摘要 :
The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via...
展开
The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.
收起
摘要 :
Estrogens are hormones that modulate a diverse array of effects during development and adulthood. The effects of estrogen are mediated by two estrogen receptor (ER) isotypes, ERalpha and ERbeta, which classically function as trans...
展开
Estrogens are hormones that modulate a diverse array of effects during development and adulthood. The effects of estrogen are mediated by two estrogen receptor (ER) isotypes, ERalpha and ERbeta, which classically function as transcription factors to modulate specific target gene expression and in addition regulate a growing list of intracellular signaling cascades. These receptors share protein sequence homology and protein-motif organization but have distinct differences in their tissue distribution and binding affinities for their ligands. In the nervous system estrogen has been implicated to play a role in a number of processes which regulate synaptic plasticity including synaptogenesis and neurogenesis. The role for estrogen in a range of neurological and neuropsychiatric diseases is also becoming very apparent. Estrogen is able to regulate processes and behaviours relevant for both Alzheimer's disease and schizophrenia and to modulate neuroendocrine and inflammatory processes important in neuroinflammation, anxiety and depressive disorders as well as chronic pain. We will consider the rationale for estrogen-based therapies for diseases of the nervous system. In particular we will highlight the molecular mechanisms and signal transduction pathways most likely underlying the effects of estrogen in the CNS.
收起
摘要 :
IMPORTANCE OF THE FIELD: Gastric cancer is one of the most common causes of cancer death worldwide. P21-activated kinases (PAKs), regulators of cancer-cell signalling networks, play fundamental roles in a range of cellular process...
展开
IMPORTANCE OF THE FIELD: Gastric cancer is one of the most common causes of cancer death worldwide. P21-activated kinases (PAKs), regulators of cancer-cell signalling networks, play fundamental roles in a range of cellular processes through their binding partners or kinase substrates. AREAS COVERED IN THIS REVIEW: The complex regulation of PAKs through their upstream or downstream effectors in human cancers, especially in gastric cancer, are described and the identified inhibitors of PAKs are summarized. WHAT THE READERS WILL GAIN: The structural differences and activation mechanisms between two subgroups of PAK are described. Both groups of PAKs play complicated and important roles in human gastric cancer, which indicated a possible way for us to identify the specific inhibitors targeting PAKs for gastric cancer. TAKE HOME MESSAGE: PAKs play important roles in progression of many cancer types, the full mechanisms of PAKs in gastric cancer are still unclear. It seems there are different roles for two groups of PAKs in cancers. Group I PAKs play their functions mostly through their specific substrates, however, many binding partners that are independent of phosphorylation by group II PAKs were identified. Finding specific inhibitors of PAKs will help us discover the roles of PAKs and target these kinases in human gastric cancer.
收起
摘要 :
Gamma-aminobutyric acid type A (GABA(A)) receptors play an important role in mediating fast synaptic inhibition in the brain. They are ubiquitously expressed in the CNS and also represent a major site of action for clinically rele...
展开
Gamma-aminobutyric acid type A (GABA(A)) receptors play an important role in mediating fast synaptic inhibition in the brain. They are ubiquitously expressed in the CNS and also represent a major site of action for clinically relevant drugs. Recent technological advances have greatly clarified the molecular and cellular roles played by distinct GABA(A) receptor subunit classes and isoforms in normal brain function. At the same time, postmortem and genetic studies have linked neuropsychiatric disorders including schizophrenia and bipolar disorder with GABAergic neurotransmission and various specific GABA(A) receptor subunits, while evidence implicating GABA(A)R-associated proteins is beginning to emerge. In this review we discuss the mounting genetic, molecular, and cellular evidence pointing toward a role for GABA(A) receptor heterogeneity in both schizophrenia etiology and therapeutic development. Finally, we speculate on the relationship between schizophrenia-related disorders and selected GABA(A) receptor associated proteins, key regulators of GABA(A) receptor trafficking, targeting, clustering, and anchoring that often carry out these functions in a subtype-specific manner.
收起
摘要 :
Image-based computational models for atherosclerotic plaques have been developed to perform mechanical analysis to quantify critical flow and stress/strain conditions related to plaque rupture which often leads directly to heart a...
展开
Image-based computational models for atherosclerotic plaques have been developed to perform mechanical analysis to quantify critical flow and stress/strain conditions related to plaque rupture which often leads directly to heart attack or stroke. An important modeling issue is how to determine zero stress state from in vivo plaque geometries. This paper presents a method to quantify human carotid artery axial and inner circumferential shrinkages by using patient-specific ex vivo and in vivo MRI images. A shrink-stretch process based on patient-specific in vivo plaque morphology and shrinkage data was introduced to shrink the in vivo geometry first to find the zero-stress state (opening angle was ignored to reduce the complexity), and then stretch and pressurize to recover the in vivo plaque geometry with computed initial stress, strain, flow pressure and velocity conditions. Effects of the shrink-stretch process on plaque stress/strain distributions were demonstrated based on patient-specific data using 3D models with fluid-structure interactions (FSI). The average artery axial and inner circumferential shrinkages were 25% and 7.9%, respectively, based on a data set obtained from 10 patients. Maximum values of maximum principal stress and strain increased 349.8% and 249% respectively with 33% axial stretch. Influence of inner circumferential shrinkage (7.9%) was not very noticeable under 33% axial stretch, but became more noticeable under smaller axial stretch. Our results indicated that accurate knowledge of artery shrinkages and the shrink-stretch process will considerably improve the accuracy of computational predictions made based on results from those in vivo MRI-based FSI models.
收起
摘要 :
In bacterial-induced peripheral nervous system (PNS) inflammation, Schwann cells (SCs) are activated, producing inducible nitric oxide synthase (iNOS), contributed to the pathogenesis of demyelinating disease, such as multiple scl...
展开
In bacterial-induced peripheral nervous system (PNS) inflammation, Schwann cells (SCs) are activated, producing inducible nitric oxide synthase (iNOS), contributed to the pathogenesis of demyelinating disease, such as multiple sclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to play a protective role in cellular inflammatory responses. Here we showed that LPS-induced iNOS biosynthesis was in a concentration and time-dependent manner. In LPS-treated primary SCs, retreatment with PPAR-gamma agonist remitted the increase of iNOS, p38 phosphorylation and TLR4, MyD88, augmented the expression of PPAR-gamma and localization in nuclear. Coadministration of GW 9662 reversed the effect of PPAR-gamma agonists. These results suggest that PPAR-gamma agonists, 15d-PGJ(2) and pioglitazone, had the anti-inflammatory effects.
收起
摘要 :
The ATP-binding cassette efflux transporter, ABCG2, is widely expressed in a variety of normal tissues, stem cells, as well as cancer cells. Existing data suggest that ABCG2 plays an important role in the maintenance of the stem c...
展开
The ATP-binding cassette efflux transporter, ABCG2, is widely expressed in a variety of normal tissues, stem cells, as well as cancer cells. Existing data suggest that ABCG2 plays an important role in the maintenance of the stem cell phenotype and multidrug resistance of cancer cells. However, the potential role of ABCG2 in other cellular processes remains speculative and poorly understood. Here, we demonstrated that ABCG2 is involved in the proliferation of cancer cells. We used RNA interference approach to efficiently and specifically down-regulate ABCG2 protein levels in MCF-7/MX and A549 cells. We showed that knockdown of ABCG2 significantly inhibited the proliferation of these cells. Suppression of ABCG2 reduced the percentage of cells in the S phase of the cell cycle and enhanced G0/G1 accumulation. The G0/G1 growth arrest was associated with down-regulation of cyclin D3 and up-regulation of p21. Furthermore, blocking of ABCG2 function by chemical inhibitor fumitremorgin C also inhibited cell proliferation via the prolonged G0/G1 interval. Taken together, these findings suggest that ABCG2 correlates with cell cycle progression, highlighting a novel function of ABCG2 in cancer cell proliferation.
收起
摘要 :
A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to ne...
展开
A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.
收起
摘要 :
PURPOSE: To synthesize P[(Folate-Allylamine)-co-(N-isopropylacrylamine)- co-Acrylamide] (P(FoAAn-co-NIPA-AAm), folate-NHG) with appropriate diameter and lower critical solution temperature (LCST) for targeting to folate receptor (...
展开
PURPOSE: To synthesize P[(Folate-Allylamine)-co-(N-isopropylacrylamine)- co-Acrylamide] (P(FoAAn-co-NIPA-AAm), folate-NHG) with appropriate diameter and lower critical solution temperature (LCST) for targeting to folate receptor (FR) expressing tumors. METHODS: Folate-NHG was synthesized by free-radical precipitation polymerization method reported in our previous work and other reports. LCST, diameter and morphology of folate-NHG were characterized by UV-vis spectrophotometer, laser particle size analyzer (LPSA) and transmission electron microscope (TEM), respectively. No.12 near infrared dye (NIRD-12) was entrapped into folate-NHG by hydrophobic association to trace the in vivo dynamic behavior of folate-NHG. This process was evaluated by a homemade near infrared (NIR) imaging system. RESULTS: Spherical folate-NHG with diameter of about 50 nm and LCST of about 40 degrees C was successfully synthesized. The photo stability of NIRD-12 was strengthened after being entrapped into folate-NHG, which enabled NIRD-12 to better trace the in vivo dynamic process of folate-NHG. Folate-NHG showed good targeting capability for all three folate receptor expressing tumor models (SMMC-7721, Bel-7402 and HeLa) with different sizes, and this accumulation could last for more than 96 h. D-folate-NHG, synthesized with double amount of FoAAn, showed better targeting effect for SMMC-7721 tumor model than that of folate-NHG. CONCLUSIONS: Folate-NHG could actively accumulate in three models of folate receptor positive tumors with different sizes and keep retention for more than 96 h, which enables it to be used as a diagnostic reagent or anti-tumor drug carrier for tumor therapy.
收起
摘要 :
The aim of the study is to investigate the cholinergic deficit in Alzheimer's disease (AD) and identify candidate blood biomarkers for the diagnosis of the disease. Twenty-nine elderly Chinese diagnosed with AD and 33 age-matched ...
展开
The aim of the study is to investigate the cholinergic deficit in Alzheimer's disease (AD) and identify candidate blood biomarkers for the diagnosis of the disease. Twenty-nine elderly Chinese diagnosed with AD and 33 age-matched controls were selected. The activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in plasma were detected by a spectrophotometric method, and the mRNA levels of alpha4 and beta2 nicotinic acetylcholine receptor (nAChR) subunits in blood leukocytes were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that AChE activity in plasma was significantly lower in the AD group than in normal controls, while BuChE activity did not show any differences between AD and controls; mRNA levels of both alpha4 and beta2 nAChR subunits in blood leukocytes were significantly lower in the AD group than in controls. The AChE activity and the mRNA levels of alpha4 and beta2 nAChR subunits in the AD patients were also significantly correlated with cognitive test scores. No differences of AChE in plasma or alpha4 and beta2 nAChR subunits in blood leukocytes were detected between smoking and non-smoking subjects. The results indicated that the decreases in the activity of AChE and in the mRNA levels of nAChR alpha4 and beta2 subunits from the peripheral blood of patients with AD might serve as supplementary indicators for the clinical diagnosis of AD.
收起
原文获取