Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
Aminoglycosides ; pharmacology ; therapeutic use ; Animals ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Drug Discovery ; Drug Resistance, Multiple, Bacterial ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Ferrous Compounds ; pharmacology ; therapeutic use ; Gram-Negative Bacteria ; drug effects ; Gram-Negative Bacterial Infections ; drug therapy ; Humans ; Peptides ; pharmacology ; therapeutic use ; Peptidomimetics ; pharmacology ; therapeutic use ; Tetracyclines ; pharmacology ; therapeutic use ; beta-Lactamase Inhibitors ; beta-Lactams ; pharmacology ; therapeutic use

Influenza is a global contagious disease, which causes hundreds of thousands of people deaths. And new subtype of influenza may cause pandemic influenza, and lead to more serious consequence. Drugs for anti-influenza have played very important roles in influenza treatment and prevention, especially neuraminidase inhibitors are effective on both influenza A and B which have more safety and tolerance, therefore they have been widely used for influenza treatment. However, several viral drug-resistant cases have been reported. In this paper, the clinic therapy, prevention and drug resistance of neuraminidase inhibitors, including zanamivir, oseltamivir and peramivir, and progress in the research and development in our country are presented in order to promote research and development of new drugs for influenza treatment and prevention.
Antiviral Agents ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; drug effects ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Humans ; Influenza, Human ; drug therapy ; prevention & control ; virology ; Neuraminidase ; antagonists & inhibitors ; Oseltamivir ; pharmacology ; therapeutic use ; Zanamivir ; pharmacology ; therapeutic use

Flavanoids are important phytochemistry compositions in foods and traditional Chinese medicines (TCM) and are mainly oxidized by CYP1A family in vivo. Some methoxyflavones could also be metabolized through demethylation. Usually, flavanoids own one or more phenolic hydroxyl group in their molecular structures, which facilitate conjugation with glucuronic acid and sulphuric acid, forming metabolites with good water-solubility to excrete. Natural flavanoids mainly exist in glycoside, and after oral ,they would be easily metabolized to aglycone by hydratase in gut microflora and then absorbed into blood. Besides, many flavanoids have strong inhibitory actions on Cytochrome P450 enzymes, which are significant mechanisms in cancer precaution and tumor inhibition. In this paper, we reviewed lots of articles and summarized metabolism characteristics of flavanoids and metabolism interaction with Cytochrome P450 enzymes.
Animals ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Therapy ; Flavonoids ; metabolism ; pharmacology ; therapeutic use ; Humans

OBJECTIVETo determine the effect of MEK inhibitor (U0126) on donor testes from ischemia-reperfusion injury after orthotopic testicular transplantation in rats.

METHODSThe rats were divided into 7 groups, Group 1: normal control; Group 2: cold perfusion control; Group 3: sham operation control; Group 4: transplanted for 30 min; Group 5: transplanted for 1 week; Group 6: transplanted for 30 min with pretreatment of U0126; Group 7: transplanted for 1 week with pretreatment of U0126. The orthotopic testicular transplantation model was established with cuff. The levels of ERK1, ERK2, pERK1 and pERK2 of donor testes were evaluated; the change of histology and gonadal hormones were measured as well.

RESULTGroup 1, 2 and 3 had no significant differences in all results (P>0.05). The levels of ERK1, ERK2, pERK1 and pERK2 in Group 4 were significantly increased compared with Group 1 (P<0.05), the levels of ERK1 and ERK2 in Group 6 were not different from those of Group 4 (P >0.05), but the levels of pERK1 and pERK2 in Group 6 were lower than those in Group 4 significantly(P <0.05), the histological changes in Group 6 were similar to Group 1 but milder than that in Group 4. The histological injury was more severe in Group 5 than that in Group 7, and the levels of gonadal hormones in Group 5 were lower than those in Group 7 (P <0.05) which remained at the normal levels.

CONCLUSIONU0126 has a protective effect on the donor testes in a short period through inhibiting expression of pERK1/2 activated by testicular transplantation.

Animals ; Butadienes ; pharmacology ; therapeutic use ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Extracellular Signal-Regulated MAP Kinases ; antagonists & inhibitors ; Male ; Nitriles ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Inbred Lew ; Reperfusion Injury ; prevention & control ; Testis ; blood supply ; transplantation

Cullin-RING E3 ligases (CRLs) are the major components of ubiquitin-proteasome system, responsible for ubiquitylation and subsequent degradation of thousands of cellular proteins. CRLs play vital roles in the regulation of multiple cellular processes, including cell cycle, cell apoptosis, DNA replication, signalling transduction among the others, and are frequently dysregulated in many human cancers. The discovery of specific neddylation inhibitors, represented by MLN4924, has validated CRLs as promising targets for anti-cancer therapies with a growing market. Recent studies have focused on the discovery of the CRLs inhibitors by a variety of approaches, including high through-put screen, virtual screen or structure-based drug design. The field is, however, still facing the major challenging, since CRLs are a large multi-unit protein family without typical active pockets to facilitate the drug design, and enzymatic activity is mainly dependent on undruggable protein-protein interactions and dynamic conformation changes. Up to now, most reported CRLs inhibitors are aiming at targeting the F-box family proteins (e.g., SKP2, β-TrCP and FBXW7), the substrate recognition subunit of SCF E3 ligases. Other studies reported few small molecule inhibitors targeting the UBE2M-DCN1 interaction, which specifically inhibits CRL3/CRL1 by blocking the cullin neddylation. On the other hand, several CRL activators have been reported, such as plant auxin and immunomodulatory imide drugs, thalidomide. Finally, proteolysis-targeting chimeras (PROTACs) has emerged as a new technology in the field of drug discovery, specifically targeting the undruggable protein-protein interaction. The technique connects the small molecule that selectively binds to a target protein to a CRL E3 via a chemical linker to trigger the degradation of target protein. The PROTAC has become a hotspot in the field of E3-ligase-based anti-cancer drug discovery.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Drug Design ; Drug Discovery ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Humans ; Neoplasms ; enzymology ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination ; drug effects

BACKGROUNDRenin-angiotensin system inhibitor and calcium channel blocker (CCB) are widely used in controlling blood pressure (BP) in patients with chronic kidney disease (CKD). We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and CCB (i.e., ACEI/ARB + CCB) with ACEI/ARB monotherapy in patients with hypertension and CKD.

METHODSPublications were identified from PubMed, Embase, Medline, and Cochrane databases. Only randomized controlled trials (RCTs) of BP lowering treatment for patients with hypertension and CKD were considered. The outcomes of end-stage renal disease (ESRD), cardiovascular events, BP, urinary protein measures, estimated glomerular filtration rate (GFR), and adverse events were extracted.

RESULTSBased on seven RCTs with 628 patients, ACEI/ARB + CCB did not show additional benefit for the incidence of ESRD (risk ratio [RR] = 0.84; 95% confidence interval [CI]: 0.52-1.33) and cardiovascular events (RR = 0.58; 95% CI: 0.21-1.63) significantly, compared with ACEI/ARB monotherapy. There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] = -1.28 mmHg; 95% CI: -3.18 to -0.62), proteinuria (standard mean difference = -0.55; 95% CI: -1.41 to -0.30), GFR (WMD = -0.32 ml/min; 95% CI: -1.53 to -0.89), and occurrence of adverse events (RR = 1.05; 95% CI: 0.72-1.53). However, ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD = -4.46 mmHg; 95% CI: -6.95 to -1.97), compared with ACEI/ARB monotherapy.

CONCLUSIONACEI/ARB + CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.

Angiotensin Receptor Antagonists ; pharmacology ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; therapeutic use ; Calcium Channel Blockers ; pharmacology ; therapeutic use ; Drug Therapy, Combination ; Glomerular Filtration Rate ; Humans ; Hypertension ; drug therapy ; Kidney ; drug effects ; Renal Insufficiency, Chronic ; drug therapy

Aurora-B as an important kinase to adjust the cell normal mitosis is a potent target for cancer treatment. Aurora-B is overexpressed in a broad range of tumor and tumor cells are more sensitive while Aurora-B is inhibited. Due to the key role of the Aurora-B in cell mitosis, the development of its inhibitors is becoming more and more important. Several small molecules inhibit with a similar efficacy both Aurora-A and Aurora-B, however, in most cases the effects resemble Aurora-B disruption by genetic methods, indicating that Aurora-B represents an effective therapeutic target. There were several Aurora-B kinase inhibitors which had entered the clinics and displayed good antitumor activity. In this review, we will outline the functions of Aurora kinase B in normal cell division and in malignancy. We will focus on recent preclinical and clinical studies that have explored the mechanism of action and clinical effect of Aurora-B inhibitors in cancer treatment.
Animals ; Aurora Kinase B ; antagonists & inhibitors ; genetics ; metabolism ; Enzyme Activation ; Humans ; Mitosis ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; RNA, Messenger ; metabolism

DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Azacitidine/*pharmacology/*therapeutic use ; DNA Methylation/*drug effects ; DNA Modification Methylases/antagonists & inhibitors/metabolism ; Enzyme Inhibitors/*pharmacology/*therapeutic use ; Female ; Genes, Tumor Suppressor ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/*drug therapy/*genetics ; Young Adult

Endometriosis, an oestrogen-dependent disorder, is related to inflammation, p38 Mitogen activated protein kinases (p38 MAPK) can be activated by sex hormone and inflammatory factors, which plays an important role in many cellular reactions such as apoptosis, proliferation, inflammation and stresses, etc. Many studies showed that p38 MAPK was participated directly in regulating the pathogenesis of endometriosis. The special regulatory action of p38 MAPK on sex hormone and inflammation may help us to understand the intricate endometriosis pathological hypothesis. p38 MAPK inhibitors play a key role in the the study of endometriosis, and show great promise for the future. Blocking and regulating the expression of p38 MAPK on the signal transduction pathway level may hope to be a new strategy to prevent and treat endometriosis.
Animals ; Anti-Inflammatory Agents, Non-Steroidal ; pharmacology ; therapeutic use ; Endometriosis ; drug therapy ; metabolism ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Female ; Humans ; Imidazoles ; pharmacology ; Inflammation ; drug therapy ; metabolism ; Pyrazoles ; therapeutic use ; Pyridines ; pharmacology ; therapeutic use ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism ; pharmacology

OBJECTIVETo investigate the changes and the effects of captopril on the renal blood flow and microvascular perfusion in dogs with acute cardiac insufficiency.

METHODSAcute cardial insufficiency was induced by combining occlusion of the left anterior descending artery with right ventricular pacing in 12 mongrel dogs. The ascending aorta and left kidney were dissected and ultrasonic flow probes were placed on ascending aorta and renal artery to monitor cardiac output (CO) and renal blood flow (RBF). Contrast-enhanced ultrasound of the kidney was performed as CO was reduced to 25% (LCO25%) and 50% (LCO50%) from the basic measurement and microvascular flow velocity (beta), microvascular volume (A) and microvascular blood flow (renal cortex) were observed. After CO reduced to 50%, captopril 1 mg/kg and 2 mg/kg were injected successively and contrast-enhanced ultrasound of the kidney were performed again before and after injection.

RESULTSAt baseline, CO, RBF, CXbeta (beta of renal cortex), A and A x beta were (1.46 +/- 0.16) ml/min, (107.5 +/- 35.7) ml/min, 1.39 +/- 0.14, 120.3 +/- 14.8 and 167.4 +/- 25.0, respectively. After the LCO25% was reached, RAF, CXbeta, A and A x beta decreased to (72.50 +/- 32.4) ml/min, 0.87 +/- 0.082, 117.6 +/- 13.1, and 102.6 +/- 15.5, respectively. The corresponding values after the LCO50% was reached were (44.1 +/- 17.2) ml/min, 0.61 +/- 0.039, 106.9 +/- 12.0, and 64.7 +/- 8.83, respectively. It is suggested that the volume of the renal microvasculature remained stable until the LCO50% was reached. When captopril 1 mg/kg and 2 mg/kg were injected successively at LCO50%, MAP decreased from (85.4 +/- 7.8) mm Hg to (78.7 +/- 7.3) mm Hg and to (69.1 +/- 6.3) mm Hg (P < 0.05), respectively, while CO increased from 0.73 +/- 0.084 to 0.83 +/- 0.065 and to 0.9 +/- 0.054 (P < 0.05), respectively. RBF increased from (44.1 +/- 17.2) ml/min to 60.3 +/- 17.8 and to 79.4 +/- 17.8 (P < 0.05), respectively. After captopril 1 mg/kg and 2 mg/kg were injected, the increased flow ratios with CO were 0.15 +/- 0.084 and 0.31 +/- 0.011, respectively, and with RBF were 0.29 +/- 089 and 0.522 +/- 0.040, respectively. The increased renal blood flow ratio was higher than that of CO after captopril was used. The corresponding increases were from 0.61 +/- 0.039 to 0.75 +/- 0.020 and to 0.86 +/- 0.027 for CX beta, from 106.9 +/- 11.9 to 115.4 +/- 11.1 and to 116.6 +/- 8.9 for A, from 64.7 +/- 8.83 to 87.0 +/- 8.6 and to 100.6 +/- 8.9 for A x beta, respectively.

CONCLUSIONThe renal microvasculature plays a role by keeping its volume stable in the protection against renal ischemia when acute cardiac output decreases slightly. The role of captopril to improve renal microvascular perfusion is independent of increased total cardiac output or increased systemic blood pressure.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; therapeutic use ; Animals ; Captopril ; pharmacology ; therapeutic use ; Cardiac Output, Low ; complications ; drug therapy ; physiopathology ; Dogs ; Female ; Kidney ; blood supply ; diagnostic imaging ; Male ; Perfusion ; Renal Circulation ; drug effects ; Ultrasonography