Lai C

References (7)

Title : Probing the functional hotspots inside protein hydrophobic pockets by in situ photochemical trifluoromethylation and mass spectrometry - Lai_2024_Chem.Sci_15_2545
Author(s) : Lai C , Tang Z , Liu Z , Luo P , Zhang W , Zhang T , Dong Z , Liu X , Yang X , Wang F
Ref : Chem Sci , 15 :2545 , 2024
Abstract : Due to the complex high-order structures and interactions of proteins within an aqueous solution, a majority of chemical functionalizations happen on the hydrophilic sites of protein external surfaces which are naturally exposed to the solution. However, the hydrophobic pockets inside proteins are crucial for ligand binding and function as catalytic centers and transporting tunnels. Herein, we describe a reagent pre-organization and in situ photochemical trifluoromethylation strategy to profile the functional sites inside the hydrophobic pockets of native proteins. Unbiased mass spectrometry profiling was applied for the characterization of trifluoromethylated sites with high sensitivity. Native proteins including myoglobin, trypsin, haloalkane dehalogenase, and human serum albumin have been engaged in this mild photochemical process and substantial hydrophobic site-specific and structure-selective trifluoromethylation substitutes are obtained without significant interference to their bioactivity and structures. Sodium triflinate is the only reagent required to functionalize the unprotected proteins with wide pH-range tolerance and high biocompatibility. This "in-pocket" activation model provides a general strategy to modify the potential binding pockets and gain essential structural insights into the functional hotspots inside protein hydrophobic pockets.
ESTHER : Lai_2024_Chem.Sci_15_2545
PubMedSearch : Lai_2024_Chem.Sci_15_2545
PubMedID: 38362424

Title : Inhibition of soluble epoxide hydrolase relieves adipose inflammation via modulating M1\/M2 macrophage polarization to alleviate airway inflammation and hyperresponsiveness in obese asthma - Lin_2023_Biochem.Pharmacol__115948
Author(s) : Lin X , Zhang Y , Zhou X , Lai C , Dong Y , Zhang W
Ref : Biochemical Pharmacology , :115948 , 2023
Abstract : Obesityincreasestheriskofasthma and tends to enhance the asthma severity, however, its mechanism is not fully elucidated. The expansion of adipose tissue in obesity is accompanied by the accumulation of adiposetissue macrophages (ATMs) that could contribute to alow-gradeinflammationstate. In this study, we researched the regulatory role of soluble epoxide hydrolase (sEH) on ATMs-mediated inflammation in obese asthma. A mouse model of obese asthma that induced by high-fat diet (HFD) feeding and Ovalbumin (OVA) sensitization was employed to investigate the effects of AUDA, a sEH inhibitor (sEHi), on airway inflammation, airway hyperresponsivenesss (AHR) and pulmonary pathological changes. In addition to alleviating the key features of asthma in obese mice, we confirmed that AUDA reduced the expression of pro-inflammatory factor, such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumornecrosisfactor-alpha (TNF-alpha) in adipose tissue and serum. Moreover, AUDA could remarkedly reduce Lipopolysaccharide (LPS)-elevated IL-1beta, IL-6 and TNF-alpha in RAW264.7 macrophage cells. Mechanistically, AUDA effectively reduced inflammation in adipose tissue, resulting in reduced systemic inflammation, by inhibiting M1-type macrophage polarization and promoting M2-type macrophage polarization. These processes were found to act through ERK1/2 signaling pathway. Herein, we proved that inhibition of sEH expression helped to mitigate multiple parameters of obese asthma by regulating the balance of M1/M2 macrophage polarization in adipose tissue.
ESTHER : Lin_2023_Biochem.Pharmacol__115948
PubMedSearch : Lin_2023_Biochem.Pharmacol__115948
PubMedID: 38042452

Title : Effect of Underlying Renal Disease on Nutritional and Metabolic Profile of Older Adults with Reduced Renal Function - Lai_2017_Front.Nutr_4_4
Author(s) : Lai S , Amabile MI , Altieri S , Mastroluca D , Lai C , Aceto P , Crudo M , D'Angelo AR , Muscaritoli M , Molfino A
Ref : Front Nutr , 4 :4 , 2017
Abstract : BACKGROUND: Chronic kidney disease is a common condition in the general population, particularly among older adults. Renal impairment is in turn associated with metabolic and nutritional derangements and with increased risk of cardiovascular disease. AIM: To compare the metabolic, nutritional, and cardiovascular impact of reduced kidney function between patients with and without known renal disease. MATERIALS AND
METHODS: We enrolled consecutive outpatients (age >/=65 years) with reduced renal function who were divided into two groups: Group A with history of renal disease and Group B with unknown renal disease. Metabolic and nutritional parameters, including involuntary body weight loss (BWL) in the previous 6 months, mineral metabolism, inflammatory indices, and left ventricular mass index (LVMI), were evaluated.
RESULTS: A total of 76 patients were enrolled. Group A (n = 39, M: 24, F: 15) showed greater BWL with a significant reduction of 25-hydroxyvitamin D, transferrin, cholinesterase, albumin, and LVMI with respect to Group B (p < 0.01). Conversely, Group B (n = 37, M: 23, F: 14) showed significantly increased intact parathyroid hormone, total cholesterol, low-density lipoprotein, triglycerides, and C-reactive protein when compared to Group A (p < 0.05). CONCLUSION: The positive history of renal disease may negatively impact on several metabolic and nutritional parameters related to increased cardiovascular risk among older adults.
ESTHER : Lai_2017_Front.Nutr_4_4
PubMedSearch : Lai_2017_Front.Nutr_4_4
PubMedID: 28367435

Title : Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit - Backes_2007_Bioorg.Med.Chem.Lett_17_2005
Author(s) : Backes BJ , Longenecker K , Hamilton GL , Stewart K , Lai C , Kopecka H , von Geldern TW , Madar DJ , Pei Z , Lubben TH , Zinker BA , Tian Z , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Kempf-Grote AJ , Black-Schaefer C , Sham HL , Trevillyan JM
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2005 , 2007
Abstract : A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
ESTHER : Backes_2007_Bioorg.Med.Chem.Lett_17_2005
PubMedSearch : Backes_2007_Bioorg.Med.Chem.Lett_17_2005
PubMedID: 17276063
Gene_locus related to this paper: ratno-dpp4 , human-DPP4

Title : Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors - Pei_2007_J.Med.Chem_50_1983
Author(s) : Pei Z , Li X , von Geldern TW , Longenecker K , Pireh D , Stewart KD , Backes BJ , Lai C , Lubben TH , Ballaron SJ , Beno DW , Kempf-Grote AJ , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 50 :1983 , 2007
Abstract : Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
ESTHER : Pei_2007_J.Med.Chem_50_1983
PubMedSearch : Pei_2007_J.Med.Chem_50_1983
PubMedID: 17367123
Gene_locus related to this paper: human-DPP4

Title : Xanthine mimetics as potent dipeptidyl peptidase IV inhibitors - Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
Author(s) : Kurukulasuriya R , Rohde JJ , Szczepankiewicz BG , Basha F , Lai C , Jae HS , Winn M , Stewart KD , Longenecker KL , Lubben TW , Ballaron SJ , Sham HL , von Geldern TW
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :6226 , 2006
Abstract : A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV K(i)=2nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines.
ESTHER : Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
PubMedSearch : Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
PubMedID: 17010607
Gene_locus related to this paper: ratno-dpp4

Title : Axonal neuregulin-1 regulates myelin sheath thickness - Michailov_2004_Science_304_700
Author(s) : Michailov GV , Sereda MW , Brinkmann BG , Fischer TM , Haug B , Birchmeier C , Role LW , Lai C , Schwab MH , Nave KA
Ref : Science , 304 :700 , 2004
Abstract : In the nervous system of vertebrates, myelination is essential for rapid and accurate impulse conduction. Myelin thickness depends on axon fiber size. We use mutant and transgenic mouse lines to show that axonal Neuregulin-1 (Nrg1) signals information about axon size to Schwann cells. Reduced Nrg1 expression causes hypomyelination and reduced nerve conduction velocity. Neuronal overexpression of Nrg1 induces hypermyelination and demonstrates that Nrg1 type III is the responsible isoform. We suggest a model by which myelin-forming Schwann cells integrate axonal Nrg1 signals as a biochemical measure of axon size.
ESTHER : Michailov_2004_Science_304_700
PubMedSearch : Michailov_2004_Science_304_700
PubMedID: 15044753