An injectable and thermosensitive hydrogel with nano-aided NIR-II phototherapeutic and chemical effects for periodontal antibacteria and bone regeneration.

Periodontitis is a common public health problem worldwide and an inflammatory disease with irregular defect of alveolar bone caused by periodontal pathogens. Both antibacterial therapy and bone regeneration are of great importance in the treatment of periodontitis. In this study, injectable and thermosensitive hydrogels with 3D networks were used as carriers for controlled release of osteo-inductive agent (BMP-2) and Near Infrared Region-II (NIR-II) phototherapy agents (T8IC nano-particles). T8IC nano-particles were prepared by reprecipitation and acted as photosensitizer under 808 nm laser irradiation. Besides, we promoted photodynamic therapy (PDT) through adding H2O2 to facilitate the antibacterial effect instead of increasing the temperature of photothermal therapy (PTT). Hydrogel + T8IC + Laser + BMP-2 + H2O2 incorporated with mild PTT (45 °C), enhanced PDT and sustained release of BMP-2. It was present with excellent bactericidal effect, osteogenic induction and biosafety both in vitro and in vivo. Besides, immunohistochemistry staining and micro-CT analyses had confirmed that PTT and PDT could promote bone regeneration through alleviating inflammation state. Altogether, this novel approach with synergistic antibacterial effect, anti-inflammation and bone regeneration has a great potential for the treatment of periodontitis in the future.

Novel semiconducting nano-agents incorporating tirapazamine for imaging guided synergistic cancer hypoxia activated photo-chemotherapy.

For cancer treatment, the traditional monotherapy has the problems of low drug utilization rate, poor efficacy and easy recurrence of the cancer. Herein, nanoparticles (NPs) based on a novel semiconducting molecule (ITTC) are developed with excellent photostability, high photothermal conversion efficiency and good 1O2 generation ability. The chemotherapy of the hypoxia-activated prodrug tirapazamine (TPZ) was improved accordingly after oxygen consumption by the photodynamic therapy of ITTC NPs. Additionally, the metabolic process of ITTC NPs in vivo could be monitored in real time for fluorescence imaging guided phototherapy, which presented great passive targeting ability to the tumor site. Remarkably, both in vitro and in vivo experiments demonstrated that the combination of ITTC NPs and TPZ presented excellent synergistic tumor ablation through photothermal therapy, photodynamic therapy and hypoxia-activated chemotherapy with great potential for clinical applications in the future.

Novel NIR-II semiconducting molecule incorporating sorafenib for imaging guided synergetic cancer phototherapy and anti-angiogenic therapy.

Tumor tissues are not only independent of cancer cells, but also tumor blood vessels. Thus, targeting the tumor blood vessels is as important as targeting the tumor for cancer treatment. Herein, an organic semiconducting molecule named T8IC is developed for the potential phototeranostics in the second near-infrared window (NIR-II, 1000-1700 nm). The T8IC molecule with an electronic-rich core and electron-deficient side edge shows a typical semiconducting structure, which makes the bandgap narrow. With the addition of anti-angiogenic agent sorafenib into T8IC, TS nanoparticles (NPs) were formed by nanoprecipitation with synergetic anti-angiogenic and phototheranostic effects. Compared to the molecular state, the J-aggregative TS NPs were formed with great bathochromic-shifts in both the absorption spectrum (maximum increased from 755 nm to 826 nm) and the emission spectrum (maximum increased from 840 nm to 1030 nm), which endow them with the ideal deep tumor NIR-II fluorescence imaging ability. Besides, TS NPs present both high photothermal conversion efficiency (∼32.47%) and good ROS generation ability, making them possess excellent cancer phototherapy capability. Guided by NIR-II fluorescence imaging, the tumor blood vessels can be cut off via sorafenib and cancer cells can be killed via T8IC simultaneously, making TS NPs show promising potential for the synergistic therapeutic effect in clinical applications.

Sirtuin 6 supra-physiological overexpression in hypothalamic pro-opiomelanocortin neurons promotes obesity via the hypothalamus-adipose axis.

Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro-opiomelanocortin (POMC)-expressing cells by the loxP-Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet-induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre-dependent adeno-associated viruses into the arcuate nucleus of Pomc-Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet-induced obesity and metabolic disorders via the hypothalamus-adipose axis.

Peroxidase-mimicking evodiamine/indocyanine green nanoliposomes for multimodal imaging-guided theranostics for oral squamous cell carcinoma.

Here, evodiamine (EVO) and the photosensitizer indocyanine green (ICG) were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma (OSCC). EVO, as an active component extracted from traditional Chinese medicine, not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation, thus working as a contrast agent for positron emission tomography/computed tomography (PET/CT) imaging. Moreover, EVO could exhibit peroxidase-like catalytic activity, converting endogenous tumor H2O2 into cytotoxic reactive oxygen species (ROS), enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO. As proven by in vitro and in vivo experiments, guided by optical imaging and PET/CT imaging, we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy.

Organic Near-Infrared-II Nanophotosensitizer for Safe Cancer Phototheranostics and Improving Immune Microenvironment against Metastatic Tumor.

Current tumor immunotherapy has excellent application prospects compared with traditional radiotherapy and chemotherapy, but there are still limitations, such as considerable side effects. This problem can be partially solved by treating the local tumor to induce antitumor immunity. In our study, a novel organic photosensitizer Y8 was used to synthesize nanoparticles (Y8 NPs) via a simple nanoprecipitation method. Further investigation indicated the practical photodynamic and photothermal effects of Y8 NPs with 808 nm laser irradiation. Because of its long-wavelength absorption, Y8 NPs also have excellent imaging effects near-infrared-II region. In metastatic tumor-bearing murine models, Y8 NPs can effectively induce phototherapy, suppressing the growth of both primary and metastatic tumors without apparent systemic toxicity through local photodynamic and photothermal therapy synergistic enhancement of antitumor immunity. This study offers a promising therapeutic strategy for synergetic phototherapy and immunotherapy in tumor treatment.

Fused-Ring Small-Molecule-Based Bathochromic Nano-agents for Tumor NIR-II Fluorescence Imaging-Guided Photothermal/Photodynamic Therapy.

Optical imaging in the second near-infrared (NIR-II) windows reduces much more autofluorescence and photon scattering from biological tissues and allows further tissue penetration depth and superior spatial resolution in living bodies. Herein, a fused-ring 2,2'-((2Z,2'Z)-((12,13-bis(2-ethylhexyl)-3,9-diundecyl-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2,″3″:4',5']thieno[2',3':4,5]pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (TPBT) molecule was explored as a multifunctional tumor theranostic reagent for photothermal/photodynamic therapy guided by NIR-II imaging. The TPBT molecule has an electron-deficient core with a ladder-type multi-fused ring and shows a narrow band gap that can enhance the near-infrared absorption. The J-aggregative TPBT NPs were formed by nanoprecipitation with great bathochromic shift in absorption and emission spectra, which endows them with ideal fluorescence imaging ability in the NIR-II region. Moreover, TPBT NPs present both higher photothermal conversion efficiency (∼36.5%) and effective ROS generation ability, making them excellent candidate for cancer photothermal/photodynamic therapy. Moreover, the biocompatible TPBT NPs can effectively passively target tumor sites due to their enhanced permeability and retention effect for more precision treatment. Thus, TPBT NPs as a multifunctional phototheranostic agent in the NIR-II region present promising potential in clinical cancer NIR-II imaging-guided phototherapy.

Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling.

OBJECTIVE: Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. METHODS: For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. RESULTS: Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. CONCLUSIONS: Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.

Treatment with andrographolide sulfonate provides additional benefits to imipenem in a mouse model of Klebsiella pneumoniae pneumonia.

Klebsiella pneumoniae is a primary cause of community-acquired and nosocomial respiratory infections, and K. pneumoniae resistance to the current treatment approach with carbapenem is worsening. Andrographolide is a natural diterpenoid from Andrographis paniculata that was shown to exert anti-inflammatory activity. We herein show that pretreatment with a water-soluble andrographolide sulfonate significantly attenuate lung injury and infiltration of inflammatory cells. Interestingly, mice receiving combined treatment with andrographolide sulfonate displayed perfect survival rate than the mice treatment with imipenem alone, and monocyte chemotactic protein 5 (MCP-5) level was decreased further. These findings suggest that andrographolide sulfonate could as a potential synergist for antibiotic treatment of bacteria-induced inflammation.

The effect of CBT and its modifications for relapse prevention in major depressive disorder: a systematic review and meta-analysis.

BACKGROUND: The risk of relapse in major depressive disorder (MDD) is associated with high worldwide disease burden. Cognitive behavioral therapy (CBT) and its modifications might be effective in relapse prevention. The aim of this review was to evaluate the efficacy of these treatments for reducing relapse of MDD. METHODS: The retrieval was performed in the databases of MEDLINE via Pubmed, EMBASE and PsycINFO via OVID, The Cochrane Library and four Chinese databases. Clinical trials registry platforms and references of relevant articles were retrieved as well. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to pool evidences. RESULTS: A total of 16 eligible trials involving 1945 participants were included. In the first 12 months, CBT was more efficacious than control in reducing the risk of developing a new episode of depression for MDD patients in remission (HR:0.50, 95%CI:0.35-0.72, I2 = 11%). Mindfulness-based cognitive therapy (MBCT) was more efficacious than control only among patients with 3 or more previous depressive episodes (HR:0.46, 95%CI:0.31-0.70, I2 = 38%). Besides, compared with maintenance antidepressant medication (m-ADM), MBCT was a more effective intervention (HR:0.76, 95%CI:0.58-0.98, I2 = 0%). These positive effects might be only maintained at two and nearly 6 years follow up for CBT. CONCLUSION: The use of CBT for MDD patients in remission might reduce risk of relapse. Besides, the effect of MBCT was moderated by number of prior episodes and MBCT might only be effective for MDD patients with 3 or more previous episodes. Further exploration for the influence of previous psychological intervention is required.

[Effect of seleno-arginine on cellular immunological function in D-gal aging mice].

AIM: To study the effect of seleno-argnine on cellular immunological function in D-gal aging mice. METHODS: The mice were divided into normal group, model group, low seleno-argnine group(L-SeArg) and high seleno-argnine group (H-SeArg). D-galactose induced aging model was set up by s.c. injection for 42 days, i.g. method was used to add Seleno-argnine. Spleen index(SI) and thymus index (TI) were measured. The ability of Spleen cell multiplication and NK cell killing activity were determined by MTT colorimetry. The changes of CD40 and CD40L expression were observed by immunofluorescent assay. RESULTS: Compared with the model mice, seleno-argnine increased spleen index and thynus index, enhanced the ability of spleen cell multiplication, enhanced the expression of CD40 and CD40L, and accelerated the NK cell killing activity. Between the two seleno-argnine groups, the effect of L-SeArg on cellular immunological function was more obvious in D-gal aging mice.The result were statistic ally significantly compared with the model mice(P<0.01). CONCLUSION: D-gal injection can decrease the cellular immunological function of mice. Seleno-argnine can activate immune cells, enhance the cellular immunological function of mice, reduce the toxic effect of D-gal and delay the aging process.