Current Signal Transduction Therapy - Volume 10, Issue 1, 2015

Osteoporosis was related with depression especially in patients treated with psychotropic medicine. Selective serotonin reuptake inhibitors (SSRIs), the first-line treatment of depression, could up-regulate the extracellular serotonin (5-HT) levels and affect the serotonin system in bone metabolism. 5-HT transporter5-HTT) knockout results in bone mass decreased, architecture altered and mechanical properties impaired. Antidepressant-induced osteoporosis has direct and dose-dependent effects. Thus depression patients should evaluate skeletal system and receive antiosteoporotic treatments regularly, particularly during use of SSRI. But some reports have shown a dissociation of Major depressive disorder (MDD) and bone mineral density (BMD). The relationship between depression, BMD and bone metabolism remains elusive. Further studies will be tackled by ‘OMICS’ to understand possible mechanisms and develop new antidepressant for MDD.

The incidence of cancer is increased in patients with diabetes mellitus. Numerous epidemiological studies confirm this phenomenon, specifically with malignancies of the pancreas, liver, bile ducts, uterus, kidney, breast in postmenopausal women, colon, bladder and aggressive forms of prostate cancer. Disruption of homeostatic glucose metabolism may play a significant role in malignant cellular transformation and disease progression. Additionally, recent advances in molecular and biochemical technology allow for deeper understanding of the pathophysiology of disrupted glucose-insulin axis pathways in diabetics at the subcellular level. These technological advances may provide answers as to how malignant cellular transformation occurs and identify potential treatment targets.

Recent studies have shown that there is an interaction between fat and bone metabolisms. Adipose tissue secretes leptin and adiponectin to regulate bone metabolism. Leptin inhibits bone formation by activating the sympathetic nervous system, whereas the peripheral pathway of leptin shows a positive effect on bone formation. Opposite to leptin, adiponectin enhances or inhibits bone formation osteoblast in the central or peripheral respectively. On the other hand, osteocalcin (OCN) is decarboxylated and released from skeleton as the hormonal form of undercarboxylated-osteocalcin (ucOCN) to stimulate islets and fat to secret insulin and adiponectin respectively, thus to regulate energy metabolism. All these data indicate that there exist complex regulatory loops within fat and bone endocrine networks. In this review, we will elucidate the hormones and their receptors that mediate the communication between fat and bone metabolisms.

Objective: To investigate the effects of the DNA methyltransferase inhibitor 5-Aza-2'- Deoxycytidine (5-Aza-Dc) on DLC-1 gene expression, methylation level, and the expression of downstream signaling molecules Cdc42 in the human multiple myeloma cell line RPMI8226 cells. Methods: The RPMI8226 cells were treated with 5-Aza-Dc, the methylation status of CpG island of DLC-1 gene was detected by bisulfate sequencing PCR(BSP) in RPMI8226 cells. The expression of DLC-1 and Cdc42 mRNA was determined by reverse transcriptase polymerase chain reaction (RT-PCR). Enzyme-linked immunoabsorbent assay (ELISA) was used to detect the expression of Cdc42 protein. Results: The methylation of DLC-1 gene was detected in the RPMI8226 cells without 5-Aza-Dc pretreament. DLC-1 gene methylation status was decreased after the 5-Aza-Dc treatment for 72h, and DLC-1 gene didn't display DNA methylation on the highest concentration of 5-Aza-Dc. DLC-1 mRNA was weakly expressed in the control group, and the expression was gradually increased in 5-Aza-Dc treatment group. The Cdc42 mRNA and protein expression of experimental group were significantly decreased and were dose-dependent compared with the control group (P <0.05). Conclusion: The results of this research indicated that 5-Aza-Dc can effectively inhibit the methylation status of DLC-1 gene, reversal DLC-1 gene expression, and significantly decrease the expression of downstream signaling molecules Cdc42 mRNA and protein in RPMI-8226 cell.

Objective: To explore the therapeutic methods on surgical repair of refractory pressure ulcers around hip and sacral region, and to conclude the focuses of the surgical treatment. Materials and Methods: From January 2007 to December 2013, tissue flap transport with vascular pedicle was applied to repair 77 cases refractory pressure ulcers (96 wounds) around hip sacral region, with the patients aging from 21 to 82. For the positions of the 96 wounds, 34 wounds were on the sacrococcygeal region, 21 in femoral major trochanteric portion, and 41 on the ischial tuberosity. The size of smallest pressure ulcer was 1cm×2cm, and the biggest was 12×16cm, all were accompanied by infections with different degrees. Among all the cases, 38 wounds were repaired by gluteus maximus myocutaneous flaps, 11 wounds were repaired by gracilis myocutaneous flaps, and 12 wounds were repaired by long end of musculus biceps femoris myocutaneous flaps; 34 wounds repaired by fasciocutaneous flaps, including 10 wounds by posterior fasciocutaneous flaps; and 5 cases were healed by hip disarticulation and repaired by bone musculocutaneous flaps. Results: 75 of the 77 patients were healed after the operation, while 2 failed to be healed because of their old age and poor nutritional status. According to the follow-ups, 4 of the healed patients with pressure ulcers on ischial tuberosities relapsed 1 year after the operation, and were thoroughly healed by second operation of biceps femoris myocutaneous flaps transport; the transplanted myocutaneous flaps of other cases all survived and no recurrence of pressure ulcers happened, that the surgical treatment received satisfactory results. Conclusion: Combining the supportive therapeutics of nutritional support and control of the infections, surgical treatment of tissue flap transport with vascular pedicle could reach satisfactory results for repair refractory pressure ulcers around hip and sacral region.

Background: Video-assisted thoracic surgery (VATS) provides a minimally invasive means to resect pulmonary nodules. However, small solitary pulmonary nodules (SPN) remain problematic during VATS owing to unpredictable visualization and palpation. Intraoperative small SPN localization provides a more obvious target to facilitate intraoperative resection. This study is a single-institution validation of intraoperative CT-guided hook wire localization for small SPN in VATS. Methods: The records of 42 patients with 45 small SPN underwent intraoperative CT-guided doublethorn hook wire localization prior to video-assisted thoracoscopic wedge resection from September 2008 and August 2013 was reviewed retrospectively. All patients received VATS within 10minutes after wire localizations. The efficacy of intraoperative localization was evaluated in terms of procedure time, VATS success rate and associated complications of localization. Results: A total of 42 patients (30 males, 12 females) underwent 45 VATS resections, with simultaneous bilateral nodule resections performed in 3 patients. Nodule diameters ranged from 4 mm to 20 mm (mean, 6.8 mm). The distance of the lung lesions to the nearest pleural surfaces ranged from 2 mm to 30 mm (mean, 12.5 mm). All resections of the lesions (100%). guided by the inserted hook wires were successfully performed by VATS The mean procedure time for CTguided hook wire localization was 8.4 minutes (range: 6-15 minutes). The mean procedure time for VATS was 52 minutes (range: 14-98 minutes). Pathologic examination revealed 18 primary lung cancers, 21 atypical adenomatous hyperplasia (AAH), 4 metastases, 2 nonspecific chronic inflammation. No major complications related to the intraoperative hook wire localization and VATS were noted. Conclusion: Intraoperative CT-guided hook wire localization is useful, helps in precise small SPN localization in VATS wedge resection, and has a very low rate of minor complications.

The development of acute lung injury (ALI) is always accompanied by remarkably increased production of cytokines in plasma. However, the pathogenesis of this inflammatory response is unclear. In this study, the hypothesis whether Interleukin 33 (IL-33) is induced in the ALI patients and the possible mechanism was tested. The levels of IL-33 were found to be significantly induced in plasma of the ALI patients. Addition of IL-33, enhanced mRNA expression of NLRP-3, Caspase-3, BAX and p53 of peripheral mononuclear blood cells (PBMCs), but inhibited mRNA expression of Caspase-1 found in ALI patients. By stimulating the PBMCs with recombinant Human Interleukin (rhIL)-33, we demonstrated that the chemokines Interleukin 1β (IL-1β), Interleukin 6 (IL-6), Interleukin 18 (IL-18) and Tumor Necrosis Factor (TNF-α) were significantly increased with IL-33 administration in a dose dependent way. Concomitantly, the increase of phosphorylated p38 and enhancement of cell apoptosis were also found in the PBMCs. However, by blocking the IL-33 signaling with p38 inhibitor (SB 203580), the cytokine production and apoptosis were apparently blocked in PBMCs. The present study provided evidences for the IL-33 molecular mechanism in ALI patients. It promots cell apoptosis and cytokines production via the MAPK/p38 signaling in PBMCs.

Background: Acute aortic syndrome (AAS) is a group of serious and lethal aortic emergencies, which have so variable and non-specific clinical presentations and can be misdiagnosed as other diseases. AAS occurs frequently in daily life, but too little attention was paid on the location of its vascular flap according to different daily activity patterns. Methods: The data of 160 cases hospitalized for non-traumatic acute aortic syndrome in Chinese PLA general hospital from January 1st, 2004 to December 31st, 2013 were analyzed retrospectively. Among the 160 patients enrolled, 155 (96.9%, of160) were finally diagnosed with acute aortic dissection (AAD) and the other 5 (3.1%, of 160) with ruptured aortic aneurysm (RAA). Of those155 patients with AAD, 45 (29.0%, of 155) were definitely diagnosed with type A and 110 (71.0%, of 155) for type B according to the Stanford classification system. Results: (1) Flaps of aorta in AAS patients were found more commonly located in the thoracic descending aorta (68.1%, 109/160), and the other 24 cases (15.0%, 24/160) in the ascending aorta, 21 cases (21/160, 13.1 %) in aorta arch, and only 6 cases (6/160,3.8%) in the abdominal aorta. (2) There are 65 AAS patients (40.63%) with the body postural changes, 44 (27.50%) for body stretching, 25 (15.63%) for weighting, 17 (10.63%) for pound on the anterior body, 5 (3.13%) for turning the steering wheel and 4 (2.50%) for cycling during the onset of disease. (3) In the body postural changes group, the vessel flaps were dominantly found on thoracic descending aorta (76.92%, 50/65), which was significantly higher than the others (62.11%, 59/95; X2=3.902, P=0.040). (4) In the body stretching group, the vessel flaps on thoracic descending aorta were frequently (56.82%, 25/44), and on the ascending aorta was 31.82% (14/44), which significantly higher than the body postural change group (4.63%, 3/65; X2=15.028, P=0.0001) (5) The proportion of aortic arch flaps in the weighting group was 28.57% (6/21), which was significantly higher than the others (11.11%, 15/135; X2=3.073, P=0.081). (6) The frequency of the ascending aorta flap location in the pound on the anterior body group was significantly higher than the other activities (41.18%, 7/17 vs. 11.89%, 17/143; X2=10.222, P=0.001); and the abdominal aorta was also significantly higher than the other activities (16.65%, 3/17 vs. 20.98%, 3/143; X2=10.178, P=0.001). (7) There were 9 cases (5.63%, 9/160) with the twist movement(turning the steering wheel and cycling) had vascular flaps situated in thoracic descending aorta, which significantly higher than the others (100.00%, 9/9 vs. 65.56%, 99/151; X2=4.592, P=0.032). Conclusions: These results showed the location of vascular flap is highly related with daily activity pattern in nontraumatic acute aortic syndrome, which might be useful for clinicians when they prevent and cure this disease more timely and effectively.

Objective: To investigate the mechanism of GITRL on regulating the inflammatory reaction through the programmed death ligand (PDL1) in Kupffer cells (KCs). Methods: The KCs and the T cells were isolated and divided into 6 groups: (1) the Control group; (2) LPS group; (3) LPS+Control siRNA group, transfected with Control siRNA; (4) LPS+GITRL siRNA group, transfected with GITRL siRNA; (5) LPS+pEGFP-N1 control plasmid group, transfected with control plasmid; and (6) LPS+pEGFP-N1-GITRL plasmid group, transfected with GITRL plasmid. The control group was co-cultured in DMEM only, whereas all of the other groups were co-cultured with LPS (1 ug/m1). After 24 h of treatment, the expression levels of the TNF-α, GITRL, and PDL1 in the supernatant, proliferation and apoptosis of T cells and the transposition of P65 in KCs were evaluated. Results: The GITRL expression in KCs was obviously increased after LPS-stimulation in comparison to the control group. Concurrently, PDL1 was inhibited, the T cells proliferated, and TNF-α levels in the supernatant were obviously increased in the LPS group. With GITRL gene silencing, the restraint on PDL1 was clearly decreased, and the indexes of inflammation were not as obvious as in the LPS group. Furthermore, the results of the pEGFP-N1-GITRL group were opposite from that of the GITRL silencing group. However, the inflammation was exacerbated with the lower PDL1 expression. Conclusions: Increasing the expression of GITRL in the KCs may promote the proliferation of T cells by restraining PDL1, thus aggravating the inflammatory reaction. GITRL silencing could tilt the immunologic balance back and restraining the inflammatory reaction.

Objective: To investigate the inhibitory effects and the mechanism of NF-ΚB decoy oligodeoxynucleotides (ODN) on Kupffer cells (KCs) activation. Methods: KCs were isolated and randomly divided into three groups: (1) a control group; (2) an LPS stimu1ation group and (3) an NF-ΚB decoy group, in which the KCs were transduced with an NF-ΚB decoy ODN prior to LPS stimulation. Following 6 hours of LPS stimulation, the NF-ΚB activity was assayed by an electrophoretic mobility shift assay (EMSA). The CD80 mRNA expression in the KCs was detected by reverse transcription-polymerase chain reaction (RT-PCR), and the production of TNF-α and IL-6 in the supernatant was measured by an enzyme-linked immune sorbent assay (ELISA). Results: The NF-ΚB decoy ODN could efficiently inhibit KCs activation by LPS stimulus. The NF-ΚB activity was significantly decreased to 0.53 fold as compared with the LPS group. The CD80 mRNA expression, TNF-α production, and IL-6 level were significantly decreased to 0.46, 0.37, and 0.60 fold, respectively. Conclusion: The NF-ΚB decoy ODN could efficiently suppress transcription activity of NF-ΚB and inhibit co-stimulatory molecules and cytokines expression by KCs, which afford reliable experimental data for the in vivo application of NF-ΚB decoy ODN.

Backgroud: Tsutsugamushi disease was really uncommon in the pediatric clinical. However, it can be quite severe, those who suffer them Tsutsugamushi disease can progress to multiple organ dysfunction syndrome (MODS) and hemophagocytic syndrome (HPS). Unfortunately, there were few reports on pulmonary hemorrhage caused by tsutsugamushi disease, especially in children. Because of the nonspecific clinical presentations, it was difficult to differentiate from other diseases. The mortality would be up to 60% if inappropriate antibiotics were used. Case Presentation: We report a three-year-old girl infected with tsutsugamushi, which manifested as MODS, HPS and diffuse alveolar hemorrhage. After administation of chloromycetin, the patient’s temperature fell down to normal 2 days later and mechanical ventilation was stopped after 1 week. The patient was discharged after three weeks of treatment. Since the typical eschar of tsutsugamushi disease is mostly concealed, misdiagnosis and delay in treatment often cause severe complications. Conclusion: Chloromycetin may be an alternative antibiotic choice of treatment for severe pediatric tsutsugamushi disease, though it has toxic effects on bone marrow hematopoietic function.