Histamine deficiency exacerbates cisplatin-induced ferroptosis in cochlea hair cells of HDC knockout mice.

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC-/-) mice and histamine receptor 1 (H1R) antagonist were utilized to investigate the influence of HDC/histamine/H1R signaling on ototoxicity. The results identified HDC and H1R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC-/- mice increased. Furthermore, histamine deficiency or suppression of H1R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H1R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H1R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO.

Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation.

Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (H1R) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using Apolipoprotein E-knockout (ApoE-/-) mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC-/-) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. KEY MESSAGES: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE-/- mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.

Mutual communication between radiosensitive and radioresistant esophageal cancer cells modulates their radiosensitivity.

Radiotherapy is an important treatment modality for patients with esophageal cancer; however, the response to radiation varies among different tumor subpopulations due to tumor heterogeneity. Cancer cells that survive radiotherapy (i.e., radioresistant) may proliferate, ultimately resulting in cancer relapse. However, the interaction between radiosensitive and radioresistant cancer cells remains to be elucidated. In this study, we found that the mutual communication between radiosensitive and radioresistant esophageal cancer cells modulated their radiosensitivity. Radiosensitive cells secreted more exosomal let-7a and less interleukin-6 (IL-6) than radioresistant cells. Exosomal let-7a secreted by radiosensitive cells increased the radiosensitivity of radioresistant cells, whereas IL-6 secreted by radioresistant cells decreased the radiosensitivity of radiosensitive cells. Although the serum levels of let-7a and IL-6 before radiotherapy did not vary significantly between patients with radioresistant and radiosensitive diseases, radiotherapy induced a more pronounced decrease in serum let-7a levels and a greater increase in serum IL-6 levels in patients with radioresistant cancer compared to those with radiosensitive cancer. The percentage decrease in serum let-7a and the percentage increase in serum IL-6 levels at the early stage of radiotherapy were inversely associated with tumor regression after radiotherapy. Our findings suggest that early changes in serum let-7a and IL-6 levels may be used as a biomarker to predict the response to radiotherapy in patients with esophageal cancer and provide new insights into subsequent treatments.

Use of Ceftazidime-Avibactam for Suspected or Confirmed Carbapenem-Resistant Organisms in Children: A Retrospective Study.

Background: The incidence of carbapenem-resistant organism (CRO) infections is increasing in children. However, pediatric-specific treatment strategies present unique challenges. Ceftazidime/avibactam is a ß-lactam/ß-lactamase inhibitor combination, showing adequate efficiency against CRO isolates. However, clinical data on the efficacy of ceftazidime/avibactam in children are still lacking. Methods: This was a retrospective study of children (aged <18 years) infected with confirmed or suspected carbapenem-resistant pathogens and treated with ceftazidime-avibactam at the First Affiliated Hospital of Zhengzhou University between 2020 and 2022. Results: We identified 38 children aged 14 (5.0-16.3) years; 20 (52.6%) had hematologic malignancies. 25 children with confirmed CRO infections were administered ceftazidime-avibactam as targeted therapy. The median treatment was 10 (6.0-16.5) days. Among them, 24 had infections caused by carbapenem-resistant Enterobacterales (CRE) (18 carbapenem-resistant Klebsiella pneumoniae and six carbapenem-resistant Escherichia coli species) and one with carbapenem-resistant Pseudomonas aeruginosa strains. The source of infection was the bloodstream in 60.0% of the cases (15/25). The clinical response rate was 84.0% (21/25), and 30-day mortality rate was 20% (5/25). 13 children were administered ceftazidime-avibactam as empiric therapy for suspected infections. The median treatment was 8 (6.0-13.0) days. No deaths occurred and clinical response was achieved in 12 of the 13 patients (92.3%) who empirically treated with ceftazidime-avibactam. Conclusion: Ceftazidime-avibactam is important for improving survival, and clinical response in children with infections caused by CRO.

Disruption of Histamine-H1R signaling exacerbates cardiac microthrombosis after periodontal disease via TLR4/NFκB-p65 pathway.

Periodontal disease is a chronic inflammatory disease that is highly correlated with cardiovascular disease(CVD). Histamine has been proven to participate in the pathophysiological processes of cardiovascular disease and oral inflammation. However, the role of histamine in the development of cardiac microthrombosis caused by periodontal disease has not been fully elucidated. We established a murine periodontal inflammation model by injecting lipopolysaccharide (LPS) or Porphyromonas gingivalis (P. gingivalis). In order to examine the effect of histamine/H1R signaling on cardiac injury after periodontal disease, we used histidine decarboxylase- knockout (HDC-/-) mice and histamine 1 receptor (H1R) antagonist. Our results demonstrated that LPS-induced periodontal inflammation significantly increased CD11b+Gr-1+ neutrophils in the peripheral blood and myocardial interstitium. Histamine deficiency resulted in further increases in P. gingivalis, neutrophils, inflammatory cytokines, and cardiac microthrombosis in the myocardium of HDC-/- mice compared to wild-type (WT) mice. Mechanistic analysis showed that blocking H1R could synergistically interact with LPS, further increasing the phosphorylation of p65, exacerbating the inflammatory response of neutrophils and endothelial cell damage. Conclusively, the disruption of histamine-H1R signaling exacerbates cardiac microthrombosis after periodontal disease via TLR4/NFκB-p65 pathway. Our findings not only reveal a link between periodontal inflammation and myocardial injury but also provided some thoughts for the use of H1R antagonist in clinical practice.

The downstream network of STAT6 in promoting vascular smooth muscle cell phenotypic switch and neointimal formation.

Intimal thickening caused by the excessive multiplication of vascular smooth muscle cells (VSMCs) is the pathological process central to cardiovascular diseases, including restenosis. In response to vascular injury, VSMCs would undergo phenotypic switching from a fully differentiated, low proliferative rate phenotype to a more pro-proliferative, promigratory, and incompletely-differentiated state. The lack of a full understanding of the molecular pathways coupling the vascular injury stimuli to VSMCs phenotype switching largely limits the development of medical therapies for treating intima hyperplasia-related diseases. The role of signal transducers and activators of transcription 6 (STAT6) in modulating the proliferation and differentiation of various cell types, especially macrophage, has been well investigated, but little is known about its pathophysiological role and target genes in restenosis after vascular injury. In the present work, Stat6-/- mice were observed to exhibit less severe intimal hyperplasia compared with Stat6+/+ mice after carotid injury. The expression of STAT6 was upregulated in VSMCs located in the injured vascular walls. STAT6 deletion leads to decreased proliferation and migration of VSMCs while STAT6 overexpression enhances the proliferation and migration of VSMCs companies with reduced expression of VSMCs marker genes and organized stress fibers. The effect of STAT6 in mouse VSMCs was conserved in human aortic SMCs. RNA-deep-sequencing and experiments verification revealed LncRNA C7orf69/LOC100996318-miR-370-3p/FOXO1-ER stress signaling as the downstream network mediating the pro-dedifferentiation effect of STAT6 in VSMCs. These findings broaden our understanding of vascular pathological molecules and throw a beam of light on the therapy of a variety of proliferative vascular diseases.

Clinical study of acute toxicity of pelvic bone marrow-sparing intensity-modulated radiotherapy for cervical cancer.

OBJECTIVES: To compare the dose volume of the target area and the toxicity of pelvic bone marrow-sparing intensity-modulated radiotherapy (PBMS-IMRT) with routine IMRT in patients undergoing radiochemotherapy for cervical cancer. MATERIAL AND METHODS: Forty patients with indications for adjuvant radiochemotherapy after cervical cancer surgery were selected and randomly divided into IMRT (n = 20) and PBMS-IMRT (n = 20) groups to observe and record the toxicity and its severity in the blood, gastrointestinal tract, and genitourinary system. RESULTS: There was no significant difference in the target area conformity index (CI) or homogeneity index (HI) between the two groups (p > 0.05). The pelvic bone V10-V50 in the PBMS-IMRT group were lower than those in the IMRT group (p < 0.05), and there was lower hematological toxicity (p < 0.05) and fewer delays or interruptions in chemotherapy and/or radiotherapy (p < 0.05) in the PBMS-IMRT group. The toxicity to the gastrointestinal and genitourinary systems in the two groups was not significantly different (p > 0.05). CONCLUSIONS: PBMS-IMRT significantly reduced the dose volume of the pelvic bone marrow, thereby reducing the incidence of bone marrow suppression. However, it had no significant impact on the gastrointestinal or genitourinary systems.

Histamine deficiency deteriorates LPS-induced periodontal diseases in a murine model via NLRP3/Caspase-1 pathway.

Histamine is a versatile biogenic amine, generated by the unique enzyme histidine decarboxylase (Hdc). Accumulating evidence has proven that histamine plays important roles in numerous biological and pathophysiological processes. However, the role and mechanism of Hdc/Histamine signaling in periodontal diseases remain unclear. In our current study, the concentration of histamine increased in the serum, and Hdc gene expression was upregulated in the gingiva of WT mice with LPS-induced periodontal inflammation. With Hdc-GFP mice, we identified that Hdc/GFP in the periodontium was expressed in CD11b+ myeloid cells, rather than in tryptase-positive mast cells. Hdc-expressing CD11b+Gr-1+ neutrophils significantly increased in the peripheral blood of Hdc-GFP mice one day after LPS injection. Lack of histamine in Hdc-/- mice not only promoted the activation and infiltration of more CD11b+ cells into the peripheral blood but also upregulated mRNA expression levels of IL-1ß, IL-6, MCP-1and MMP9 in the gingiva compared to WT mice one day after LPS stimulation. 28 days after LPS treatment, we observed that Hdc-/- mice exhibited more alveolar bone loss and more osteoclasts than WT mice, which was slightly ameliorated by the administration of exogenous histamine. In vivo and in vitro mechanistic studies revealed that the mRNA expression levels of proinflammatory cytokines and protein levels of NLRP3, Caspase-1, and cleaved-Caspase-1 were upregulated after blocking histamine receptor 1 and 2, especially histamine receptor 1. Taken together, CD11b+Gr-1+ neutrophils are the predominant Hdc-expressing sites in periodontal inflammation, and deficiency of endogenous histamine in Hdc-/- mice exacerbates the destruction of the periodontium. Disruption of the histamine/H1R/H2R axis aggravates the inflammatory immune response via NLRP3/Casapse-1 pathway.

Disruption of histamine/H1R-STAT3-SLC7A11 axis exacerbates doxorubicin-induced cardiac ferroptosis.

Doxorubicin (DOX) is widely used in the treatment of various cancers, increasing the great risk of adverse cardiovascular events, while the clinical intervention effect is not ideal. Histamine has been documented to participate in pathophysiological processes of cardiovascular diseases and inflammation-associated carcinogenesis. However, the potential roles of histamine in antitumor-related cardiotoxicity have not been fully elucidated. In this study, cardiomyocytes (hiPSC-CMs, HL-1 cells) and mice were treated with DOX to establish DOX-induced cardiotoxicity (DIC) models. Histidine decarboxylase knockout mice (HDC-/-) mice and histamine 1 receptor (H1R) antagonist were used to explore the effect of histamine/H1R signaling on DIC. Our results demonstrated that histamine deficiency or pharmaceutical inhibition of H1R accelerated myocardial ferroptosis, which is responsible for the aggravated DIC both in vivo and in vitro, while the supplementation of exogenous histamine reversed these changes. Our data revealed that the dysfunction of histamine/H1R signaling repressed the activation of transducer and activator of transcription 3 (STAT3), accompanying with decreased expression of solute carrier family7member11 (SLC7A11), a major modulator of ferroptosis. Conclusively, the disruption of histamine/H1R axis triggered ferroptosis and exacerbated DIC possibly by modulating STAT3-SLC7A11 pathway. Our findings point to a potential therapeutic target for DIC and provide more consideration on the usage of antihistamine drugs.

Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction.

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts L-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

Abnormal histidine metabolism promotes macrophage lipid accumulation under Ox-LDL condition.

Distinct macrophage populations exert highly heterogeneity and perform various functions, among which, a crucial function of lipid metabolism is highlighted. However, the role of histidine metabolism disorder in macrophage lipid metabolism remains elusive. Addressed this question, we sorted and cultured the bone marrow-derived macrophages (BMDMs) of histidine decarboxylase (Hdc) knockout (Hdc-/-) mice with an in vitro oxidized low-density lipoprotein (ox-LDL) model, and detected the intracellular lipids by Oil Red O staining as well as lipid probe staining. Astemizole, a canonical and long-acting histamine H1 receptor (H1R) antagonist, was applied to elucidate the impact of antagonizing the H1R-dependent signaling pathway on macrophage lipid metabolism. Subsequently, the differential expressed genes were screened and analyzed in the bone marrow-derived CD11b+ immature myeloid cells of Hdc-/- and Hdc+/+ mice with a high fat diet by the microarray study. The expression levels of cholesterol metabolism-related genes were examined by qRT-PCR to explore underlying mechanisms. Lastly, we used a high-sensitivity histidine probe to detect the intracellular histidine in the BMDMs after oxidative stress. The results revealed that histidine metabolism disorder and histamine deficiency aggravated lipid accumulation in the ox-LDL-treated BMDMs. The expression level of H1R gene in the BMDMs was down-regulated after ox-LDL stimulation. The disruption of the H1R-dependent signaling pathway by astemizole further exacerbated ox-LDL-induced lipid deposition in the BMDMs partly by up-regulating scavenger receptor class A (SR-A) for lipid intake, down-regulating neutral cholesteryl ester hydrolase (nCEH) for cholesterol esterification and down-regulating ATP-binding cassette transporters A1 (ABCA1) and ABCG1 for reverse cholesterol transport. The intracellular histidine increased under ox-LDL condition, which was further increased by Hdc knockout. Collectively, these results partially reveal the relationship between histidine metabolism and lipid metabolism in the BMDMs and offer a novel strategy for lipid metabolism disorder-associated diseases.

NF-κB and neutrophil extracellular traps cooperate to promote breast cancer progression and metastasis.

Aberrant NF-κB activation and neutrophil extracellular traps (NETs) are associated with breast cancer progression. How NF-κB and NETs modulate each other in breast cancer development remains unclear. Here, we found that NETs induced by phorbol 12-myristate 13-acetate promote breast cancer cell progression. In turn, cancer cells-derived factors, such as IL-8 and granulocyte colony-stimulating factor, stimulate neutrophils to form NETs. Mechanistically, NETs increased the interaction of NF-κB essential modifier (NEMO) with IκB kinase (IKK)α/ß and enhanced NF-κB activation. We then employed a cell-permeable peptide corresponding to the NEMO-binding domain (NBD) of IKKα/ß, termed NBD peptide, which disrupts NETs-mediated NEMO interaction with IKKα/ß and abolished NF-κB activation in vitro. NBD peptide also reduced IL-8 level and NETs formation, and suppressed primary tumor growth and/or lung metastasis in human breast cancer mouse xenograft models and mouse spontaneous breast cancer model. Blockade of NET formation using a peptidylarginine deiminase 4 (PAD4) pharmacologic inhibitor decreased NF-κB activation and tumor metastasis. Collectively, these data suggest that NF-κB associates with NETs to form a positive loop facilitating breast tumor progression and metastasis, and that selective inhibition of NF-κB and PAD4-dependent NETs provides an effective therapeutic approach for treating breast cancer.

The role of MYB proto-oncogene like 2 in tamoxifen resistance in breast cancer.

Despite the efficacy of tamoxifen in preventing disease relapse, a large portion of breast cancer patients show intrinsic or acquired resistance to tamoxifen, leading to treatment failure and unfavorable clinical outcome. MYB proto-oncogene like 2 (MYBL2) is a transcription factor implicated in the initiation and progression of various human cancers. However, its role in tamoxifen resistance in breast cancer remained largely unknown. In the present study, by analyzing public transcriptome dataset, we found that MYBL2 is overexpressed in breast cancer and is associated with the poor prognosis of breast cancer patients. By establishing tamoxifen-resistant breast cancer cell lines, we also provided evidence that MYBL2 overexpression contributes to tamoxifen resistance by up-regulating its downstream transcriptional effectors involved in cell proliferation (PLK1, PRC1), survival (BIRC5) and metastasis (HMMR). In contrast, inhibiting those genes via MYBL2 depletion suppresses cancer progression, restores tamoxifen and eventually reduces the risk of disease recurrence. All these findings revealed a critical role of MYBL2 in promoting tamoxifen resistance and exacerbating the progression of breast cancer, which may serve as a novel therapeutic target to overcome drug resistance and improve the prognosis of breast cancer patients.

Disruption of STAT6 Signal Promotes Cardiac Fibrosis Through the Mobilization and Transformation of CD11b+ Immature Myeloid Cells.

Cardiac fibrosis is an important pathological basis of various cardiovascular diseases. The roles of STAT6 signal in allergy, immune regulation, tumorigenesis, and renal fibrosis have been documented. However, the function and mechanism of STAT6 signal in sympathetic overactivation-induced cardiac fibrosis have not been fully elucidated. This study explores the novel role of STAT6 signal in isoproterenol (ISO)-induced cardiac fibrosis through the regulation of inflammatory response and the differentiation of macrophages from immature myeloid cells. The expression levels of STAT6, ß1-adrenergic receptor (ß1-AR), and inflammatory factors [interleukin α (IL-1α), IL-6, IL-18, and transforming growth factor ß (TGF-ß)] in CD11b+ myeloid cells were analyzed with a microarray study. The levels of IL-6 and TGF-ß1 in the CD11b+ myeloid cells-derived macrophages were detected with reverse transcriptase-polymerase chain reaction (RT-PCR). STAT6-knockout (KO) and WT mice were used to establish a murine cardiac fibrosis model by ISO injection. Cardiac fibroblasts were isolated from the hearts of newborn STAT6-KO and WT mice, and STAT6 expression was measured by Western blotting and RT-PCR after ISO stimulation, while α-smooth muscle actin (α-SMA) expression was detected by immunofluorescence and immunohistochemistry staining. Cardiac function and pathological characteristics were examined by echocardiography and immunohistochemistry staining, respectively. Immunohistochemistry staining with anti-CD11b was performed to detect the infiltration of CD11b+ myeloid cells in heart tissue. Flow cytometry analysis was used to measure the percentages of CD11b+ myeloid cells and CD11b+Ly6C+ macrophages in the peripheral blood. The results showed that STAT6 was highly expressed in CD11b+ myeloid cells located in injured hearts, and STAT6 expression in cardiac fibroblasts was down-regulated after ISO treatment. STAT6 deficiency further aggravated ISO-induced increased expression of α-SMA in cardiac fibroblasts, myocardial fibrosis, and cardiac dysfunction. The activation of ISO/ß1-AR signal aggravated cardiac inflammatory infiltration, promoted CD11b+ myeloid cell mobilization, and enhanced CD11b+Ly6C+/low macrophage differentiation, which was further exacerbated by STAT6 deficiency. Furthermore, ß1-AR mRNA expression significantly increased in splenic CD11b+ myeloid cells compared to their bone marrow-derived controls, and STAT6 deficiency promoted ß1-AR expression in an MI-induced sensitive cardiac fibrosis mouse model. The spleen-derived CD11b+ myeloid cells of STAT6-KO mice produced more IL-1α, IL-18, and TGF-ß than their WT counterparts. Taken together, these results suggest that STAT6 signal plays a critical role in ISO-induced ß1-AR overactivation and systemic inflammatory cascades, contributing to cardiac fibrogenesis. STAT6 should be a promising cardioprotective target against myocardial fibrosis and heart failure after ß1-AR overactivation-induced myocardial injury.

Periodontal Disease and Tooth Loss Are Associated with Lung Cancer Risk.

BACKGROUND: The associations between periodontal disease, tooth loss, and lung cancer risk remain debatable. Therefore, the purpose of the present study is to evaluate whether periodontal disease and tooth loss are associated with lung cancer risk. METHODS: A literature search was performed for relevant studies using PubMed and Embase databases. Risk ratio (RR) with 95% confidence interval (CI) was applied as effect size to summarize the associations between periodontal disease, tooth loss, and lung cancer risk. A further dose-response analysis was also performed. RESULTS: A total of twelve studies comprising 263,238 participants were included. The results indicated that periodontal disease was positively associated with lung cancer risk (RR = 1.37, 95%CI = 1.16-1.63). There was a positive association between tooth loss and lung cancer risk (RR = 1.69, 95%CI = 1.46-1.96). Moreover, there was a significantly linear dose-response relationship between tooth loss and lung cancer risk, and every 5 increment in tooth loss was associated with 10% increased lung cancer risk. Similar results were obtained in subgroup analysis. CONCLUSIONS: Periodontal disease and tooth loss are increased risk factors for lung cancer. Prevention and treatment of periodontal disease may be effective potential prevention strategies for lung cancer.

Association between periodontal disease, tooth loss and liver diseases risk.

AIM: The purpose of this study is to assess the associations between periodontal disease, tooth loss and liver diseases. MATERIALS AND METHODS: PubMed and Embase databases were utilized to search eligible studies. Odds ratio (OR) with 95% confidence interval (CI) was used as effect size to assess the associations between periodontal disease, tooth loss and liver diseases risk. RESULTS: Our results indicated positive associations between periodontal disease and non-alcoholic fatty liver disease (NAFLD) (OR = 1.19, 95% CI = 1.06-1.33), liver cirrhosis (OR = 2.28, 95% CI = 1.50-3.48) and elevated transaminase level risk (OR = 1.08, 95% CI = 1.02-1.15). Moreover, tooth loss could increase NAFLD (OR = 1.33, 95% CI = 1.12- 1.56) and liver cancer risk (OR = 1.34, 95% CI = 1.04-1.74), and every five increment in tooth loss was associated with 5% increased liver cancer risk (OR = 1.05, 95% CI = 1.01 - 1.10) with a linear relationship. In addition, tooth loss had a positive tendency towards liver cirrhosis risk (OR = 2.03, 95% CI = 0.85-4.85) although there was no statistical significance. CONCLUSION: Periodontal disease and tooth loss are positively associated with liver diseases including NAFLD, elevated transaminase level, liver cirrhosis and liver cancer.

Effect of bisphosphonates on overall survival in subgroups of patients with prostate cancer.

Adjuvant therapy with bisphosphonates in prostate cancer is effective in improving bone mineral density and thus reducing fractures and skeletal-related events. We analyzed the effect of bisphosphonates on overall survival (OS) in subgroups of patients with prostate cancer. A systematic literature search was conducted of the PubMed database and the bibliographies of related studies. The long-term OS rates were extracted from every eligible trial. The hazard ratio (HR) was pooled with the fixed effects model, and preplanned subgroup analyses were performed. The search yielded 112 articles, of which 10 articles with 13 patient subgroups met the eligibility criteria. The meta-analysis of all 13 subgroups showed that adjuvant bisphosphonate therapy did not significantly improve OS versus the control group (HR = 0.961, 95% CI 0.899-1.026, p = 0.233) with low heterogeneity (I2 = 13.47%, degrees of freedom = 12, p = 0.336). There was no significant improvement in OS with the addition of bisphosphonates in the major subgroup analyses (metastatic (M1) versus non-metastatic, clodronate versus zoledronic acid, castration-sensitive prostate cancer (CSPC) versus castration-refractory prostate cancer). When the subgroups were further divided, adjuvant bisphosphonate therapy significantly improved OS in patients with CSPC + M1 (HR = 0.874, 95% CI 0.778-0.982, p = 0.023; I2 = 0.0%, degrees of freedom = 3, p = 0.579). Our study demonstrated that bisphosphonates do not significantly improve long-term OS in patients with prostate cancer. However, adjuvant bisphosphonate therapy significantly improves OS in the subgroup of patients with CSPC + M1.

Polyethylene-glycol-coated gold nanoparticles improve cardiac function after myocardial infarction in mice.

Gold nanoparticles (AuNPs) are widely used for drug delivery because of their unique biological properties, such as their safety and ability to prolong drug action. Some studies have demonstrated that AuNPs accumulate in the heart, especially during pathological processes. Therefore, it is very important to understand the effect of AuNPs on the heart. Myocardial infarction (MI) is a major cause of morbidity and mortality; however, the effect of AuNPs on MI remains unclear. In the present study, we carried out a comprehensive evaluation of AuNPs on acute MI. The results showed that AuNPs accumulated in infarcted hearts, decreased infarction size, improved systolic function, and inhibited cardiac fibrosis and TNF-α accumulation. Our work indicated that AuNPs have cardioprotective effects and can be used in drug delivery systems for the treatment of cardiac diseases.

Senescence as a novel mechanism involved in ß-adrenergic receptor mediated cardiac hypertrophy.

Pathological cardiac hypertrophy used to be elucidated by biomechanical, stretch-sensitive or neurohumoral mechanisms. However, a series of hints have indicated that hypertrophy process simulates senescence program. However, further evidence need to be pursued. To verify this hypothesis and examine whether cardiac senescence is a novel mechanism of hypertrophy induced by isoproterenol, 2-month-old male Sprague Dawley rats were subjected to isoproterenol infusion (0.25mg/kg/day) for 7 days by subcutaneous injection). Key characteristics of senescence (senescence-associated ß-galactosidase activity, lipofuscin, expression of cyclin-dependent kinase inhibitors) were examined in cardiac hypertrophy model. Senescence-like phenotype, such as increased senescence-associated ß-galactosidase activity, accumulation of lipofuscin and high levels of cyclin-dependent kinase inhibitors (e.g. p16, p19, p21 and p53) was found along the process of cardiac hypertrophy. Cardiac-specific transcription factor GATA4 increased in isoproterenol-treated cardiomyocytes as well. We further found that myocardial hypertrophy could be inhibited by resveratrol, an anti-aging compound, in a dose-dependent manner. Our results showed for the first time that cardiac senescence is involved in the process of pathological cardiac hypertrophy induced by isoproterenol.

PEG-coated gold nanoparticles attenuate ß-adrenergic receptor-mediated cardiac hypertrophy.

Gold nanoparticles (AuNPs) are widely used as a drug delivery vehicle, which can accumulate in the heart through blood circulation. Therefore, it is very important to understand the effect of AuNPs on the heart, especially under pathological conditions. In this study, we found that PEG-coated AuNPs attenuate ß-adrenergic receptor (ß-AR)-mediated acute cardiac hypertrophy and inflammation. However, both isoproterenol, a non-selective ß-AR agonist, and AuNPs did not induce cardiac function change or cardiac fibrosis. AuNPs exerted an anti-cardiac hypertrophy effect by decreasing ß1-AR expression and its downstream ERK1/2 hypertrophic pathway. Our results indicated that AuNPs might be safe and have the potential to be used as multi-functional materials (drug carrier systems and anti-cardiac hypertrophy agents).