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Graphical abstract, Introduction Insulin-like growth factor-I receptor (IGF1R) mediated survival signaling is a crucial mechanism for cellular endurance and a potential indicator of recuperation in deteriorating hearts. Objective This study evaluates the impact of long-term exercise training in enhancing cardiac survival mechanism in D-galactose-induced toxicity associated aging rats. Methods Forty-eight male SD-rats were segregated into 4 groups (n=9) and were named as control, exercise training groups, aging group and aging group with exercise training. Aging was induced by intraperitoneal (IP) D-galactose (150 mL/kg) injection for 8 weeks and for exercise training, the rats were left to swim in warm water for 60 min every day and 5 times/week. Western blotting of proteins from the left ventricles was performed to identify the modulations in the survival signaling. Tissue sections were analyzed to determine the extent of fibrosis and apoptosis. Results Western-blot analysis performed on the excised left ventricles (LV) showed that proteins of the cardiac survival pathway including IGF1R and Akt and the pro-survival Bcl-2 showed significant decrease in the aging group, whereas the levels were restored in the aging rats subjected to exercise training. In addition, aging groups showed increased interstitial space and collagen accumulation. Further, TUNEL assay showed higher number of apoptotic cells in the LV of aging group, which was correlated with increase in the proteins involved in FAS-FADD-dependent apoptosis. However, these aging associated effects were ameliorated upon exercise training in the D-galactose-induced aging rats that showed elevated IGF1R/Akt signaling. Conclusion The results suggest that IGFIR survival signaling cascadeis elevated in following long-term exercise training and thereby provide cardio-protective benefits in D-galactose induced aging rats.

Although various advancements in radical surgery and neoadjuvant chemotherapy have been developed in treating osteosarcoma (OS), their clinical prognosis remains poor. A synthetic chemical compound, 3-hydroxylflavone, that is reported to regulate ROS production is known to inhibit human bone osteosarcoma cells. However, its role and mechanism in human OS cells remains unclear. In this study, we have determined the potential of 3-Hydroxy-2-phenylchromone (3-HF) against OS using human osteosarcoma (HOS) cells. Our previous studies showed that Zipper sterile-alpha-motif kinase (ZAK), a kinase member of the MAP3K family, was involved in various cellular events such as cell proliferation and cell apoptosis, and encoded two transcriptional variants, ZAK&alpha, and &beta, In this study, we show that 3-HF induces the expression of ZAK and thereby enhances cellular apoptosis. Using gain of function and loss of function studies, we have demonstrated that ZAK activation by 3-HF in OS cells is confined to a ZAK&beta, form that presumably plays a leading role in triggering ZAK&alpha, expression, resulting in an aggravated cancer apoptosis. Our results also validate ZAK&beta, as the predominant form of ZAK to drive the anticancer mechanism in HOS cells.

Hepatocellular carcinoma (HCC) metastasis is often associated with the activation of Wnt/β-catenin signaling pathway. Zanthoxylum avicennae (Ying Bu Bo, YBB), a traditional herb with hepatoprotective effect, has been proven to inhibit human HCC in in vivo models however, the in vitro and in vivo effect of YBB on tumor metastasis is not clear yet. To determine whether YBB could inhibit HA22T human HCC cell by acting on β-catenin metastatic signaling in vitro and in vivo, HA22T cells were treated with different concentrations of YBB extracts (YBBE) and analyzed by Immunofluorescence staining assay, western blot analysis, siRNA mediated gene knock-down assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mice were used to confirm the assessed cellular effects. Mice treated with YBBEs showed a strong increasing trend in PP2Acα, GSK-3β, APC, and β-TrCP/HOS levels, however the expression of β-catenin, p-GSK-3β, TBX 3, and IL8 proteins showed a decreasing trend. YBBE significantly downregulated the nuclear and cytosolic β-catenin levels by facilitating the proteosomal degradation of β-catenin. Moreover, as observed by co-immunoprecipitation assay, YBBE directly promoted the protein interactions between GSK-3β, β-TrCP, APC, PP2A, and β-catenin. In conclusion, both in vitro and in vivo models clearly demonstrated that YBBE inhibits β-catenin involved metastatic signaling in highly metastatic HA22T cells through PP2A activation.

Background: Beta-catenin has been implicated in cell-cell communication in a wide variety of developmental and physiological processes. Defective Wnt signaling could result in various cardiac and vascular abnormalities. Little is known regarding Wnt/frizzled pathway in cardiomyocyte apoptosis. Methods: In this study, the role of b-catenin in apoptosis was investigated in H9c2 cardiomyocytes and primary cardiomyocytes isolated in diabetic Wistar rats. The cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-b-catenin plasmid in order to overexpress b-catenin. Results: The transcription factor displayed a significant nuclear localization in Wistar rats with cardiac hypertension. Transfection of b-catenin plasmid induced apoptosis and reduced expression of survival pathway markers in cardiomyocytes in a dose-dependent manner. Furthermore, expression of fibrosis protein markers was upregulated by the overexpression. Conclusions: Taken together, these results revealed that altered Wnt/b-catenin signaling might provoke heart failure. (Cardiol J 2017; 24, 2: 195–205)

Background. Existing literature suggests that an association exists between coronary artery disease (CAD) and carpal tunnel syndrome (CTS), but few researchers have explored whether CTS is a risk for CAD. Materials and Methods. This large case-control study explored the association between CTS and CAD, using health insurance claims data from Taiwan’s National Health Insurance Research Database (NHIRD) between January 2000 and December 2013. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes identified 70,622 patients with CAD (ICD-9-CM codes 410–414; cases); 70,622 patients without CAD were frequency-matched by age, sex, and index year of CAD and served as controls. Results. The likelihood of a previous diagnosis of CTS (ICD-9-CM codes 354.0, 354.1) was significantly higher in the CAD group than in the comparison control group (crude OR: 1.75, 95% CI 1.63-1.89; p Conclusion. A significant positive correlation was observed between CAD and a previous diagnosis of CTS.

Insufficient angiogenesis and microcirculatory intravascular clotting have been implicated in the pathophysiology of skin flap failure. Salvianolic acid B (Sal B), isolated from Salvia miltiorrhiza, has been reported to enhance angiogenesis in vitro. This study was aimed to determine the efficacy of Sal B on ischemia-reperfusion injury of the skin flap in Sprague-Dawley rats. Sal B was administered intraperitoneally 2 h before operation, and on the 2nd and 4th days after surgical elevation of an extended epigastric adipocutaneous flap (5 x 7 cm) in ketamine-anesthetized rats. Flap ischemia was achieved by ligating the right superficial epigastric artery and vein and clamping the left superficial epigastric artery and vein for 3 h and then released. Percentage of flap necrosis area (FNA) and plasma levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and malondialdehyde were measured at 7 days after the operation. Animals were divided into six groups, including: vehicle, Sal B low dose (5 mg/kg), Sal B high dose (50 mg/kg) and each with [mesh(+)] or without mesh [mesh(-)] placement. In the three groups with mesh(+), FNA in control flaps was 53.7 +/- 6.9%, whereas low-dose and high-dose Sal B significantly improved flap survival with FNA 27.4 +/- 3.8% and 25.3 +/- 4.3%, respectively (P < 0.05, one-way ANOVA). In the three groups with mesh(-), control flaps were 35.9 +/- 4.5%, whereas high-dose Sal B also significantly improved flap survival with FNA 17.9 +/- 4.7% (P < 0.05, one-way ANOVA). There were no differences in aspartate aminotransferase, alanine aminotransferase, creatinine, or malondialdehyde between groups. We conclude that Sal B attenuates ischemia-reperfusion injury of skin flap, and provides therapeutic potential in reconstructive plastic surgery.

Inflammation is a serious health issue worldwide that induces many diseases, such as inflammatory bowel disease (IBD), sepsis, acute pancreatitis and lung injury. Thus, there is a great deal of interest in new methods of limiting inflammation. In this study, we investigated the leaves of Nelumbo nucifera Gaertn, an aquatic perennial plant cultivated in eastern Asia and India, in anti-inflammatory pharmacological effects in the murine macrophage cell line RAW264.7. Results showed that lipopolysaccharide (LPS) increased the protein expression of inducible nitric oxide synthase (iNOS) and COX-2, as well as the mRNA expression and level of IL-6 and TNF-α, while NNE significantly reduced these effects of LPS. LPS also induced phospho-JNK protein expression. The JNK-specific inhibitor SP600125 decreased the proteins expression of phospho-JNK, iNOS, COX-2, and the mRNAs expression and levels of IL-6 and TNF-α. Further, NNE reduced the protein expression of phospho-JNK. LPS was also found to promote the translocation of NF-κB from the cytosol to the nucleus and to decrease the expression of cytosolic IκB. NNE and SP600125 treatment recovered the LPS-induced expression of NF-κB and IκB. While phospho-ERK and phospho-p38 induced by LPS, could not be reversed by NNE. To further investigate the major components of NNE in anti-inflammatory effects, we determined the quercetin and catechin in inflammatory signals. Results showed that quercetin and catechin significantly decreased the proteins expression of iNOS, COX-2 and phospho-JNK. Besides, the mRNAs and levels of IL-6 and TNF-α also decreased by quercetin and catechin treatment in LPS-induced RAW264.7 cells. These results showed that NNE and its major components quercetin and catechin exhibit anti-inflammatory activities by inhibiting the JNK- and NF-κB-regulated pathways and could therefore be an useful anti-inflammatory agent.

Insufficient angiogenesis and microcirculatory intravascular clotting have been implicated in the pathophysiology of skin flap failure. Salvianolic acid B (Sal B), isolated from Salvia miltiorrhiza, has been reported to enhance angiogenesis in vitro. This study was aimed to determine the efficacy of Sal B on ischemia-reperfusion injury of the skin flap in Sprague-Dawley rats. Sal B was administered intraperitoneally 2 h before operation, and on the 2nd and 4th days after surgical elevation of an extended epigastric adipocutaneous flap (5 x 7 cm) in ketamine-anesthetized rats. Flap ischemia was achieved by ligating the right superficial epigastric artery and vein and clamping the left superficial epigastric artery and vein for 3 h and then released. Percentage of flap necrosis area (FNA) and plasma levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and malondialdehyde were measured at 7 days after the operation. Animals were divided into six groups, including: vehicle, Sal B low dose (5 mg/kg), Sal B high dose (50 mg/kg) and each with [mesh(+)] or without mesh [mesh(-)] placement. In the three groups with mesh(+), FNA in control flaps was 53.7 +/- 6.9%, whereas low-dose and high-dose Sal B significantly improved flap survival with FNA 27.4 +/- 3.8% and 25.3 +/- 4.3%, respectively (P0.05, one-way ANOVA). In the three groups with mesh(-), control flaps were 35.9 +/- 4.5%, whereas high-dose Sal B also significantly improved flap survival with FNA 17.9 +/- 4.7% (P0.05, one-way ANOVA). There were no differences in aspartate aminotransferase, alanine aminotransferase, creatinine, or malondialdehyde between groups. We conclude that Sal B attenuates ischemia-reperfusion injury of skin flap, and provides therapeutic potential in reconstructive plastic surgery.

Wogonin from Scutellaria baicalensis, was demonstrated to increase nitric oxide (NO) in the murine macrophage cell line RAW 264.7. It is our aim to investigate the modulatory effect of wogonin on tumor necrosis factor-alpha (TNF-alpha) gene expression. By using RAW 264.7 as an in vitro model, the effects of wogonin on inducible nitric oxide synthase (NOS2) and TNF-alpha gene expression were evaluated by ELISA and reverse transcribed polymerase chain reaction (RT-PCR). Aspirin and H7 were used to determine the possible signal transduction pathways. The results showed that wogonin at the concentration of 10 (-5) M and 10 (-6) M up-regulated NOS2 gene expression in RAW 264.7 cells. Besides, wogonin up-regulated the gene expression of TNF-alpha, in terms of TNF-alpha secretion and transcription, in a dose dependent manner. The fact that aspirin but not H7 blocks the enhancing effect suggests that NF-kappaB might be involved in wogonin-enhanced TNF-alpha gene expression. We conclude that a low concentration of wogonin up-regulates NOS2 and TNF-alpha gene expression through NF-kappaB pathway.