Endogenous hydrogen sulphide deficiency and exogenous hydrogen sulphide supplement regulate skin fibroblasts proliferation via necroptosis.

An excessive proliferation of skin fibroblasts usually results in different skin fibrotic diseases. Hydrogen sulphide (H2 S) is regarded as an important endogenous gasotransmitter with various functions. The study aimed to investigate the roles and mechanisms of H2 S on primary mice skin fibroblasts proliferation. Cell proliferation and collagen synthesis were assessed with the expression of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), Collagen I and Collagen III. The degree of oxidative stress was evaluated by dihydroethidium (DHE) and MitoSOX staining. Mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining. Necroptosis was evaluated with TDT-mediated dUTP nick end labelling (TUNEL) and expression of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). The present study found that α-SMA, PCNA, Collagen I and Collagen III expression were increased, oxidative stress was promoted, ΔΨm was impaired and positive rate of TUNEL staining, RIPK1 and RIPK3 expression as well as MLKL phosphorylation were all enhanced in skin fibroblasts from cystathionine γ-lyase (CSE) knockout (KO) mice or transforming growth factor-ß1 (TGF-ß1, 10 ng/mL)-stimulated mice skin fibroblasts, which was restored by exogenous sodium hydrosulphide (NaHS, 50 µmol/L). In conclusion, endogenous H2 S production impairment in CSE-deficient mice accelerated skin fibroblasts proliferation via promoted necroptosis, which was attenuated by exogenous H2 S. Exogenous H2 S supplement alleviated proliferation of skin fibroblasts with TGF-ß1 stimulation via necroptosis inhibition. This study provides evidence for H2 S as a candidate agent to prevent and treat skin fibrotic diseases.

Prevalence of impaired awareness of hypoglycaemia in people with diabetes mellitus: A systematic review and meta-analysis from 21 countries and regions.

AIMS: Impaired awareness of hypoglycaemia (IAH) is a complication of glucose-lowering therapies for diabetes. The purpose of this review was to estimate the pooled prevalence of IAH and unawareness of hypoglycaemia (UAH). METHODS: We searched the major databases from inception to 8 August 2022 and included all cross-sectional and cohort studies reporting IAH prevalence in people with diabetes. A random-effects model was used to pool effect values. Subgroup analysis and meta-regression were used to identify study-level characteristics affecting prevalence. RESULTS: Sixty-two studies from 21 countries published between 2000 and 2022 were included, with 39,180 participants (type 1 diabetes: 19,304 vs. Type 2 diabetes: 14,650). The pooled prevalence was 23.2% (95% CI: 18.4%-29.3%) via the Clarke questionnaire, 26.2% (95% CI: 22.9%-29.9%) via the Gold score, and 58.5% (95% CI: 53.0%-64.6%) via the Pedersen-Bjergaard method, all from studies classified as presenting a moderate and low risk of bias. The prevalence of IAH was generally higher in people with type 1 diabetes than in those with type 2 diabetes and lowest in Europe. Meta-regression results show that the duration of diabetes was a factor influencing the prevalence of IAH. The prevalence of UAH by the Pedersen-Bjergaard method was 17.6 (95% CI: 14.9%-20.3%). CONCLUSIONS: IAH is a prevalent risk event among people with type 1 and type 2 diabetes, showing clinical heterogeneity and regional variability. UAH, an adverse progression of IAH, is also a serious burden. More primary research on the prevalence of IAH is needed in areas with a high diabetes burden.

SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement.

Sirtuin 3 (SIRT3) plays a vital role in several dermatological diseases. However, the role and detailed mechanism of SIRT3 in diabetic wound healing are unknown well yet. To explore possible involvement of SIRT3 and necroptosis in diabetic skin wound healing, SIRT3 knockout (KO) mice and 129S1/SvImJ wild-type (WT) mice were injected with streptozotocin (STZ), and mice skin fibroblasts were exposed to high glucose (HG). It was found that SIRT3 expression decreased in the skin of diabetic patients. SIRT3 deficiency delayed healing rate, reduced blood supply and vascular endothelial growth factor expression, promoted superoxide production, increased malondialdehyde (MDA) levels, decreased total antioxidant capacity (T-AOC), reduced superoxide dismutase (SOD) activity and aggravated ultrastructure disorder in skin wound of diabetic mice. SIRT3 deficiency inhibited mice skin fibroblasts migration with HG stimulation, which was restored by SIRT3 overexpression. SIRT3 deficiency also suppressed α-smooth muscle actin (α-SMA) expression, enhanced superoxide production but decreased mitochondrial membrane potential with HG stimulation after scratch. SIRT3 deficiency further elevated receptor-interacting protein kinase 3 (RIPK3), RIPK1 and caspase 3 expression both in vitro and in vivo. Collectively, SIRT3 deficiency delayed skin wound healing in diabetes, the mechanism might be related to impaired mitochondria function, enhanced oxidative stress and increased necroptosis. This may provide a novel therapeutic target to accelerate diabetic skin wound healing.

Hematoporphyrin monomethyl ether-mediated photodynamic therapy inhibits the growth of keloid graft by promoting fibroblast apoptosis and reducing vessel formation.

Photodynamic therapy (PDT) has been shown to significantly inhibit fibroblast activity. However, the effect of PDT mediated by the photosensitizer hematoporphyrin monomethyl ether (HMME) on keloids is not known well. The aim of our study was to examine the efficacy of HMME-PDT in cellular and animal models of keloids. Keloid fibroblasts (KFbs) were isolated from human keloid specimens and the proliferation, invasion, and migration of KFbs after HMME-PDT treatment was examined in vitro. Apoptosis in cells was measured by flow cytometry. Cysteinyl aspartate specific proteinase 3 (Caspase3) expression was determined by immunofluorescence staining and western blot. HMME-PDT inhibited KFbs proliferation, invasion, migration, increased apoptosis rate and enhanced caspase3 and cleaved caspase3 expression. The keloid graft transplantation was performed by using nude mice. The growth of the graft was monitored every third day. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) mRNA expression were detected by quantitative real time PCR. It was observed that HMME-PDT attenuated graft growth and reduced vessel density in the keloid grafts. However, HMME-PDT did not alter IL-6 and TNF-α mRNA expression in the keloid grafts. Moreover, HMME-PDT suppressed transforming growth-ß1 (TGF-ß1) and small phenotype and Drosophila Mothers Against Decapentaplegic 3 (Smad3) expression in both KFbs and keloid grafts. Collectively, the evidence suggests that HMME-PDT inhibits the growth of the keloid graft by promoting the apoptosis of fibroblasts and reducing vessel formation of the keloid graft.

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement.

Hydrogen sulphide (H2 S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2 S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 µmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T-AOC), expression of vascular endothelial growth factor (VEGF), dynamin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 µmol/L) pre-administration for 4 hours, cell migration rate, DRP1, OPA1 and α-smooth muscle actin (α-SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T-AOC in the wound. NaHS also promoted skin fibroblasts migration and α-SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2 S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.

In vitro Antichlamydial Activity of 1,2,3,5-Tetrasubstituted Pyrrole Derivatives.

BACKGROUND: Chlamydia is a group of bacterial pathogens distributed worldwide that can lead to serious reproductive and other health problems. The rise of antibiotic-resistant pathogens promotes the development of novel antichlamydial agents. The aim of this study is to assess in vitro antichlamydial activity of our previously synthesized 1,2,3,5- tetrasubstituted pyrroles. METHODS: The derivatives were screened for their antichlamydial activity against three Chlamydia strains by calculating IC50 values using concentration-response inhibition data between 1 and 32 µM. The action of the compounds on Chlamydia elementary body (EB) infectivity and the impact of the chemicals' administration time on their antichlamydial effect were evaluated to reveal the inhibitory mechanism. RESULTS: Some of the compounds moderately inhibited the Chlamydia strains. Compound 10 exhibited the strongest inhibitory activity, with IC50 values from 4.34 to 5.83 µM. These pyrrole derivatives inhibited Chlamydia infection by reducing EB infectivity during the early stage and disturbing Chlamydia growth by targeting the early-to-middle stage prior to 12 h of the chlamydial life cycle. CONCLUSION: Our findings highlight the potential of 1,2,3,5-tetrasubstituted pyrrole derivatives as promising lead molecules for the development of antichlamydial agents.

Attenuating effects of dihydromyricetin on angiotensin II-induced rat cardiomyocyte hypertrophy related to antioxidative activity in a NO-dependent manner.

CONTEXT: Dihydromyricetin (DMY) displays a range of biological properties. However, whether DMY attenuates cardiomyocyte hypertrophy is unknown. OBJECTIVE: To investigate whether DMY had potential therapeutic value to protect against angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. MATERIALS AND METHODS: Neonatal rat cardiomyocytes were pretreated with DMY (0-320 µM) followed with Ang II (100 nM) stimulation for 24 h, and then degree of hypertrophy was evaluated by cell surface analysis. Levels of reactive oxygen species (ROS) were measured with 2',7'-dichlorfluorescein-diacetate (DCFH-DA) fluorescent staining. Antioxidative activity was evaluated by malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and total antioxidant capacity (T-AOC). Cyclic guanosine monophosphate (cGMP) was determined with a radioimmunoassay. RESULTS: Pre-incubation with DMY (20, 40, 80, and 160 µM) for 8 h, 12 h, 24 h, or 48 h decreased cell surface areas. It down-regulated mRNA expression of atrial natriuretic factor (1.95- to 1.24-fold) and ß-myosin heavy chains (3.51- to 2.32-fold), reduced levels of MDA as well as increased SOD activity and T-AOC. Expression of SOD and thioredoxin were enhanced by DMY, whereas p22(phox) and phosphorylation of mitogen-activated protein kinases were inhibited. Content of cGMP (0.54- to 0.80-fold) and phosphorylation of endothelial nitric oxide synthase at serine 1177 (0.70- to 1.05-fold) were augmented by DMY. Moreover, attenuating effect of DMY on hypertrophy was abolished when NO production was inhibited by l-NAME. CONCLUSION: Attenuating effects of DMY on Ang II-induced cardiomyocyte hypertrophy related to antioxidative activity in a NO-dependent manner.

Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing.

Hydrogen sulfide (H2S), recognized as the third gasotransmitter, plays a pivotal role in the pathophysiological processes of various diseases. Cystathionine γ-lyase (CSE) is the main enzyme for H2S production in the skin. However, effects and mechanisms of H2S in diabetic skin wound healing remain unclear. Our findings revealed a decrease in plasma H2S content in diabetic patients with skin wounds. CSE knockout (KO) diabetic mice resulted in delayed wound healing, reduced blood perfusion, and CD31 expression around the wounds. It also led to increased infiltration of inflammatory cells and M1-type macrophages, decreased collagen levels, α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA) expression. Additionally, there were enhanced expressions of necroptosis related proteins, including receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain like protein (MLKL). In comparison, sodium hydrosulfide (NaHS), H2S donor, accelerated skin wound healing in leptin receptor deficiency (db/db) mice. This acceleration was accompanied by increased blood perfusion and CD31 expression, reduced infiltration of inflammatory cells and M1-type macrophages, elevated collagen levels, α-SMA, and PCNA expressions, and decreased necroptosis-related protein expressions together with nuclear factor-κB (NF-κB) p65 phosphorylation. In conclusion, H2S regulates macrophage polarization and necroptosis, contributing to the acceleration of diabetic skin wound healing. These findings offer a novel strategy for the treatment of diabetic skin wounds.

Research Progress of m6A RNA Methylation in Skin Diseases.

N6-Methyladenosine (m6A) is the most common mRNA modification in eukaryotes and is a dynamically reversible posttranscriptional modification. The enzymes involved in m6A modification mainly include methyltransferases (writers), demethylases (erasers), and methylated readers (Readers). m6A modification is mainly catalyzed by m6A methyltransferase and removed by m6A demethylase. The modified RNA can be specifically recognized and bound by m6A recognition protein. This protein complex then mediates RNA splicing, maturation, nucleation, degradation, and translation. m6A also alters gene expression and regulates cellular processes such as self-renewal, differentiation, invasion, and apoptosis. An increasing body of evidence indicates that the m6A methylation modification process is closely related to the occurrence of various skin diseases. In this review, we discuss the role of m6A methylation in skin development and skin diseases including psoriasis, melanoma, and cutaneous squamous cell carcinoma.

PRR14 acts a novel oncogene activating the PI3K signal pathway in human cutaneous squamous cell carcinoma.

Proline rich protein 14 (PRR14) is considered as a new component of the nuclear fiber layer, it may be a key molecule in mediating nuclear morphological changes and functional changes in tumorigenesis. But, it's still unclear in human cutaneous squamous cell carcinoma (cSCC). In the study, the expression profiles of PRR14 in patients with cSCC were investigated by immunohistochemistry (IHC), also the PRR14 expression in cSCC tissues were detected using the methods of real-time quantitative PCR (RT-qPCR) and Western blot; cell counting kit-8 (CCK-8) assay, wound healing assay, matrigel-based transwell assay and Annexin V-FITC and PI double-staining with flow cytometry assay were used to investigate the biological functions of PRR14 in A431 and HSC-1 cSCC cells. Overexpression of PRR14 in cSCC patients was reported firstly in this study and its high expression was related to differentiation, thickness and tumor node metastasis (TNM) stage of cSCC. PRR14 inhibition with RNA interfering (RNAi) method resulted in the suppression of cell proliferation, migration and invasion but promotion the apoptosis of cSCC cells, and upregulation of the protein phosphorylation levels of mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K) and Akt. The study shows PRR14 maybe an activator of cSCC carcinogenesis through PI3K/Akt/mTOR signal pathway, and it also maybe a prognostic factor and new therapeutical target for cSCC treatment.

LINC00467 induces melanoma deterioration by targeting miR-485-5p/p21 activated kinase 1.

Background: The purpose of the current research was to investigate the biological roles of LINC00467 in inducing melanoma deterioration. Methods: Differential level of LINC00467 in melanoma tissues and its prognostic value were analyzed in GEPIA, which were further confirmed in clinical samples we collected. Regulatory effects of LINC00467 on proliferation, migration and invasion capacities of A375 and SKMEL1 cell lines were examined by a series of functional experiments. Potential downstream targets of LINC00467 were identified through dual-luciferase reporter assay, and their synergistic role in melanoma process was finally explored by rescue experiments. Results: LINC00467 was up-regulated in melanoma samples, but it did not have a prognostic potential in melanoma. LINC00467 has the capacities to stimulate proliferation, migration and invasion of A375 and SKMEL1 cell lines. The feedback loop LINC00467/miR-485-5p/PAK1 was identified, which was responsible for inducing melanoma deterioration. Conclusions: LINC00467 stimulates proliferation, migration and invasion capacities of melanoma via targeting miR-485-5p to upregulate PAK1, which provides potential targets for treatment of melanoma.

Systemic Infection Predictive Value of Procalcitonin to Lactic Acid Ratio in Diabetes Ketoacidosis Patients.

Introduction: Early detection of bacterial infections associated with adequate antibiotic treatment is key to improving diabetic ketoacidosis (DKA) outcomes. Our study aimed to investigate the different sepsis markers (including procalcitonin to lactic acid ratio, PLR) to diagnose bacterial infection in patients with DKA within one hour after admission. Methods: A total of 165 patients diagnosed with DKA were enrolled between July 2014 and July 2018 and divided into an infection group (N =62) and a non-infection group (N=103) based on the positive aetiological tests such as blood culture, sputum culture, urine culture, or definite focus of pulmonary, soft tissue, kidney, etc. Results: Our findings suggest the following: 1) leucocytes (threshold above 10×109 /L) and PLR (threshold above 0.438) within one hour after admission can help to identify patients with infection in the context of DKA. 2) A subgroup analysis demonstrated that PLR also has a high diagnostic efficacy for infection in patients with DKA, regardless of the type of diabetes. Conclusion: This study concludes that leucocyte count (threshold > 10×109/L) and PLR (threshold above 0.438) show a diagnostic value to help distinguish DKA patients with infection. By combining these two markers, the reduction of antibiotic misuse may be possible.

Hydrogen Sulfide Suppresses Skin Fibroblast Proliferation via Oxidative Stress Alleviation and Necroptosis Inhibition.

Keloid is a common dermatofibrotic disease with excessive skin fibroblast proliferation. Hydrogen sulfide (H2S) as the third gasotransmitter improves fibrosis of various organs and tissues. Our study is aimed at investigating the effects and possible mechanisms of H2S on skin fibroblast proliferation. Scar tissues from six patients with keloid and discarded skin tissue from six normal control patients were collected after surgery, respectively. Plasma H2S content and skin H2S production in patients with keloid were measured. Keloid fibroblasts and transforming growth factor-ß 1- (TGF-ß 1, 10 ng/mL) stimulated normal skin fibroblasts were pretreated with H2S donor as NaHS (50 µM) for 4 h. Cell migration after scratch was assessed. The expressions of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), collagen I, and collagen III were detected by immunofluorescence, real-time PCR, and/or Western blot. Intracellular superoxide anion and mitochondrial superoxide were evaluated by dihydroethidium (DHE) and MitoSOX staining, respectively. Mitochondrial membrane potential was detected by JC-1 staining. Apoptotic cells were detected by TDT-mediated dUTP nick end labeling (TUNEL). The expressions of receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) were measured by Western blot. We found that H2S production was impaired in both the plasma and skin of patients with keloid. In keloid fibroblasts and TGF-ß 1-stimulated normal skin fibroblasts, exogenous H2S supplementation suppressed the expressions of α-SMA, PCNA, collagen I, and collagen III, reduced intracellular superoxide anion and mitochondrial superoxide, improved the mitochondrial membrane potential, decreased the positive rate of TUNEL staining, and inhibited RIPK1 and RIPK3 expression as well as MLKL phosphorylation. Overall, H2S suppressed skin fibroblast proliferation via oxidative stress alleviation and necroptosis inhibition.

Hydrogen sulfide: Recent progress and perspectives for the treatment of dermatological diseases.

BACKGROUND: Hydrogen sulfide (H2S) is now recognized as a vital endogenous gasotransmitter with a variety of biological functions in different systems. Recently, studies have increasingly focused on the role of H2S in the skin. AIM OF REVIEW: This review summarizes recent progress and provides perspectives on H2S in the treatment of dermatological diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: Three H2S production enzymes, cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS) and 3-mercaptopyruvate sulfur transferase (3-MST), are all present in the skin, and it is likely that different cell types in the skin express them differently. Previous studies have demonstrated that H2S protects against several dermatological diseases, such as burns, diabetic skin wounds, psoriasis, skin flap transplantation, systemic sclerosis, melanoma, and pruritus. The mechanism might be related to the regulation of oxidative stress, inflammation, angiogenesis, apoptosis, and allergic reactions. H2S-based therapeutics require certain characteristics for topical delivery, for example, controlled release, appropriate physicochemical properties, good storage stability, acceptable odor, and advanced delivery systems. H2S-induced S-sulfhydration on proteins are potential novel targets for therapeutic intervention and drug design for the skin, which may lead to the development and application of H2S-related drugs for dermatological diseases.

Wogonin inhibits the growth of HT144 melanoma via regulating hedgehog signaling-mediated inflammation and glycolysis.

Hedgehog (Hh) signaling has been proved to be closely associated with the occurrence of melanoma. Wogonin is one of the active components of flavonoids that extracts from Scutellariae radix. Previous studies showed that wogonin could inhibit the invasion and migration of B16F10 cells, and suppress the synthesis of melanin in A375 melanoma cells. However, the regulatory effects of Hh signaling in wogonin against melanoma and its potential mechanisms remain largely unknown. The present study aimed to investigate the effect of wogonin on the growth of HT144 melanoma, and to elucidate the role of Hh signaling in wogonin-induced antitumor effects by focusing on inflammation and glycolysis regulation. Wogonin inhibited the proliferation, colony formation and tumor growth of HT144 melanoma cells. Wogonin showed strong anti-inflammatory effect in HT144 melanoma, as shown by the decreased levels of pro-inflammatory factors, the increased level of anti-inflammatory factor and the decreased expression of inflammatory cytokines. Wogonin decreased the glucose consumption and the production of lactic acid and ATP, and decreased the activities of hexokinase (HK), phosphofructokinase(PFK) and pyruvate kinase (PK), and further inhibited the expression of monocarboxylate transporter 1 (MCT-1), MCT-4 and glucosecotransporter-1 (GLUT1), showing potent anti-glycolysis effect against HT144 melanoma. Wogonin inhibited the patched and Smo expression while increased Hhip expression in HT144 cells, suggesting that wogonin blocked the Hh signaling in HT144 cells. The Hh signaling inhibitor cyclopamine, like wogonin, inhibited the colony formation of HT144 cells, however, the inhibitory effect of wogonin on colony formation of HT144 cells was abrogated by the Hh signaling agonist SAG. In addition, SAG abrogated the inhibitory effect of wogonin on the secretion of inflammatory factors and the expression of inflammatory cytokines. Furthermore, SAG abrogated the inhibitory effect of wogonin on several key molecules controlling glycolysis. Overall, these findings suggested that the anti-tumor effect of wogonin can be attributed to the inhibition of Hh signaling-mediated regulation of inflammation and glycolysis in HT144 melanoma.

Inhibitory Activity of Pyrroloisoxazolidine Derivatives against Chlamydia trachomatis.

The obligate intracellular bacterium Chlamydia trachomatis is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited C. trachomatis in a dose-dependent manner in vitro. Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC50 values from 7.25 to 9.73 µM. The compounds disturbed the whole intracellular life cycle of C. trachomatis, mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.

Association between Thyroid Function and Nonalcoholic Fatty Liver Disease in Euthyroid Type 2 Diabetes Patients.

Thyroid function and type 2 diabetes mellitus (T2DM) are both associated with increased risks of adverse clinical outcomes in nonalcoholic fatty liver disease (NAFLD). Our study is aimed at evaluating the association between thyroid function and NAFLD in T2DM patients with normal thyroid function (euthyroid) and analyzing the potential effects of metformin on the pathological process. Overall, 369 T2DM patients were enrolled between July 2017 and September 2018 and stratified into NAFLD and non-NAFLD groups. Data on age, gender, body mass index (BMI, kg/m2), metformin use, and basal metabolic rate (BMR) were obtained from participants' records. All patients were tested for biochemical markers, indexes of glucose metabolism, lipid metabolism, bone metabolism, and thyroid function at baseline. Multivariate analyses detected increased odds of NAFLD among individuals with T2DM per unit increase in their BMI and free triiodothyronine (FT3) and thyroid stimulating hormone (TSH); the odds ratios (OR) were 1.25, 3.02, and 1.58, respectively (all p < 0.05). Positive correlations were detected between alanine aminotransferase (ALT) and FT3 (r = 0.221, p = 0.010), and negative correlations were noted between TSH and BMR (r = -0.618, p < 0.001) and between BMR and FT3 (r = -0.452, p < 0.001) in T2DM subjects with NAFLD. A significant difference in serum FT3 (t = 2.468, p = 0.0167) and TSH (t = 2.658, p = 0.010) levels was found between obese individuals with NAFLD who used and did not use metformin. The pathological mechanism of T2DM complicated by NAFLD in euthyroid patients may be associated with insulin resistance and a thyroid hormone resistance-like manifestation, i.e., relevant hypothyroidism. Metformin can potentially decrease the double-resistance situation, especially in obese individuals.

Iron-Based Theranostic Nanoplatform for Improving Chemodynamic Therapy of Cancer.

Chemodynamic therapy (CDT) has aroused extensive attention for cancer treatment in the last five years, as it could suppress tumor progression through in situ detrimental oxidative stress of the tumor cells via the Fenton reaction. Under a tumor acidic microenvironment, the Fenton reaction can be initiated for disproportioning endogenous hydrogen peroxide into highly toxic hydroxyl radical. Taking advantage of the highly tumor-specific therapy modality, various Fenton nanocatalysts have been developed for CDT. In particular, iron-containing Fenton nanocatalysts with minimal cytotoxicity exhibit great promise for clinical translation. In this review, we summarize the recent progress of CDT based on iron-containing nanomaterials, including iron oxide nanoparticles, glassy iron nanoclusters, ferrocene nanoparticles, metal polyphenol networks, metal-organic frameworks, etc. We also discuss the challenges and perspectives for promoting CDT by rational design of iron-containing nanomaterials, highlighting their potential for precise cancer therapy.

Synthesis and Assessment of 3-Substituted Phenazines as Novel Antichlamydial Agents.

BACKGROUND: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity. OBJECTIVE: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. METHODS: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method. RESULTS: Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 µM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 µM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. CONCLUSION: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.