High-Performance NIR-II Fluorescent Type I/II Photosensitizer Enabling Augmented Mild Photothermal Therapy of Tumors by Disrupting Heat Shock Proteins.

NIR-II fluorescent photosensitizers as phototheranostic agents hold considerable promise in the application of mild photothermal therapy (MPTT) for tumors, as the reactive oxygen species generated during photodynamic therapy can effectively disrupt heat shock proteins. Nevertheless, the exclusive utilization of these photosensitizers to significantly augment the MPTT efficacy has rarely been substantiated, primarily due to their insufficient photodynamic performance. Herein, the utilization of high-performance NIR-II fluorescent type I/II photosensitizer (AS21:4) is presented as a simple but effective nanoplatform derived from molecule AS2 to enhance the MPTT efficacy of tumors without any additional therapeutic components. By taking advantage of heavy atom effect, AS21:4 as a type I/II photosensitizer demonstrates superior efficacy in producing 1O2 (1O2 quantum yield = 12.4%) and O2 •- among currently available NIR-II fluorescent photosensitizers with absorption exceeding 800 nm. In vitro and in vivo findings demonstrate that the 1O2 and O2 •- generated from AS21:4 induce a substantial reduction in the expression of HSP90, thereby improving the MPTT efficacy. The remarkable phototheranostic performance, substantial tumor accumulation, and prolonged tumor retention of AS21:4, establish it as a simple but superior phototheranostic agent for NIR-II fluorescence imaging-guided MPTT of tumors.

Near-Infrared-II Fluorophore with Inverted Dependence of Fluorescence Quantum Yield on Polarity as Potent Phototheranostics for Fluorescence-Image-Guided Phototherapy of Tumors.

Organic phototheranostics simultaneously having fluorescence in the second near-infrared (NIR-II, 1000-1700 nm) window, and photothermal and photodynamic functions possess great prospects in tumor diagnosis and therapy. However, such phototheranostics generally suffer from low brightness and poor photodynamic performance due to severe solvatochromism. Herein, an organic NIR-II fluorophore AS1, which possesses an inverted dependence of fluorescence quantum yield on polarity, is reported to serve as potent phototheranostics for tumor diagnosis and therapy. After encapsulation of AS1 into nanostructures, the obtained phototheranostics (AS1R ) exhibit high extinction coefficients (e.g., 68200 L mol-1  cm-1 at 808 nm), NIR-II emission with high fluorescence quantum yield up to 4.7% beyond 1000 nm, photothermal conversion efficiency of ≈65%, and 1 O2 quantum yield up to 4.1%. The characterization of photophysical properties demonstrates that AS1R is superior to other types of organic phototheranostics in brightness, photothermal effect, and photodynamic performance at the same mass concentration. The excellent phototheranostic performance of AS1R enables clear visualization and complete elimination of tumors using a single and low injection dose. This study demonstrates the merits and prospects of NIR-II fluorophore with inverted polarity dependence of fluorescence quantum yield as high-performance phototheranostic agents for fluorescence imaging and phototherapy of tumors.

Design and Discovery of Novel 1,3,5-Triazines as Dipeptidyl Peptidase-4 Inhibitor against Diabetes.

This study aims at synthesizing novel di-morpholine 1,3,5-triazine derivatives as antidiabetic agent via inhibition of dipeptidyl peptidase-4 (DPP-4). The molecules were developed via sequential nucleophilic reaction to afford target derivatives 5(a-f) and subsequently tested for inhibitory potency against DPP iso-enzymes, such as DPP-4, DPP-8, and DPP-9. The in vitro inhibition assay suggested that these derivatives prominently and selectively inhibit DPP-4 over -DPP-8 and DPP-9. These molecules also showed no presence of cardiotoxicity, as confirmed by no activity against human Ether-à-go-go related gene channel. The study disclosed compound 5c as the most potent inhibitor of DPP-4 with IC50 of 1.10 nmol/L as compared to the standard. Compound 5c was further evaluated for oral glucose tolerance test (OGTT) and antidiabetic activity in ICR mice and Wistar rats, respectively. In OGTT, compound 5c showed dose-dependent -improvement of glucose tolerance with a maximum at 30 mg/kg. It also showed reduction in area under the curve from 0 to 120 min, similar to alogliptin (standard). In Wistar rats, compound 5c causes reduction in the blood glucose level, total cholesterol, triglyceride, low density lipoprotein (LDL) and very LDL level as compared to the diabetic control group, whereas the level of high-density lipoprotein was found to be increased. Compound 5c causes improvement in antioxidant defense mechanism, as confirmed via improving superoxide dismutase, catalase, glutathione peroxidase and reducing the malondialdehyde level as compared to normal control group rats.

Tanshinone IIA improves diabetes mellitus via the NF-κB-induced AMPK signal pathway.

Diabetes mellitus (DM) is a systemic metabolic disease. Tanshinone IIA (Tan-IIA) presents potential benefits for DM. The purpose of this study was to investigate the efficacy of Tan-IIA in type 2 DM rats and explore its potential mechanism in renal cells. A type 2 DM rat model was established and administered with Tan-IIA or PBS. It was demonstrated that Tan-IIA treatment significantly reduced levels of total cholesterol, non-esterified fatty acids, total triglyceride and low-density lipoprotein cholesterol in experimental DM rats compared with the control group. The results indicated that Tan-IIA treatment significantly decreased levels of interleukin (IL)-8, tumor necrosis factor-α, C-reactive protein and IL-6. It was identified that Tan-IIA treatment significantly decreased nuclear factor-κB levels and significantly elevated 5' adenosine monophosphate-activated protein kinase levels. Western blot analysis indicated that Tan-IIA elevated immunocyte precipitation in renal cells. Furthermore, Tan-IIA treatment improved lipid metabolism, glucose metabolism, insulin resistance and body weight of type 2 DM rats. In conclusion, Tan-IIA administration may inhibit inflammatory cytokines and alleviate type 2 DM symptoms in experimental rats.

Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance.

OBJECTIVE: We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet ß cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated. METHODS: A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of ß cell function (HOMA-ß), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and ß cell function, IR and IS were analyzed. RESULTS: The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-ß , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and ß cell function, IR (P<0.05). CONCLUSIONS: The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and ß cell function, IR and IS.

Community-based population data indicates the significant alterations of insulin resistance, chronic inflammation and urine ACR in IFG combined IGT group among prediabetic population.

AIMS: To investigate alterations of insulin resistance (IR), chronic inflammation and urine albumin-to-creatinine ratio (ACR) in Chinese community-based prediabetic population. MATERIALS AND METHODS: 252 prediabetics [prediabetes (PD), including impaired fasting glucose (IFG), 91; impaired glucose tolerance (IGT), 123; IFG+IGT, 38] and 38 newly diagnosed-diabetics (NDDM) aged over 35 years older were screened from 2336 community individuals. 123 age and gender matched individuals with normal glucose tolerance (NGT) were selected as controls. Serum adiponectin, interleukin-6 (IL-6) levels and urine ACR were determined, HOMA-IR and Gutt's index were calculated to evaluate IR and insulin sensitivity, respectively. RESULTS: The data displayed significant difference of serum adiponectin, IL-6, ACR and Gutt's index among PD, NDDM and NGT groups. Adiponectin level and Gutt's index decreased, but IL-6 level and ACR increased gradually among NGT, PD and NDDM groups (P<0.01). Unlike adiponectin and IL-6, ACR analysis indicates a gradual increase from NGT, IFG, IGT, IFG+IGT to NDDM individuals (P<0.01). Gutt's index showed significant difference between IFG and NDDM, IFG+IGT and NDDM (P<0.01), but HOMA-IR index did not. CONCLUSIONS: IR, chronic inflammation and endothelial dysfunction dose exist in prediabetic individuals, especially in IFG+IGT population. Gutt's index and ACR might seem to be more sensitive than adiponectin and HOMA-IR index as IR and chronic inflammation maker in prediabetic population.