When Iodine Meets Starch: On-Demand Generation of Photothermal Hydrogels for Mild-Temperature Photothermal-Chemo Disinfection.

As an emerging antibacterial strategy, photothermal disinfection attracts increasing attention due to its advantages of high efficacy, wide pertinence, and non-drug resistance. However, the unavoidable shielding of observation by photothermal components and the possible damage to normal tissue caused by hyperthermia restrict its applications. Herein, we propose a composite hydrogel with the ability of on-demand generation of photothermal components and mild-temperature photothermal disinfection by elegantly tuning the binding and release of iodine and starch. The composite hydrogel is obtained by blending iodine-adsorbed pH-responsive ZIF-8 nanoparticles (NPs) with a starch-based hydrogel matrix. Through a convenient pH response, the composite hydrogel leverages the triple functions of iodine, which serves as a disinfectant and reacts with starch to generate a photothermal agent and color indicator, allowing photothermal-chemotherapy combined disinfection on demand. In vitro antibacterial experiments show that the composite hydrogel can respond to the acidification of the microenvironment caused by bacterial metabolism and produce corresponding color changes, realizing naked-eye observation. Meanwhile, under the combined treatment of heating/I2/Zn2+, the composite hydrogel can completely kill Escherichia coli and Staphylococcus aureus at a mild temperature of ∼41 °C. This study represents a breakthrough in on-demand generation of photothermal hydrogels for mild-temperature photothermal disinfection.

Skin optical clearing enabled by dissolving hyaluronic acid microneedle patches.

Optical imaging and phototherapy are of great significance in the detection, diagnosis, and therapy of diseases. Depth of light in the skin tissues in optical imaging and phototherapy can be significantly improved with the assistance of optical clearing technology by weakening the scattering from the refractive indexes inhomogeneity among skin constituents. However, the barrier of the stratum corneum restricts the penetration of optical clearing agents into deep tissues and limits the optical clearing effects. Herein, we develop an optical clearing strategy by using dissolving microneedle (MN) patches made of hyaluronic acid (HA), which can effortlessly and painlessly penetrate the stratum corneum to reach the epidermis and dermis. By using the HA MN patches, the transmittance of skin tissues is improved by about 12.13 %. We show that the HA MN patches enhance the clarity of blood vessels to realize naked-eyes observation. Moreover, a simulated subcutaneous tumor cells experiment also verifies that the optical clearing effects of the HA MN patch efficiently boost the efficiency of the photodynamic killing of tumor cells by 26.8 %. As a courageous attempt, this study provides a promising avenue to improve the optical clearing effects for further clinical application of optical imaging and phototherapy.

Water depth and land-use intensity indirectly determine phytoplankton functional diversity and further regulate resource use efficiency at a multi-lake scale.

Biodiversity-ecosystem functioning relationships under multiple pressures have recently been the subject of broad studies. For the key primary producer in aquatic ecosystems, phytoplankton, several studies have focused on trait-based functional diversity (FD) and the related functioning (e.g., resource use efficiency, RUE), and their linkages. However, investigations of the effects of environmental factors at different levels (e.g., land use, lake morphometry, climate and nutrients) on FD and RUE are sparse. We developed a data-driven-model framework to simultaneously elucidate the effects of multiple drivers on FD (functional diversity based on dendrograms, FDc and functional richness, FRic) and RUE (of nitrogen and phosphorus) of phytoplankton based on data from 68 Yunnan-Guizhou Plateau lakes, Southwest China. We found that the concentration of total phosphorus, which is mainly affected by land-use intensity and influenced by water depth, was the primary (positive) driver of changes in both FDc and FRic, while RUE was mainly explained by phytoplankton FD (i.e., FRic). These results indicate that water depth and land-use intensity influence indirectly phytoplankton FD and further regulate RUE. Moreover, nonlinear correlations of RUE with FRic were found, which may be caused by interspecific competition and niche differentiation of the phytoplankton community related to nutrient levels. Our finding may help managers to set trade-off targets between FD and RUE in lake ecosystems except for extremely polluted ones, in which the thresholds derived from the Bayesian network, of total phosphorus, total nitrogen and land-use intensity were approximately 0.04 mg/L, 0.50 mg/L and 244 (unitless), respectively. The probability of meeting the RUE objectives was lower in shallow lakes than in deep lakes, but for FRic the opposite was observed.

Photosensitizer-loaded gold nanocages for immunogenic phototherapy of aggressive melanoma.

Malignant melanoma remains the life-threatening form of skin cancer with high mortality and poor prognosis. Thus, an ideal melanoma therapeutic strategy is of immediate importance which can remove the primary tumor, as well as inhibit the metastasis and recurrence. Here, we report the fabrication of adjuvant monophosphoryl lipid A (MPLA) lipid bilayer-enveloped and photosensitizer indocyanine green (ICG)-loaded gold nanocages (MLI-AuNCs) for immunogenic phototherapy of aggressive melanoma. Hollow porous AuNCs are used as carriers to deliver MPLA and ICG, and protect ICG from photodegradation. Both AuNCs and ICG absorb near infrared (NIR) light and can be applied in controllable NIR-triggered photothermal and photodynamic combination therapy (PTT/PDT) of melanoma. MLI-AuNCs coated by thermosensitive lipid bilayer exhibit uniform size, good biocompatibility and bioavailability with prominent tumor accumulation, which further improve the PTT/PDT efficacy. MLI-AuNCs under NIR irradiation not only destroy the primary tumor by PTT/PDT, but also elicit robust antitumor immune response with melanoma associated antigens and MPLA released in situ. The released antigens and MPLA subsequently enhance the recruitment and maturation of dendritic cells, which further activate the effector T cells to inhibit metastases and recurrence of melanoma. This immunomodulatory-boosted PTT/PDT nanoplatform provides a new opportunity for highly aggressive melanoma treatment. STATEMENT OF SIGNIFICANCE: An ideal tumor therapeutic strategy not only can remove the primary tumor, but also inhibit metastasis and recurrence. Here, we introduced a versatile nanoplatform MLI-AuNCs for immunogenic phototherapy of aggressive melanoma. Adjuvant MPLA and photosensitizer ICG can be protected and co-delivered to the tumors by thermosensitive lipid-enveloped AuNCs. MLI-AuNCs exhibited prominent tumor accumulation ability and produced the potent PTT/PDT effect to destroy the primary tumors with a single dose of NIR irradiation, as well as elicited the strong antitumor immunity to inhibit the metastasis and relapse. This study may provide a potential therapeutic vaccination strategy against advanced melanoma and other difficult-to-treat cancers.

Behavior of Nutritional Supplements Use in Association With Inflammatory Skin Diseases in Chinese College Students.

Objectives: It is understudied how frequently adolescents use nutritional supplements (NS) and whether the corresponding behavior is associated with skin diseases that may cause unpleasant symptoms and disfigurement. The current study aimed to investigate the prevalence of NS use in Chinese college students and its association with inflammatory skin diseases. Methods: This was a university-based epidemiologic investigation that included 20,138 students who underwent dermatological examinations. A questionnaire survey was conducted to inquire about the use of NS along with related information. Skin diseases were diagnosed by dermatologists during the health examination. Logistic regression models were used for analysis. Adjusted odds ratios (aORs) were presented as the effect size. Results: Survey responses from a total of 20,138 participants were analyzed. Specifically, 18.3% of the participants reported the use of NS in the past year. The use of vitamin C was most frequently reported, accounting for a proportion of 12.9%, followed by vitamin B and mineral supplements. The use of NS was found to be associated with female sex, Han ethnicity, higher annual household income, and a series of healthy lifestyles such as more physical activity, less second-hand smoke exposure, less alcohol consumption, and higher intake of milk and yogurt (p < 0.001). Participants with chronic urticaria (aOR = 1.3; 95% CI, 1.0-1.7), atopic dermatitis (aOR = 1.4; 95% CI, 1.2-1.6), or acne (aOR = 1.17; 95% CI, 1.04-1.31) were more likely to use NS, especially herbs (aOR = 2.7; 95% CI, 1.2-3.7), followed by vitamin B (aOR = 1.6; 95% CI, 1.2-2.0) and mineral supplements (aOR = 1.4; 95% CI, 1.0-2.0). Conclusion: College students with inflammatory skin diseases are more likely to use NS.

Multifunctional CuxS- and DOX-loaded AuNR@mSiO2 platform for combined melanoma therapy with inspired antitumor immunity.

Combined antitumor therapies based on nanomedicines have shown efficacy in various tumor models in recent years, overcoming the disadvantages of inefficiency and undesired toxicity of traditional therapies. Herein, we present a copper sulfide- and doxorubicin-loaded gold nanorods@mesoporous SiO2 multifunctional nanocomposite (AuNR@mSiO2@DOX-CuxS-PEG) to integrate chemotherapy, the photothermal properties of AuNRs, and the photodynamic properties of CuxS into a single nanoplatform based on hydrophobic interaction and electrostatic attraction. Upon near-infrared light irradiation, the AuNR@mSiO2@DOX-CuxS-PEG nanocomposites exhibit a synergistic therapeutic effect and inhibit the in situ tumor growth and lung metastasis in a melanoma model. This occurs because of the high photothermal conversion efficiency, boosted intracellular reactive oxygen species production, and excellent doxorubicin (DOX) release, as well as an induced tumor-specific immune response. The inspired antitumor immunity was confirmed by elevated infiltration of activated T cells in tumor tissues and improved maturation and activation of dendritic cells in tumor-draining lymph nodes. This study highlights the superior antitumor therapeutic effect elicited by a multifunctional nanoplatform for skin with in situ melanoma and lung metastasis inhibition, indicating its satisfactory clinical application prospects.

Polyethylenimine Hybrid Thin-Shell Hollow Mesoporous Silica Nanoparticles as Vaccine Self-Adjuvants for Cancer Immunotherapy.

Conventional adjuvants (e.g., aluminum) are insufficient to trigger cell-mediated immunity, which plays a crucial role in triggering specific immunity against cancer. Therefore, developing appropriate adjuvants for cancer vaccines is a central way to stimulate the antitumor immune response. Hollow mesoporous silica nanoparticles (HMSNs) have been proven to stimulate Th1 antitumor immunity in vivo and promote immunological memory in the formulation of novel cancer vaccines. Yet, immune response rates of existing HMSNs for anticancer immunity still remain low. Here, we demonstrate the generation of polyethylenimine (PEI)-incorporated thin-shell HMSNs (THMSNs) through a facile PEI etching strategy for cancer immunotherapy. Interestingly, incorporation of PEI and thin-shell hollow structures of THMSNs not only improved the antigen-loading efficacy and sustained drug release profiles but also enhanced the phagocytosis efficiency by dendritic cells (DCs), enabled DC maturation and Th1 immunity, and sustained immunological memory, resulting in the enhancement of the adjuvant effect of THMSNs. Moreover, THMSNs vaccines without significant side effects can significantly reduce the potentiality of tumor growth and metastasis in tumor challenge and rechallenge models, respectively. THMSNs are considered to be promising vehicles and excellent adjuvants for the formulation of cancer vaccines for immunotherapy.

Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating the progression of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels.

BACKGROUND: Vitex negundo L (Verbenaceae) is an aromatic shrub that is abundant in Asian countries. A series of compounds from Vitex negundo have been used in traditional Chinese medicine for the treatment of various diseases. Cutaneous melanoma is one of the most aggressive malignancies. A significant feature of melanoma is its resistance to traditional chemotherapy and radiotherapy; therefore, there is an urgent need to develop novel treatments for melanoma. METHODS: We first examined the effects of VB1 (vitexin compound 1) on cell viability by CCK-8 (cell counting kit) and Colony Formation Assay; And then, we analyzed the apoptosis and cell cycle by flow cytometry, verified apoptosis by Immunoblotting. The in vivo effect of VB1 was evaluated in xenograft mouse model. Potential mechanisms of VB1's antitumor effects were explored by RNA sequencing and the key differential expression genes were validated by real-time quantitative PCR. Finally, the intracellular reactive oxygen species (ROS) level was detected by flow cytometry, and the DNA damage was revealed by Immunofluorescence and Immunoblotting. RESULTS: In this study, we show that VB1, which is a compound purified from the seed of the Chinese herb Vitex negundo, blocks melanoma cells growth in vitro and in vivo, arrests the cell cycle in G2/M phase and induces apoptosis in melanoma cell lines, whereas the effects are not significantly observed in normal cells. To study the details of VB1, we analyzed the alteration of gene expression profiles after treatment with VB1 in melanoma cells. The findings showed that VB1 can affect various pathways, including p53, apoptosis and the cell cycle pathway, in a variety of melanoma cell lines. Furthermore, we confirmed that VB1 restored the P53 pathway protein level, and then we demonstrated that VB1 significantly induced the accumulation of ROS, which resulted in DNA damage in melanoma cell lines. Interestingly, our results showed that VB1 also increased the ROS levels in BRAFi (BRAF inhibitor)-resistant melanoma cells, leading to DNA cytotoxicity, which caused G2/M phase arrest and apoptosis. CONCLUSIONS: Taken together, our findings indicate that vitexin compound 1 might be a promising therapeutic Chinese medicine for melanoma treatment regardless of BRAFi resistance.

Au Nanocage-Strengthened Dissolving Microneedles for Chemo-Photothermal Combined Therapy of Superficial Skin Tumors.

For superficial skin tumors (SST) with high incidence, surgery and systemic therapy are relatively invasive and possible to cause severe side effect, respectively. Yet, topical therapy is confronted with the limited transdermal capacity because of the stratum corneum barrier layer of skin. Therefore, it is crucial to develop a highly effective and minimally invasive alternative transdermal approach for treating SST. Here, we developed gold nanocage (AuNC)- and chemotherapeutic drug doxorubicin (DOX)-loaded hyaluronic acid dissolving microneedle (MN) arrays. The loaded AuNCs are not only reinforcers to enhance the mechanical strength of the MNs, but also effective agents for photothermal therapy to obtain effective transdermal therapy for SST. The resultant MNs can effectively penetrate the skin, dissolve in the skin and release cargoes within the tumor site. Photothermal effect of AuNCs initiated by near-infrared laser irradiation combined with the chemotherapy effect of DOX destroyed tumors synergistically. Moreover, we verified the potent antitumor effects of the DOX/AuNC-loaded MNs after four administrations to SST-bearing mice without obvious side effects. Therefore, the drug/AuNC-loaded dissolving MN system provides a promising platform for effective, safe, minimally invasive combined treatment of SST.

Encapsulation of Hydrophilic and Hydrophobic Peptides into Hollow Mesoporous Silica Nanoparticles for Enhancement of Antitumor Immune Response.

Codelivery of combinational antigenic peptides and adjuvant to antigen presenting cells is expected to amplify tumor specific T lymphocytes immune responses while minimizing the possibility of tumor escaping and reducing immune tolerance to single antigenic peptide. However, the varied hydrophobicities of these multivariant derived short antigenic peptides limit their codelivery efficiency in conventional delivery systems. Here, a facile yet effective route is presented to generate monodisperse and stable hollow mesoporous silica nanoparticles (HMSNs) for codelivering of HGP10025-33 and TRP2180-188 , two melanoma-derived peptides with varied hydrophobicities. The HMSNs with large pore size can improve the encapsulation efficiency of both HGP100 and TRP2 after NH2 modification on the inner hollow core and COOH modification in the porous channels. HGP100 and TRP2 loaded HMSNs (HT@HMSNs) are further enveloped within monophosphoryl lipid A adjuvant entrapped lipid bilayer (HTM@HMLBs), for improved stability/biocompatibility and codelivery efficiency of multiple peptides, adjuvant, and enhanced antitumor immune responses. HTM@HMLBs increase uptake by dendritic cells (DCs) and stimulate DCs maturation efficiently, which further induce the activation of both tumor specific CD8+ and CD4+ T lymphocytes. Moreover, HTM@HMLBs can significantly inhibit tumor growth and lung metastasis in murine melanoma models with good safety profiles. HMSNs enveloped with lipid bilayers (HMLBs) are believed to be a promising platform for codelivery of multiple peptides, adjuvant, and enhancement of antitumor efficacy of conventional vaccinations.

Skin healing and collagen changes of rats after fractional erbium:yttrium aluminum garnet laser: observation by reflectance confocal microscopy with confirmed histological evidence.

The fractional erbium:yttrium aluminum garnet (Er:YAG) laser is widely applied. Microstructural changes after laser treatment have been observed with histopathology. Epidermal and dermal microstructures have also been analyzed using reflectance confocal microscopy (RCM). However, no studies have compared these two types of microstructural changes in the same subject at multiple time points after irradiation, and it is unclear if these two types of changes are consistent. We use RCM to observe the effect of different laser energies on skin healing and collagen changes in the skin of Sprague-Dawley rats that had been irradiated by fractional Er:YAG lasering at different energies. RCM was used to observe skin healing and detect collagen changes at different time points. Collagen changes were observed using hematoxylin and eosin (H&E) staining and quantitatively analyzed by western blot. RCM showed that, irrespective of laser energy, microscopic treatment zones (MTZs) were larger at 1 day after irradiation. The MTZs then reduced in size from 3 to 7 days after irradiation. The higher the energy, the larger the MTZ area. The amount of collagen also increased with time from 1 day to 8 weeks. However, the increase in the collagen amount on both RCM and H&E staining was not influenced by the laser energy. Western blotting confirmed that the amount of type I and type III collagens increased over time, but there were no significant differences between the different energy groups (p > 0.05). In conclusion, RCM is a reliable technique for observing and evaluating skin healing and collagen expression after laser irradiation.

Traditional Chinese medicine compound ShengJinRunZaoYangXue granules for treatment of primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Traditional Chinese medical treatment of primary Sjögren's syndrome has advantages over Western medicine in terms of fewer side effects and improved patient conditions. This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of ShengJinRunZaoYangXue granules for the treatment of primary Sjögren's syndrome, including the symptoms of dry mouth and dry eye. METHODS: We undertook a 6-week, double-blind, randomized trial involving 240 patients with primary Sjögren's syndrome at five centers in East China. A computer-generated randomization schedule assigned patients at a 2:1 ratio to receive either ShengJinRunZaoYangXue granules or placebo once daily. Patients and investigators were blinded to treatment allocation. The primary endpoints were the salivary flow rate, Schirmer test results, and sugar test results. Intention-to-treat and per-protocol analyses were performed. RESULTS: All 240 patients were randomly allocated to either the treatment group (n = 160, ShengJinRunZaoYangXue granules) or placebo group (n = 80) and were included in the intention-to-treat analysis. After program violation and loss to follow-up, a total of 199 patients were included in the per-protocol analysis. At six week, intention-to-treat and per-protocol analyses of the left-eye Schirmer I test results showed an improved difference of 1.36 mm/5 min (95% CI: 0.03 to 2.69 mm/5 min) and 1.35 mm/5 min (95% CI: 0.04 to 2.73 mm/5 min), respectively, and those of the right-eye Schirmer I test results showed an improved difference of 1.12 mm/5 min (95% CI: 0.02 to 2.22 mm/5 min) and 1.12 mm/5 min (95% CI: -0.02 to 2.27 mm/5 min), respectively. There was no significant difference between the two groups before treatment. After treatment, the between-group and within-group before-and-after paired comparison results were statistically significant (P < 0.05). Intention-to-treat and per-protocol analyses showed an improved salivary flow rate by 0.04 ml/15 min (95% CI: -0.49 to 0.58 ml/15 min) and 0.04 ml/15 min (95% CI: -0.52 to 0.60 ml/15 min), respectively, but the differences were not significant. Intention-to-treat and per-protocol analyses showed that the sugar test results were improved by 1.77 minutes (95% CI: 0.11 to 3.44 minutes) and 1.84 minutes (95% CI: 0.12 to 3.55 minutes), respectively, but the differences were not significant. For the secondary endpoint, intention-to-treat and per-protocol analyses showed significant improvement in the integrated evaluation of treated patients with dry eye and dry mouth after six weeks of treatment. The incidence of adverse events was 15.6% in the treatment group and 10.0% in the placebo group. Most (94%) adverse events were mild to moderate in the two groups, and only two cases of serious adverse events occurred in the treatment group; both were caused by autoimmune liver disease. CONCLUSIONS: Six-week treatment with ShengJinRun ZaoYangXue granules for primary Sjögren's syndrome in this large-scale study improved the symptoms of dry mouth, dry eyes, and low tear flow rate with minimal adverse events.

Gambogic acid induces apoptosis by regulating the expression of Bax and Bcl-2 and enhancing caspase-3 activity in human malignant melanoma A375 cells.

OBJECTIVES: To investigate the effect of a Chinese traditional medicine, gambogic acid (GA), on human malignant melanoma (MM) A375 cells and to study the mechanism of apoptosis induced by GA. METHODS: A375 cells were treated with GA at different doses and for different times, and their proliferation and viability were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induced by GA in A375 cells was observed by annexin-V/propidium iodide doubling staining flow cytometry assay and Hoechst staining. To further determine the molecular mechanism of apoptosis induced by GA, the changes in expression of Bcl-2 and Bax were detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, and caspase-3 activity was measured by fluorescence resonance energy transfer (FRET) probe. RESULTS: After incubation with GA, A375 cell proliferation was dramatically inhibited in a dose-dependent manner. After these cells had been exposed to GA for 24, 36 and 48 h, the IC(50) values were 1.57 +/- 0.05, 1.31 +/- 0.20, and 1.12 +/- 0.19 microg/mL, respectively. Treatment of A375 cells with GA (2.5-7.5 microg/mL) for 36 h resulted in an increased number of early apoptotic cells, which ranged from 27.6% to 41.9%, in a dose-dependent manner, compared with only 3.5% apoptotic cells in the non-GA-treated group. An increase in Bax and decrease in Bcl-2 expression were found by real-time RT-PCR and Western blot. Caspase-3 activity was increased in a dose-dependent manner, observed by FRET probe. CONCLUSION: GA can inhibit the proliferation of A375 cells and induce their apoptosis, which may be related to the up-regulation of the Bax/Bcl-2 ratio and caspase-3 activity.