Advances in molecular agents targeting toll-like receptor 4 signaling pathways for potential treatment of sepsis.

Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response. Accordingly, as part of efforts to improve the inflammatory response and survival rate of patients with sepsis, several drugs have been developed to regulate the inflammatory signaling pathways mediated by TLR4. Inhibition of TLR4 signal transduction can be directed toward either TLR4 directly or other proteins in the TLR4 signaling pathway. Here, we review the advances in the development of small-molecule agents and peptides targeting regulation of the TLR4 signaling pathway, which are characterized according to their structural characteristics as polyphenols, terpenoids, steroids, antibiotics, anthraquinones, inorganic compounds, and others. Therefore, regulating the expression of the TLR4 signaling pathway and modulating its effects has broad prospects as a target for the treatment of lung, liver, kidneys, and other important organs injury in sepsis.

Advances in thiosemicarbazone metal complexes as anti-lung cancer agents.

The great success of cisplatin as a chemotherapeutic agent considerably increased research efforts in inorganic biochemistry to identify more metallic drugs having the potential of treating lung cancer. Metal coordination centres, which exhibit a wide range of coordination numbers and geometries, various oxidised and reduced states and the inherent ligand properties offer pharmaceutical chemists a plethora of drug structures. Owing to the presence of C=N and C=S bonds in a thiosemicarbazone Schiff base, N and S atoms in its hybrid orbital has lone pair of electrons, which can generate metal complexes with different stabilities with most metal elements under certain conditions. Such ligands and complexes play key roles in the treatment of anti-lung cancer. Research regarding metallic anti-lung cancer has advanced considerably, but there remain several challenges. In this review, we discuss the potential of thiosemicarbazone Schiff base complexes as anti-lung cancer drugs, their anti-cancer activities and the most likely action mechanisms involving the recent families of copper, nickel, platinum, ruthenium and other complexes.

[Correlation of behavioral performance with expressions of substance P and neurokinin-1 receptor in the L5－S2 spinal cord of chronic prostatitis rats].

OBJECTIVE: To investigate the correlation between the behavioral performance and the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in rats with chronic prostatitis (CP). METHODS: A CP model was made in 30 adult male SD rats by intraperitoneal injection of 0.5 ml dyphtheria pertussis tetanus (DPT) vaccine and mixed solution of 1 ml prostatein extract and complete adjuvant in a 1∶1 ratio, and another 10 rats were injected with the same volume of normal saline as controls. At 45 (n = 10), 60 (n = 10) and 90 days (n = 10) after modeling, the behavioral changes of the rats were observed by open-field and sucrose consumption tests, the prostatic indexes and levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were obtained, and the expressions of SP and NK1-R in the L5－S2 spinal cord were determined by immunohistochemistry. RESULTS: Compared with the controls, the CP model rats showed obviously decreased horizontal and vertical movement scores and sucrose consumption, particularly in the 90 d group (P < 0.05), significantly reduced prostatic indexes in the 45 d, 60 d and 90 d groups (all P < 0.05), even lower in the 90 d than in the 45 d and 60 d groups (P < 0.05). Edema and lymphocytes were increased in the prostatic tissue with the prolonged time of modeling. The levels of serum TNF-α, IL-1ß, IL-2 and IL-10 were markedly elevated in all the CP rats as compared with those in the controls (P < 0.05), and so were the expressions of SP and NK-1R in the L5－S2 spinal cord (P < 0.05), even more significantly in the 90 d than in the 45 d and 60 d groups (P < 0.05). CONCLUSIONS: Rats with chronic prostatitis are characterized by behavioral manifestation of depression, increased levels of serum TNF-α, IL-1ß, IL-2 and IL-10, and a time-dependent upregulation of the expressions of SP and NK-1R in the posterior horn of the L5-S2 spinal cord, which suggests a correlation between the behavioral performance and the expressions of SP and NK-1R in the L5－S2 spinal cord of the rats.

[Expressions of SP and NK-1R increase in the posterior horn of the L5－S2 spinal cord in rats with chronic nonbacterial prostatitis].

OBJECTIVE: To investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in the rat model of chronic nonbacterial prostatitis (CNP) at different time points of modeling. METHODS: Forty adult male SD rats were randomly divided into four groups of equal number, control, 45 d model, 60 d model, and 90 d model, and proteins were obtained from the prostatic tissue of another 30 rats. The CNP model was made by intraperitoneal injection of 0.5 ml DPT vaccineand intradermal injection of mixed solution of 1 ml prostatein extract and complete adjuvant at a 1∶1 ratio, while the control rats were injected with the same volume of normal saline. At 45, 60, and 90 days after modeling, we measured the paw withdrawal threshold (PWT) of the rats, determined the levels of TNF-α, IL-1ß, IL-2, and IL-10 in the prostate tissue by ELISA, observed the histomorphological changes in the prostate by transmission electron and light microscopy, and detected the expressions of SP and NK1-R in the L5－S2 spinal cord by immunohistochemistry. RESULTS: The model rats showed significantly increased sensitivity to pain, with remarkably lowered PWT at 45, 60, and 90 days after modeling. The levels of TNF-α, IL-1ß, IL-2, and IL-10 in the prostate tissue were markedly elevated in the CNP models as compared with those in the controls (all P<0.05), most significantly at 90 days (all P<0.05). Immunohistochemistry showed that the expressions of SP and NK-1R were remarkably higher in the CNP model groups than in the control (all P<0.05), the highest at 90 days. Light microscopy revealed no inflammatory cell infiltration in the prostate tissue of the control rats, and obvious edema and increased lymphocytes were observed with the prolonged time of modeling.Transmission electron microscopy showed inflammatory changes in the prostate tissue of the model rats and that peritubular interstitial edema was most obvious at 90 days, with widened intervals between peritubular cells and the epithelial base and increased numbers of fibroblasts and collagen fibrils. CONCLUSIONS: The synthesis of SP and the level of NK-1R were increased in the posterior horn of the L5－S2 spinal cord in the rat model of CNP.

Acute Liver Failure and Myelosuppression due to Parvovirus B19 Infection: A Case Report.

Parvovirus B19 has been associated with different diseases, such as erythema infectiosum, arthropathy and transient aplastic crisis. However, parvovirus B19 infection presenting as hepatic dysfunction and myelosuppression is rarely reported in adult patients. Herein, we report an adult case of acute parvovirus B19 infection presented with acute liver failure and myelosuppression. After being treated with gamma globulin, the patient's liver function and bone marrow test improved. We conclude that the parvovirus B19 infection should be considered as a possible cause of acute liver injury and bone marrow suppression. The antibody for B19 virus should be routinely tested in patients with liver dysfunction and/or myelosuppression of unclear etiology.

Methodologic research on TIMP-1, TIMP-2 detection as a new diagnostic index for hepatic fibrosis and its significance.

AIM: To set up a new method to detect tissue inhibitors of metalloproteinase-1 and -2(TIMP-1 and TIMP-2) in sera of patients with hepatic cirrhosis, and to investigate the expression and location of TIMP-1 and TIMP-2 in liver tissue of patients with hepatic cirrhosis, and the correlation between TIMPs in liver and those in sera so as to discuss whether TIMPs can be used as a diagnosis index of hepatic fibrosis. METHODS: The monoclonal antibodies (McAbs) of TIMP-1 and TIMP-2 were used to sensitize erythrocytes, and solid-phase absorption to sensitized erythrocytes (SPASE) was used to detect TIMP-1 and TIMP-2 in the sera of patients with hepatic cirrhosis. Meanwhile, with the method of in situ hybridization and immunohistochemistry, we studied the mRNA expression and antigen location of TIMP-1 and TIMP-2 in the livers of 40 hepatic cirrhosis patients with pathologic diagnosis. RESULTS: With SPASE, they were 16.4% higher in the acute hepatitis group, 33.3% higher in the chronic hepatitis group, and the positive rates were 73.6% and 61.2% respectively in sera of hepatic cirrhosis patients, which were remarkably higher than those in chronic hepatitis and acute hepatitis group (P<0.001). In 40 samples of hepatic cirrhosis tissues, all of them showed positive expression of TIMP-1 and TIMP-2 mRNA detected with immunohistochemistry or in situ hybridization (positive rate was 100%). Expression of TIMPs in different degrees could be found in liver tissue with cirrhosis. TIMPs were located in cytoplasm of liver cells of patients with hepatic cirrhosis. There was a significant correlation between serum TIMPs level and liver TIMPs level. CONCLUSION: SPASE is a useful method to detect the TIMP-1 and TIMP-2 in sera of patients with hepatic cirrhosis, and TIMP-1 and TIMP-2 can be considered as a useful diagnostic index of hepatic fibrosis, especially TIMP-1.