrolled 391 CRC patients hospitalized in our center between 2008 and 2013. Data of their first fasting plasma glucose (FPG) and 2-h postprandial glucose (2hPPG) level after admission, their clinicopathological features, and survival were collected. The correlations between blood glucose level and clinicopathological features were analyzed by Pearson chi-square analysis. Patient survival was analyzed by Kaplan-Meier and Cox-regression analysis. RESULTS There were 116 out of the 391 CRC patients who had high blood glucose level (H-G group, 29.67%), among which 58 (14.83%), 18 (4.60%), and 40 (10.23%) were diabetes mellitus (DM), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG), respectively, while 275 (70.33%) patients had normal glucose level (N-G group). Compared with the N-G group, patients in the H-G group had larger tumor diameters and lower tumor differentiation (p<0.05). A higher ratio of patients in the H-G group also had more advanced TNM staging and more ulcerative CRC gross type (p<0.05). No significant difference was observed in patient overall survival among different glucose groups. No effect of insulin therapy on CRC development and patient survival was observed. CONCLUSIONS Blood glucose level in CRC patients correlates significantly with local tumor malignancy, but no significant effect on distant metastasis and patient overall survival was observed.

Clinical observation of docetaxel or gemcitabine combined with cisplatin in the chemotherapy after surgery for stage II-III non-small cell lung cancer.

AIM OF THE STUDY: This study aimed to compare the efficacy and toxicity of docetaxel combined with cisplatin (DP) and gemcitabine combined with cisplatin (GP) in postoperative chemotherapy after surgery of non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: A total of 92 patients diagnosed with NSCLC after surgery were enrolled, and they were treated with DP (DP group) and GP (GP group). The efficacy and toxicity of the medications were then compared. RESULTS: Approximately 92.4% (85 out of 92) of the patients received chemotherapy for more than three weeks. In the DP and GP groups, the incidence rates of grade III-IV thrombocytopenia were 24.4% and 6.38%, respectively, whereas the incidence rates of alopecia were 88.9% and 25.5%, respectively. The difference between the two groups was statistically significant (p < 0.05). Disease-free survival rates in DP group in one and two years were 76.5% and 50.47%, respectively, whereas in the GP group they were 77.8% and 49.52%, respectively. No significant difference was observed between the two groups (p > 0.05). CONCLUSIONS: These results showed similar disease-free survival rates of DP and GP therapies in one and two years after surgery for NSCLC. However, the DP group exhibited higher incidence rates of grade III-IV thrombocytopenia and alopecia than the GP group. Therefore, we should select a specific treatment for each patient according to individual differences.

Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition.

BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for colorectal cancer. Eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, has been reported to be a new oncogene in many types of human cancer. In the present study, we aimed to investigate whether eIF5A2 was involved in the chemoresistance to doxorubicin in colorectal cancer. METHODS: Cell viability was measured by CCK-8 assay with or without doxorubicin treatment. Protein expression was detected by western blot. Tumor cells were transfected with eIF5A2 siRNA or plasmid encoding eIF5A2 to down- or up regulate the expression of eIF5A2. RESULTS: We found that eIF5A2-negtive colon cancer cells (HCT116 and HT29) were more sensitive to doxorubicin compare with the eIF5A2-positive cells (LOVO and SW480). Downregulation of eIF5A2 in LOVO and SW480 cells enhanced the chemosensitivity to doxorubicin. On the contrary, overexpression of eIF5A2 reduced doxorubicin sensitivity in colon cancer cells. In addition, eIF5A2 knockdown increased the protein level of E-cadherin and reduced vimentin expression in LOVO and SW480 cells. Meanwhile, upregulation of eIF5A2 potentiated epithelial mesenchymal transition (EMT) in colon cancer cells. Moreover, blockade of EMT with Twist siRNA abolished eIF5A2-regulated chemoresistance in colon cancer cells. CONCLUSION: Our present study demonstrated that eIF5A2 promoted the chemoresistance to doxorubicin via regulation of EMT in colon cancer cells. Therefore, eIF5A2 inhibition may be a new potential strategy for the reversal of drug resistance in colorectal cancer therapy.

[Effectiveness of endoscopic ulnar neurolysis and minimal medial epicondylectomy in treating cubital tunnel syndrome with ulnar nerve subluxation].

OBJECTIVE: To investigate the methods and outcome of endoscopic ulnar neurolysis and minimal medial epicondylectomy in treatment of cubital tunnel syndrome with ulnar nerve subluxation. METHODS: Between June 2004 and June 2009, 11 cases of cubital tunnel syndrome with ulnar nerve subluxation were treated with endoscopic ulnar neurolysis and minimal medial epicondylectomy. There were 7 males and 4 females with an average age of 36 years (range, 18-47 years). All cases had numbness in little finger and ring finger. The disease duration varied from 3 to 18 months (7 months on average). Nine cases had atrophy in the first dorsal interosseous muscle and hypothenar muscles. The preoperative electromyography showed that the ulnar nerve conduction velocity (NCV) were slowed down at elbow, which was (27.0 +/- 1.5) m/s. RESULTS: All incisions healed by first intention, and no complication occurred. Eleven cases were followed up 6-37 months (19 months on average). All cases had normal sensation after 1 month of operation. The muscle strength was obviously improved in 11 cases after 3 months postoperatively (grade 4 in 7 cases and grade 3-4 in 4 cases). The postoperative electromyography showed that the NCV was obviously improved, which was (43.5 +/- 9.5) m/s, showing significant difference when compared with preoperative one (P < 0.05). According to Amadio' efficacy appraisal standard, the results were excellent in 7 cases and good in 4 cases. CONCLUSION: The method of endoscopic ulnar neurolysis and minimal medial epicondylectomy has the advantages of safety, convenient manipulation, small incision, and early recovery for cubital tunnel syndrome with ulnar nerve subluxation.

[Operative treatment of abduction and lateral rotation limitation of shoulder in obstetric brachial plexus palsy].

OBJECTIVE: To study the treatment method and effect of abduction and lateral rotation limitation of the shoulder in obstetric brachial plexus palsy (OBPP). METHODS: From February 2005 to August 2008, 11 patients with abduction and lateral rotation limitation of the shoulder in OBPP were treated with dissection of the origin of subscapular muscle, transfer of the tendons of latissimus dorsi and teres major muscle to the tendons of supraspinous and infraspinous muscles. Among them, there were 6 males and 5 females with a mean age of 6 years (1-15 years). The main clinical manifestations showed adduction, internal rotation contracture deformity of shoulder, limited active and passive external rotation and severely restricted active abduction of shoulder. The passive abduction was more than 90 degrees. According to Gilbert grading, there were 7 cases of grade 1 and 4 cases of grade 2. Based on Mallet score systems, the scores were 5 points in 3 cases, 6 points in 3 cases, and 7 points in 5 cases. The muscle strength of deltoid, supraspinatus, infraspinatus, teres major muscle and latissimus dorsi all reached 3-4 grades. RESULTS: One patient developed postoperative hematoma, wound healed after symptomatic management. Other patients achieved incision healing by first intention. All patients were followed up for 12 to 37 months (17 months on average). The active abduction and external rotation of the shoulder joints recovered obviously. The Gilbert grading were grade 2 in 1 case, grade 3 in 1 case, and grade 4 in 9 cases; the Mallet scores were 10 points in 1 case, 11 points in 2 cases, 12 points in 4 cases, 13 points in 3 cases, and 14 points in 1 case; showing significant differences when compared with those before operation (P < 0.01). The muscle strength of deltoid, supraspinatus, infraspinatus, teres major muscle and latissimus dorsi increased to 4-5 grades. CONCLUSION: The dissection of the origin of subscapular muscle, transfer of the tendons of latissimus dorsi and teres major muscle to the tendons of supraspinous and infraspinous muscles can resolve shoulder adduction, internal rotation contracture, and can enhance abduction, external rotation strength. It is an effective operation for abduction and lateral rotation limitation of the shoulder in OBPP.

[Recent development of extraplexal neurotization as a treatment for brachial plexus injuries].

OBJECTIVE: To review the recent development of extraplexal neurotization as a treatment for brachial plexus injuries. METHODS: Relevant literature was extensively reviewed. The new development, the advantages and disadvantages of extraplexal neurotization were comprehensively evaluated and analyzed. RESULTS: After many years of clinical research, great improvement in treatment of brachial plexus injuries was achieved. There were more donor nerves and better use of every donor nerve was made. CONCLUSION: Extraplexal neurotization is an effective treatment for brachial plexus injuries.

[Clinical application and efficiency of two stage multiple nerves transfer for treatment of root avulsion of brachial plexus].

OBJECTIVE: To investigate the results of two stage multiple nerves transfer for treatment of complete brachial plexus root avulsion. METHODS: Eight patients with complete brachial plexus avulsion, aging 18-38 years and with a mean 6 months interval of injury and repair, were surgically treated with the following procedures. One stage surgical procedure was that the contralateral C7 never root was transferred to the ulnar nerve, the phrenic nerve to the anterior division of upper trunci plexus brachialis and the accessory nerve to the suprascapular nerve. Two stage surgical procedure was that the ulnar nerve was transferred to the median nerve , the intercostal nerves to the radial nerve and the thoracodorsal nerve. RESULTS: All patients were followed up from 13 months to 25 months (21 months on average), muscle reinnervation was observed in all patients. Return of muscle power of M3 or better are regarded as effective. The effective recovery results were 75% in musculocutaneous nerve, 37.5% in suprascapular nerve, 37.5% in radial nerve, 75% in thoracodorsal nerve and 62.5% in median nerve. In sensory recovery of the median nerve, 4 patients obtained S3, 3 patients S2 and 1 patient S1. CONCLUSION: Two stage multiple nerves transfer for treatment of root avulsion of brachial plexus can achieve better motor function results and is safe and effective. The procedure should be recommended for treatment of root avulsion of brachial plexus in selected patients with complete brachial plexus root avulsion, especially in young patients with a short interval between injury and repair. It is one of the alternative options.