Biomedical Application of Porphyrin-Based Amphiphiles and Their Self-Assembled Nanomaterials.

Porphyrins have been vastly explored and applied in many cutting-edge fields with plenty of encouraging achievements because of their excellent properties. As important derivatives of porphyrins, porphyrin-based amphiphiles (PBAs) not only maintain the advanced properties of porphyrins (catalysis, imaging, and energy transfer) but also possess self-assembly and encapsulation capability in aqueous solution. Accordingly, PBAs and their self-assembles have had important roles in diagnosing and treating tumors and inflammation lesions in vivo, but not limited to these. In this article, we introduce the research progress of PBAs, including their constitution, structure design strategies, and performances in tumor and inflammation lesion diagnosis and treatments. On that basis, the defects of synthesized PBAs during their application and the possible effective strategies to overcome the limitations are also proposed. Finally, perspectives on PBAs exploration are updated based on our knowledge. We hope this review will bring researchers from various domains insights about PBAs.

Probing the serum albumin binding site of fenamates and photochemical protein labeling with a fluorescent dye.

Human serum albumin (HSA) can bind with numerous drugs, leading to a significant influence on drug pharmacokinetics as well as undesirable drug-drug interactions due to competitive binding. Probing the HSA drug binding site thus offers great opportunities to reveal drug-HSA binding profiles. In the present study, a fluorescent probe (E)-4-(2-(5-(4-(diphenylamino)phenyl)thiophen-2-yl)vinyl)-1-propylpyridin-1-ium (TTPy) has been prepared, which exhibits enhancement of deep-red to near-infrared (NIR) fluorescence upon HSA binding. The competitive binding assay indicated that TTPy can target the HSA binding site of fenamates, a group of non-steroidal anti-inflammatory drugs (NSAIDs), with moderate binding affinity (1.95 × 106 M-1 at 303 K). More interestingly, TTPy enables fluorescent labeling of HSA upon visible light irradiation. This study provides promising ways for HSA drug binding site identification and photochemical protein labeling.

Impaired pancreatic beta cell compensatory function is the main cause of type 2 diabetes in individuals with high genetic risk: a 9 year prospective cohort study in the Chinese population.

AIMS/HYPOTHESIS: We aimed to evaluate the combined effects of type 2 diabetes risk variants on predicting deterioration of blood glucose and progression of beta cell function and insulin sensitivity in a 9 year prospective cohort from the Chinese population. METHODS: We constructed a weighted genetic risk score (GRS) model based on 40 variants associated with type 2 diabetes validated in an established cross-sectional Chinese population (n = 6,822). The weighted scores were categorised into tertiles to assess the predictive capacity for incidence of type 2 diabetes and impaired glucose regulation (IGR), as well as for changes in Stumvoll first- and second-phase insulin secretion indices and Gutt's insulin sensitivity index (ISI) in a community-based 9 year prospective cohort (n = 2,495), including 2,192 individuals with normal glucose tolerance and 303 with IGR at baseline, through logistic, Cox and multiple linear regression tests. RESULTS: Weighted GRS predicted the incidence of type 2 diabetes and IGR in logistic regression (OR 1.236, 95% CI 1.100, 1.389, p = 0.0004) as well as in the Cox model (HR 1.129, 95% CI 1.026, 1.242, p = 0.0128) after adjusting for age, sex, BMI, smoking and alcohol status at baseline. Moreover, we observed that weighted GRS was able to predict deterioration in beta cell function (ß = -0.0480, p = 9.66 × 10(-5) and ß = -0.0303, p = 3.32 × 10(-5) for first- and second-phase insulin secretion, respectively), but not insulin sensitivity (p = 0.3815), during the 9 year follow-up period. CONCLUSIONS/INTERPRETATION: The weighted GRS predicted blood glucose deterioration arising from change in beta cell function in the Chinese population. Individuals in the intermediate- or high-weighted GRS group exhibited progressive deterioration of beta cell function.

Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes.

AIMS/HYPOTHESIS: Three recent genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms (SNPs) with modest effects on diabetic retinopathy in Mexican-American and white patients with diabetes. This study aimed to evaluate the effects of these variants on diabetic retinopathy in Chinese patients with type 2 diabetes. METHODS: A total of 1,972 patients with type 2 diabetes were recruited to this study, including 819 patients with diabetic retinopathy and 1,153 patients with diabetes of ≥5 years duration but without retinopathy. Forty SNPs associated with diabetic retinopathy in three GWAS were genotyped. Fundus photography was performed to diagnose and classify diabetic retinopathy. RESULTS: rs17684886 in ZNRF1 and rs599019 near COLEC12 were associated with diabetic retinopathy (OR 0.812, p = 0.0039 and OR 0.835, p = 0.0116, respectively) and with the severity of diabetic retinopathy (p = 0.0365 and p = 0.0252, respectively, for trend analysis). Sub-analysis in patients with diabetic retinopathy revealed that rs6427247 near SCYL1BP1 (also known as GORAB) and rs899036 near API5 were associated with severe diabetic retinopathy (OR 1.368, p = 0.0333 and OR 0.340, p = 0.0005, respectively). The associations between rs6427247 and rs899036 and severe diabetic retinopathy became more evident after a meta-analysis of published GWAS data (OR 1.577, p = 2.01 × 10(-4) for rs6427247; OR 0.330, p = 5.84 × 10(-7) for rs899036). CONCLUSIONS/INTERPRETATION: We determined that rs17684886 and rs599019 are associated with diabetic retinopathy and that rs6427247 and rs899036 are associated with severe diabetic retinopathy in Chinese patients with type 2 diabetes.

C-reactive protein genetic variant is associated with diabetic retinopathy in Chinese patients with type 2 diabetes.

BACKGROUND: Diabetic retinopathy (DR) is an important microvascular complication of diabetes with a high concordance rate in patients with diabetes. Inflammation is supposed to participate in the development of DR. This study aimed to investigate whether genetic variants of CRP are associated with DR. METHODS: A total of 1,018 patients with type 2 diabetes were recruited in this study. Of these patients, 618 were diagnosed with DR, 400 were patients with diabetes for over 10 years but without DR, considered as cases and controls for DR, respectively. Four tagging SNPs (rs2808629, rs3093077, rs1130864 and rs2808634) within CRP region were genotyped for all the participants. Fundus photography was performed for diagnosis and classification for DR. RESULTS: rs2808629 was significantly associated with increased susceptibility to DR (odds ratio 1.296, 95% CI 1.076-1.561, P = 0.006, empirical P = 0.029, for G allele). This association remained significant after adjustment for confounding factors (odds ratio 1.261, 95% CI 1.022-1.555, P = 0.030). CONCLUSIONS: In this study, we found CRP rs2808629 was associated with DR in the Chinese patients with type 2 diabetes.

Effects of active and passive smoking on the development of cardiovascular disease as assessed by a carotid intima-media thickness examination in patients with type 2 diabetes mellitus.

Carotid intima-media thickness has been widely used as a surrogate end-point for cardiovascular disease, myocardial infarction, and stroke. This study aimed to assess the effects of active and passive smoking exposure on the development of cardiovascular disease in patients with type 2 diabetes mellitus. Seven hundred twenty-two patients with type 2 diabetes mellitus were recruited for the study. A standardized questionnaire on smoking status, pack-years of smoking, and the number of years of smoking cessation was provided to the patients, and their responses were collected for analysis. The carotid intima-media thickness, carotid plaque, and the internal diameter of the common carotid artery were determined by high-resolution B-mode ultrasonography. Compared to non-smokers, passive female smokers had a higher risk of cardiovascular disease (odds ratio = 3.50, 95% confidence interval: 1.29-9.49, P = 0.009); they also had a significantly larger common carotid artery (P = 0.041) and risk of carotid plaque (odds ratio = 2.20, 95% confidence interval: 1.1980-4.0505, P = 0.01). Both active and passive male smokers had a significantly greater carotid intima-media thickness than non-smokers (P = 0.003 and P = 0.005, respectively). Male active smokers had a significantly higher risk of carotid plaque (odds ratio = 2.88, 95% confidence interval: 1.4788-5.6094, P = 0.001). In conclusion, cumulative active and passive smoking exposures are significant risk factors for carotid atherosclerosis in patients with type 2 diabetes mellitus. Our results highlight the importance of endorsing a smoke-free environment for patients with type 2 diabetes mellitus.

Circulating irisin levels are associated with lipid and uric acid metabolism in a Chinese population.

Irisin is a novel hormone secreted by skeletal muscle after exercise, which may ameliorate insulin resistance. In this study, we aimed to explore the relationship between circulating irisin levels and type 2 diabetes mellitus (T2DM) as well as related metabolic traits in a Chinese population. A total of 203 subjects were recruited. Of these, 68 subjects with normal glucose tolerance (NGT), 63 subjects with impaired glucose regulation (IGR) and 72 subjects with new-onset T2DM. Circulating irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). Detailed clinical investigations and biochemistry measurements were carried out in all of the subjects. Multivariate linear regression analysis was performed to assess the association between irisin levels and related metabolic characteristics. All subjects were classified into normal weight and overweight/obese subgroups according to body mass index (BMI). No significant differences in circulating irisin levels were identified among the three groups (P = 0.9741). After adjusting for covariates, multiple linear regression analysis revealed that serum irisin level was independently and significantly associated with total cholesterol (P = 0.0005), low-density lipoprotein cholesterol (P = 0.0014), fasting fatty acids (P = 0.0402) and uric acid (P = 0.0062). By dividing the serum irisin levels into three tertile groups, the values of total cholesterol, low-density lipoprotein cholesterol, fasting fatty acids and uric acid were all increased significantly with the increase of irisin (P < 0.05). Moreover, serum irisin levels remain closely related to total cholesterol in both normal weight and overweight/obese subgroups. Our study suggests that circulating irisin concentrations are significantly associated with lipid and uric acid metabolism in a Chinese population.

Serum uric acid levels are associated with polymorphisms in the SLC2A9, SF1, and GCKR genes in a Chinese population.

AIM: Genome-wide association studies have identified several novel loci associated with serum uric acid concentrations in individuals of European descent. In the current study, we aimed to evaluate the associations between these loci and serum uric acid concentrations in a Chinese population. METHODS: Fourteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped in 2329 Chinese subjects in Shanghai. Serum biochemical parameters including uric acid concentrations were determined. All the variants were analyzed for gender differences since uric acid metabolism differed between genders. RESULTS: In males after adjustments for age and BMI, GCKR rs780094, SLC2A9 rs11722228 and SF1 rs606458 were associated with the uric acid concentrations, which were statistically significant (P=0.016, 0.001 and 0.03, respectively), whereas SLC2A9 rs3775948 was marginally associated with the uric acid concentrations (P=0.071). In females, SLC22A12 rs506338 was also marginally associated with the uric acid concentrations (P=0.057). The meta-analysis for combined data from both males and females revealed that rs3775948 and rs606458 were associated with the uric acid concentrations (P=0.036 and 0.043, respectively). Furthermore, the gender significantly affected the association of rs11722228 with serum uric acid levels (P=0.012). CONCLUSION: The SLC2A9 rs11722228, SF1 rs606458 and GCKR rs780094 variants modulate uric acid concentrations in Chinese males, while SF1 rs606458 and SLC2A9 rs3775948 are associated with the uric acid concentrations in both Chinese males and females.

Fluorinated hydrogel nanoparticles with regulable fluorine contents and T2 relaxation times as 19F MRI contrast agents.

Medical imaging contrast agents that are able to provide detailed biological information have attracted increasing attention. Among the new emerging imaging contrast agents, 19F magnetic resonance imaging contrast agents (19F MRI CAs) are extremely promising for their weak background disturbing signal from the body. However, to prepare 19F MRI CAs with a long T2 relaxation time and excellent biocompatibility in a simple and highly effective strategy is still a challenge. Herein, we report a new type of 19F MRI hydrogel nanocontrast agents (19F MRI HNCAs) synthesized by a surfactant-free emulsion polymerization with commercial fluorinated monomers. The T2 relaxation time of 19F MRI HNCA-1 was found to be 25-40 ms, guaranteeing its good imaging ability in vitro. In addition, according to an investigation into the relationship between the fluorine content and 19F MRI signal intensity, the 19F MRI signal intensity was not only determined by the fluorine content in 19F MRI HNCAs but also by the hydration microenvironment around the fluorine atoms. Moreover, 19F MRI HNCAs demonstrated excellent biocompatibility and imaging capability inside cells. The primary exploration demonstrated that 19F MRI HNCAs as a new type of 19F MRI contrast agent hold potential for imaging lesion sites and tracking cells in vivo by 19F MRI technology.

Machine Learning Prediction of Iron Deficiency Anemia in Chinese Premenopausal Women 12 Months after Sleeve Gastrectomy.

Premenopausal women, who account for more than half of patients for bariatric surgery, are at higher risk of developing postoperative iron deficiency anemia (IDA) than postmenopausal women and men. We aimed at establishing a machine learning model to evaluate the risk of newly onset IDA in premenopausal women 12 months after sleeve gastrectomy (SG). Premenopausal women with complete clinical records and undergoing SG were enrolled in this retrospective study. Newly onset IDA after surgery, the main outcome, was defined according to the age- and gender-specific World Health Organization criteria. A linear support vector machine model was developed to predict the risk of IDA after SG with the top five important features identified during feature selection. Four hundred and seven subjects aged 31.0 (Interquartile range (IQR): 26.0-36.0) years with a median follow-up period of 12 (IQR 7-13) months were analyzed. They were divided into a training set and a validation set with 285 and 122 individuals, respectively. Preoperative ferritin, age, hemoglobin, creatinine, and fasting C-peptide were included. The model showed moderate discrimination in both sets (area under curve 0.858 and 0.799, respectively, p < 0.001). The calibration curve indicated acceptable consistency between observed and predicted results in both sets. Moreover, decision curve analysis showed substantial clinical benefits of the model in both sets. Our machine learning model could accurately predict newly onset IDA in Chinese premenopausal women with obesity 12 months after SG. External validation was required before the model was used in clinical practice.

Incidence rate and risk factors for hypoglycemia among individuals with type 1 diabetes or type 2 diabetes in China receiving insulin treatment.

AIMS: We investigated the real-world incidence of hypoglycemic events among patients with type 1 or type 2 diabetes (T1DM or T2DM) receiving insulin in routine clinical practice in China. METHODS: In this observational study, data were collected electronically via the Lilly Connected Care Program (LCCP) electronic system from adults with T1DM or T2DM who had registered on LCCP between 1 February 2019 and 31 January 2022, had used insulin for a full 12-week period following registration. The following outcomes were assessed during the 12 weeks following registration: incidence of level 1 and level 2 hypoglycemia. RESULTS: In total, 22,752 patients were enrolled. Among patients with monitoring data, over the 12-week study period, level 1 and 2 hypoglycemia were experienced by 48.8% and 25.9% of patients with T1DM and 26.5% and 13.9% of patients with T2DM. The proportion of patients treated with oral anti-diabetes drugs (OADs) capable of producing hypoglycemia (sulfonylurea or glinide) was 1.3% in T1DM and 1.6% in T2DM, respectively. Questionnaire data revealed that up to 92.5% of hypoglycemic events occurred outside of hospital and 18.6% were serious. CONCLUSIONS: These real-world data collected from Chinese patients with diabetes receiving insulin treatment reveal a relatively high percentage of patients experiencing hypoglycemia, with around one quarter of these events classified as severe and as many as 92.5% occurring outside of a hospital or clinic.

Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

A Reliable Estimate of Visceral Fat Area From Simple Anthropometric Measurements in Chinese Overweight and Obese Individuals.

Objective: Visceral obesity, reflected by the amount of visceral adipose tissue (VAT), is associated with multiple chronic diseases and metabolic disorders. The visceral fat area (VFA), measured by MRI, is the 'gold standard' for diagnosis of visceral obesity. In this study, a simple model to predict VFA was constructed to facilitate the identification and monitoring of patients who are at high risk of visceral obesity. Methods: The 721 overweight and obese participants were divided into two groups according to sex, then randomly assigned to derivation and validation cohorts in a 1:2 ratio. Data from the derivation group were used to construct a multiple linear regression model; data from the validation group were used to verify the validity of the model. Results: The following prediction equations, applicable to both sexes, were developed based on age, waist circumference (WC) and neck circumference (NC) that exhibited strong correlations with the VFA: VFA=3.7×age+2.4×WC+5.5×NC-443.6 (R2 = 0.511, adjusted R2 = 0.481, for men) and VFA=2.8×age+1.7×WC+6.5×NC-367.3 (R2 = 0.442, adjusted R2 = 0.433, for women). The data demonstrated good fit for both sexes. A comparison of the predicted and actual VFA in the verification group confirmed the accuracy of the equations: for men, R2 = 0.489, adjusted R2 = 0.484 and intra-class correlation coefficient (ICC) = 0.653 (p < 0.001) and for women: R2 = 0.538, adjusted R2= 0.536 and ICC = 0.672 (p < 0.001). The actual and predicted VFAs also showed good agreement in a Bland-Altman plot, indicating the significant correlations of both equations with the actual VFA. Conclusions: Based on readily available anthropometric data, VFA prediction equations consisting of age, WC and NC were developed. The equations are robust, with good predictive power in both sexes; they provide ideal tools for the early detection of visceral obesity in Chinese overweight and obese individuals.

Common variants in genes involved in islet amyloid polypeptide (IAPP) processing and the degradation pathway are associated with T2DM risk: A Chinese population study.

AIM: To explore the genetic effects of SLC30A8, IAPP, PCSK1, PCSK2, CPE, PAM and IDE, key genes involved in IAPP processing and degradation pathway on T2DM risk and metabolic traits in Chinese population. METHODS: Common variants were genotyped in 10936 Chinese subjects by Asian Screening Array and Multi-Ethnic Global Array. Associations of SNPs with occurrences of T2DM and related traits were evaluated through logistic and multiple linear regression. Genetic risk score (GRS) model was constructed based on 6 T2DM-variants, and its relationship with T2DM and related traits was assessed. RESULTS: SLC30A8-rs13266634, PCSK1-rs155980, PCSK2-rs6136035, CPE-rs532192464, PAM-rs7716941, and IDE-rs117929184 were the top SNPs significantly associated with T2DM after adjusting for age, sex, and BMI, associated with blood glucose level, insulin secretion, and insulin sensitivity (all FDR p < 0.05). GRS calculated based on the above SNPs was remarkably correlated with T2DM, blood glucose, and insulin secretion. Furthermore, there was a significant interaction between SLC30A8 and IAPP in patients with T2DM (P = 0.0083). CONCLUSION: Our study showed that common variants in genes involved in IAPP processing and the degradation pathway were associated with T2DM in Chinese population. Subjects with high GRS exhibited poorer glucose metabolism and insulin secretion.

Synthesis of Dihydroquinolines as Scaffolds for Fluorescence Sensing of Hydroxyl Radical.

A mild synthetic method to prepare dihydroquinolines has been presented. These dihydroquinolines, for the first time, showed great potential for fluorescence detection of the important biorelevant hydroxyl radicals (•OH). Sensitive and selective •OH detection and intracellular organelle-targeted fluorescence imaging of •OH have been demonstrated by using one of the synthetic dihydroquinolines. Moreover, dihydroquinoline has also exhibited promising potential to construct advanced fluorescence probes for •OH with tunable photophysical properties.

Magnetic Nanoparticle-Based Ligand Replacement Strategy for Chemical Luminescence Determination of Cholesterol.

Determination of serum cholesterol (Chol) is important for disease diagnosis, and has attracted great attention during the last few decades. Herein, a new magnetic nanoparticle-based ligand replacement strategy has been presented for chemical luminescence detection of Chol. The detection depends on ligand replacement from ferrocene (Fc) to Chol through a ß-cyclodextrin (ß-CD)-based host-guest interaction, which releases Fc-Hemin as a catalyst for the luminol/hydrogen peroxide chemical luminescence system. More importantly, the luminescence signal can be captured by the camera of a smartphone, thus realizing Chol detection with less instrument dependency. The limit of detection of this method is calculated to be 0.18 µM, which is comparable to some of the developed methods. Moreover, this method has been used successfully to quantify Chol from serum samples with a simple extraction process.

Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10.

Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0.09% of cases. Intracellular trafficking of insulin proteins was assessed in INS1-E and HEK293T cells. p.Ala2Thr preproinsulin-GFP was markedly retained in the endoplasmic reticulum (ER) in INS1-E cells. Activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in INS responsible for maturity-onset diabetes of the young 10 (MODY10) in a Chinese population and demonstrated that this mutation affected ß cell function by inducing ER stress.

CDKAL1 rs7756992 is associated with diabetic retinopathy in a Chinese population with type 2 diabetes.

Diabetic retinopathy (DR) is a major microvascular complication of diabetes. Susceptibility genes for type 2 diabetes may also impact the susceptibility of DR. This case-control study investigated the effects of 88 type 2 diabetes susceptibility loci on DR in a Chinese population with type 2 diabetes performed in two stages. In stage 1, 88 SNPs were genotyped in 1,251 patients with type 2 diabetes, and we found that ADAMTS9-AS2 rs4607103, WFS1 rs10010131, CDKAL1 rs7756992, VPS26A rs1802295 and IDE-KIF11-HHEX rs1111875 were significantly associated with DR. The association between CDKAL1 rs7756992 and DR remained significant after Bonferroni correction for multiple comparisons (corrected P = 0.0492). Then, the effect of rs7756992 on DR were analysed in two independent cohorts for replication in stage 2. Cohort (1) consisted of 380 patients with DR and 613 patients with diabetes for ≥5 years but without DR. Cohort (2) consisted of 545 patients with DR and 929 patients with diabetes for ≥5 years but without DR. A meta-analysis combining the results of stage 1 and 2 revealed a significant association between rs7756992 and DR, with the minor allele A conferring a lower risk of DR (OR 0.824, 95% CI 0.743-0.914, P = 2.46 × 10-4).