Risk Prediction Models for Sarcopenia in Dialysis Patients: A Systematic Review.

Nowadays, numerous studies have developed risk prediction models for sarcopenia in dialysis patients. However, the quality and performance of these models have not been integrated. The purpose of our study is to provide a comprehensive overview of the current risk prediction models for sarcopenia in dialysis patients and to offer a reference for the development of high-quality prediction models. Ten electronic databases were searched from inception to March 8, 2024. Two researchers independently assessed the risk of bias and applicability of the studies, and used Revman, 5.4, software to conduct a meta-analysis of common predictors in the models. A total of 12 studies described 13 risk prediction models for dialysis patients with sarcopenia. In dialysis patients, the prevalence of sarcopenia ranged from 6.60% to 63.73%. The area under curve (AUC) of the 13 models ranged from 0.776 to 0.945. Only six models (AUC ranging from 0.73 to 0.832) were internally validated, while two were externally evaluated (AUC ranging from 0.913 to 0.955). Most studies had a high risk of bias. The most common effective predictors in the models were age, body mass index, muscle circumference, and C-reactive protein. Our study suggests that developing a prediction model for the onset of sarcopenia in dialysis patients requires a rigorous design scheme, and future verification methods will necessitate multicenter external validation.

A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Biomarkers for neuromyelitis optica: a visual analysis of emerging research trends.

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system that differs from multiple sclerosis. Over the past 20 years, the search for biomarkers for neuromyelitis optica has been ongoing. Here, we used a bibliometric approach to analyze the main research focus in the field of biomarkers for neuromyelitis optica. Research in this area is consistently increasing, with China and the United States leading the way on the number of studies conducted. The Mayo Clinic is a highly reputable institution in the United States, and was identified as the most authoritative institution in this field. Furthermore, Professor Wingerchuk from the Mayo Clinic was the most authoritative expert in this field. Keyword analysis revealed that the terms "neuromyelitis optica" (261 times), "multiple sclerosis" (220 times), "neuromyelitis optica spectrum disorder" (132 times), "aquaporin 4" (99 times), and "optical neuritis" (87 times) were the most frequently used keywords in literature related to this field. Comprehensive analysis of the classical literature showed that the majority of publications provide conclusive research evidence supporting the use of aquaporin-4-IgG and neuromyelitis optica-IgG to effectively diagnose and differentiate neuromyelitis optica from multiple sclerosis. Furthermore, aquaporin-4-IgG has emerged as a highly specific diagnostic biomarker for neuromyelitis optica spectrum disorder. Myelin oligodendrocyte glycoprotein-IgG is a diagnostic biomarker for myelin oligodendrocyte glycoprotein antibody-associated disease. Recent biomarkers for neuromyelitis optica include cerebrospinal fluid immunological biomarkers such as glial fibrillary acidic protein, serum astrocyte damage biomarkers like FAM19A5, serum albumin, and gamma-aminobutyric acid. The latest prospective clinical trials are exploring the potential of these biomarkers. Preliminary results indicate that glial fibrillary acidic protein is emerging as a promising candidate biomarker for neuromyelitis optica spectrum disorder. The ultimate goal of future research is to identify non-invasive biomarkers with high sensitivity, specificity, and safety for the accurate diagnosis of neuromyelitis optica.

Efficient Removal of Pb(â ¡) by Highly Porous Polymeric Sponges Self-Assembled from a Poly(Amic Acid).

Lead (II) (Pb(II)) is widespread in water and very harmful to creatures, and the efficient removal of it is still challenging. Therefore, we prepared a novel sponge-like polymer-based absorbent (poly(amic acid), PAA sponge) with a highly porous structure using a straightforward polymer self-assembly strategy for the efficient removal of Pb(II). In this study, the effects of the pH, dosage, adsorption time and concentration of Pb(II) on the adsorption behavior of the PAA sponge are investigated, revealing a rapid adsorption process with a removal efficiency up to 89.0% in 2 min. Based on the adsorption thermodynamics, the adsorption capacity increases with the concentration of Pb(II), reaching a maximum adsorption capacity of 609.7 mg g-1 according to the Langmuir simulation fitting. Furthermore, the PAA sponge can be efficiently recycled and the removal efficiency of Pb(II) is still as high as 93% after five adsorption-desorption cycles. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy analyses reveal that the efficient adsorption of Pb(II) by the PAA sponge is mainly due to the strong interaction between nitrogen-containing functional groups and Pb(II), and the coordination of oxygen atoms is also involved. Overall, we propose a polymer self-assembly strategy to easily prepare a PAA sponge for the efficient removal of Pb(II) from water.

The largest and heaviest giant juvenile fibroadenoma of the breast in the Chinese population: A case report.

RATIONALE: Fibroadenoma is the most common benign tumor of the breast, but giant juvenile fibroadenoma exceeding 20 cm is much rare. This report presents the largest and heaviest giant juvenile fibroadenoma in an 18-year-old Chinese girl. DIAGNOSIS AND INTERVENTIONS: An 18-year-old adolescent girl with a 2-year history of a large left breast mass with progressive expansion over 11 months. A 28 × 21 cm soft swelling occupied the entire outer quadrants of the left breast. The huge mass sagged below the belly button, resulting in high asymmetry of the shoulders. Contralateral breast examination results were normal except for hypopigmentary detected on the nipple-areola complex. Under general anesthesia, the lump was completely excised along the outer envelope of the tumor, while reserving excessive resection of the skin. The patient's postoperative recovery was uneventful, and the surgical wound healed well. OUTCOMES: A radial incision operation was finally performed to remove the huge mass and to preserve the normal breast tissue and the nipple-areolar complex, not only considering the aesthetics but also preserving the ability to lactate. LESSONS: Currently, there is a lack of clear guidelines regarding the diagnostic and treatment modalities for a giant juvenile fibroadenoma. The principle of surgical choice is to balance aesthetics and function preservation.

TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis.

Excessive apoptosis of intestinal epithelial cell (IEC) is a crucial cause of disrupted epithelium homeostasis, leading to the pathogenesis of ulcerative colitis (UC). The regulation of Takeda G protein-coupled receptor-5 (TGR5) in IEC apoptosis and the underlying molecular mechanisms remained unclear, and the direct evidence from selective TGR5 agonists for the treatment of UC is also lacking. Here, we synthesized a potent and selective TGR5 agonist OM8 with high distribution in intestinal tract and investigated its effect on IEC apoptosis and UC treatment. We showed that OM8 potently activated hTGR5 and mTGR5 with EC50 values of 202 ± 55 nM and 74 ± 17 nM, respectively. After oral administration, a large amount of OM8 was maintained in intestinal tract with very low absorption into the blood. In DSS-induced colitis mice, oral administration of OM8 alleviated colitis symptoms, pathological changes and impaired tight junction proteins expression. In addition to enhancing intestinal stem cell (ISC) proliferation and differentiation, OM8 administration significantly reduced the rate of apoptotic cells in colonic epithelium in colitis mice. The direct inhibition by OM8 on IEC apoptosis was further demonstrated in HT-29 and Caco-2 cells in vitro. In HT-29 cells, we demonstrated that silencing TGR5, inhibition of adenylate cyclase or protein kinase A (PKA) all blocked the suppression of JNK phosphorylation induced by OM8, thus abolished its antagonizing effect against TNF-α induced apoptosis, suggesting that the inhibition by OM8 on IEC apoptosis was mediated via activation of TGR5 and cAMP/PKA signaling pathway. Further studies showed that OM8 upregulated cellular FLICE-inhibitory protein (c-FLIP) expression in a TGR5-dependent manner in HT-29 cells. Knockdown of c-FLIP blocked the inhibition by OM8 on TNF-α induced JNK phosphorylation and apoptosis, suggesting that c-FLIP was indispensable for the suppression of OM8 on IEC apoptosis induced by OM8. In conclusion, our study demonstrated a new mechanism of TGR5 agonist on inhibiting IEC apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway in vitro, and highlighted the value of TGR5 agonist as a novel therapeutic strategy for the treatment of UC.

Facile Preparation of Cobalt Nanoparticles Encapsulated Nitrogen-Doped Carbon Sponge for Efficient Oxygen Reduction Reaction.

The facile preparation of non-noble metal nanoparticle loaded carbon nanomaterials is promising for efficient oxygen reduction reaction (ORR) electrocatalysis. Herein, a facile preparation strategy is proposed to prepare nitrogen-doped carbon sponge loaded with fine cobalt nanoparticles by the direct pyrolysis of the cobalt ions adsorbed polymeric precursor. The polymeric sponge precursor with continuous framework and high porosity is formed by the self-assembly of a poly(amic acid). Taking advantage of the negatively charged surface and porous structure, cobalt ions can be efficiently adsorbed into the polymeric sponge. After pyrolysis, fine cobalt nanoparticles covered by carbon layers are formed, while the sponge-like structure of the precursor is also well-preserved in order to give cobalt nanoparticles loaded nitrogen-doped carbon sponges (Co/CoO@NCS) with a high loading content of 44%. The Co/CoO@NCS exhibits promising catalytic activity toward ORR with a half-wave potential of 0.830 V and a limiting current density of 4.71 mA cm-2. Overall, we propose a facile polymer self-assembly strategy to encapsulate transition metal nanoparticles with high loading content on a nitrogen-doped carbon sponge for efficient ORR catalysis.

Discovery of Highly Potent and Selective Thyroid Hormone Receptor ß Agonists for the Treatment of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. While there are currently no approved therapies for NASH, the thyroid hormone receptor ß (THR-ß), primarily expressed in the liver, is emerging as an effective molecular target for the treatment of NASH. However, the adverse cardiac and bone effects mediated by thyroid hormone receptor α (THR-α) need to be minimized. Herein, we reported the discovery of a series of novel THR-ß agonists featuring pyrrolo[3,2-b]pyridin-5-one skeletons based on structure-based drug design. Further optimization led to compound 15, which exhibited higher potency and selectivity for THR-ß over THR-α compared to clinical drug MGL-3196. More significantly, an excellent liver-to-serum ratio of 93:1 was observed for compound 15. We believe that the high hepatic concentration of compound 15 may result in no cardiotoxicity.

Regulation of the nanostructures self-assembled from an amphiphilic azobenzene homopolymer: influence of initial concentration and solvent solubility parameter.

The control over the morphology and nanostructure of soft nanomaterials self-assembled from amphiphilic polymers is of high interest, but is still challenging. Herein, we manipulate the morphology of bowl-shaped nanoparticles by changing initial polymer concentrations, and prepare nanotubes and nanowires, both twisted and not, by using solvents with different solubility parameters. An amphiphilic azobenzene homopolymer (poly(4-(phenyldiazenyl)phenyl methacrylamide), PAzoMAA) is designed and synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization, which can self-assemble into bowl-shaped nanoparticles promoted by the synergy of hydrogen bonding and π-π interaction. More significantly, the opening size of the bowl-shaped nanoparticles can be controlled by changing initial polymer concentrations. Nanotubes and nanowires, both twisted and not, are also obtained using a solvothermal method in alcohols. The relationship between the structure of the nanomaterials and the solubility parameters of the alcohols is investigated, revealing the molecular arrangement patterns of PAzoMAA in different nanostructures. Overall, we propose a facile strategy to manipulate the microstructure of bowl-shaped nanoparticles and one-dimensional nanomaterials by adjusting initial polymer concentration and solvent solubility parameters. Our study may bring new avenues for controlling the nanostructures of soft nanomaterials.

Phenotypic screening-based drug discovery of furan-2-carboxylic acid derivatives for the amelioration of type 2 diabetes mellitus (T2DM).

Phenotypic screening still plays an important role in discovering new drugs, especially for diseases with complex pathogenesis, such as diabetes. As excessive gluconeogenesis is considered an important factor in the occurrence of hyperglycemia in T2DM, we previously screened our compounds library for active molecules which inhibit gluconeogenesis, resulting in the discovery of SL010110 with a unique mechanism, different from metformin and a thienopyridine derivative (DMT). The SARs study of SL010110 led to the discovery of 10v. Compared with SL010110, 10v showed improved anti-gluconeogenesis potency and pyruvate tolerance. A further pharmacokinetic study demonstrated that 10v displayed a relatively short half-life, moderate volume of distribution, and moderate to high oral bioavailability. In vivo chronic experiments showed an improved capability of 10v in ameliorating hyperglycemia as the 5 mg/kg 10v treatment greatly reduced non-fasting and fasting blood glucose levels, making it a promising candidate for the treatment of T2DM. The progression from in vitro screening to in vivo testing of the derivatized compounds provided a useful phenotypic screening drug discovery strategy based on the inhibition of gluconeogenesis.

Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice.

Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 µM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3ß phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 µM) or PI3K inhibitor LY294002 (10 µM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 µM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, ß-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with ß-catenin inhibitor IWR-1-endo (10 µM) or ERK inhibitor SCH772984 (1 µM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 µM) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM.

Development and structure-activity relationships of tanshinones as selective 11ß-hydroxysteroid dehydrogenase 1 inhibitors.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11ß-HSD1 inhibitors. To improve the druggability and explore the structure-activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11ß-HSD1 inhibitory activity and good selectivity over 11ß-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11ß-HSD1. Remarkably, compounds 1, 17 and 30 significantly inhibited 11ß-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11ß-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones.

Spicatulides A-G, Phenolic-Monoterpenoid Hybrids from Chloranthus spicatus.

Spicatulides A-G (1-7), seven new phenolic-monoterpenoid hybrid molecules, along with two known compounds, 8 and 9, were isolated and identified from Chloranthus spicatus. Compound 1 represents an unprecedented skeleton featuring an aryl-fused 2-oxabicyclo[4.3.1]decane moiety, and compound 2 is the first example of a denudaquinol-normonoterpenoid adduct. Their structures with absolute configurations were elucidated on the basis of spectroscopic data analyses and TDDFT-ECD calculations. Compounds 3, 5, 6, and 9 exhibited the activity of reducing lipogenesis in HepG2 cells in a dose-dependent manner.

Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis.

Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs.

Alisol B Alleviates Hepatocyte Lipid Accumulation and Lipotoxicity via Regulating RARα-PPARγ-CD36 Cascade and Attenuates Non-Alcoholic Steatohepatitis in Mice.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated from Alisma orientalis (Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl4)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.

Lateral growth of cylinders.

The precise control of the shape, size and microstructure of nanomaterials is of high interest in chemistry and material sciences. However, living lateral growth of cylinders is still very challenging. Herein, we propose a crystallization-driven fusion-induced particle assembly (CD-FIPA) strategy to prepare cylinders with growing diameters by the controlled fusion of spherical micelles self-assembled from an amphiphilic homopolymer. The spherical micelles are heated upon glass transition temperature (Tg) to break the metastable state to induce the aggregation and fusion of the amorphous micelles to form crystalline cylinders. With the addition of extra spherical micelles, these micelles can attach onto and fuse with the cylinders, showing the living character of the lateral growth of cylinders. Computer simulations and mathematical calculations are preformed to reveal the total energy changes of the nanostructures during the self-assembly and CD-FIPA process. Overall, we demonstrated a CD-FIPA concept for preparing cylinders with growing diameters.

Transformation of Amorphous Nanobowls to Crystalline Ellipsoids Induced by Trans-Cis Isomerization of Azobenzene.

The stimuli-responsive transition of nanostructures from amorphous to crystalline state is of high interest in polymer science, but is still challenging. Herein, the transformation of amorphous nanobowls to crystalline ellipsoids triggered by UV induced trans-cis isomerization is demonstrated, using an azobenzene-containing amphiphilic homopolymer (PAzoAA) as a building block. The amide bond and azobenzene pendants are introduced to the side chain of PAzoAA to afford hydrogen bonding and π-π interactions, which promote the formation of nanobowls rather than spherical nanostructures. Upon exposure to UV irradiation, trans-cis isomerization of azobenzene pendants occurs, leading to the increase of hydrophilicity and destruction of π-π interaction, further resulting in the disassembly of the nanobowls. Then the PAzoAA re-assembles to form crystalline ellipsoids instead of amorphous nanostructures when recovered at 70 °C without UV light. Further, it is confirmed that the high incubation temperature after UV irradiation is critical for the cis-trans transformation and the high mobility of the polymer chains to facilitate the regular rearrangement of azobenzene pendants. Overall, a facile method to achieve the transformation of amorphous nanobowls to crystalline ellipsoids is proposed, which may bring new insight into preparation of crystalline nanoparticles using amorphous precursors.

Design, synthesis and structural-activity relationship studies of phanginin A derivatives for regulating SIK1-cAMP/CREB signaling to suppress hepatic gluconeogenesis.

Persistent activation of hepatic gluconeogenesis is a main cause of fasting hyperglycemia in patients with type 2 diabetes (T2D), and the salt-induced kinase 1 (SIK1) acts as a key modulator in regulating hepatic gluconeogenesis. Recently, we first reported phanginin A (PA, 1), a natural cassane diterpenoid isolated from the seeds of Caesalpinia sappan, exhibited potent anti-diabetic effect through activation of SIK1 and increasing PDE4 activity to inhibit hepatic gluconeogenesis pathway by suppressing the cAMP/PKA/CREB pathway in the liver. In present study, we designed and prepared 25 PA derivatives and their structure-activity relationship (SAR) for gluconeogenesis inhibitory activity were established. Among them, compound 7 exhibited remarkable inhibitory activity on hepatic gluconeogenesis by enhancing the SIK1 phosphorylation and ameliorated the hyperglyceamia of type 2 diabetic mice. Our results supported that compound 7 could be served as a potential candidate for the treatment of T2D.

Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK.

The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.