Search

Psoriasis is an autoimmune inflammatory skin disease. In the past several decades, phototherapy has been widely used to treat stable psoriatic lesions, including trunk, scalp, arms and legs, and partial nail psoriasis. A variety of light/lasers with different mechanisms of action have been developed for psoriasis including ultraviolet B (UVB), psoralen ultraviolet A (PUVA), pulsed dye laser (PDL), photodynamic therapy (PDT), intense pulsed light (IPL), light-emitting diodes (LED), and so on. Because light/laser each has specific therapeutic and adverse effects, it is important to adequately choose the sources and parameters in management of psoriasis with different pathogenic sites, severities, and duration of the disorder. This review aims at providing most updated clinic information to physicians about how to select light/laser sources and individual therapeutic regimens. To date, UV light is primarily for stable plaque psoriasis and PDL for topical psoriatic lesions with small area, both of which are safe and effective. On the other hand, PUVA has better curative effects than UVB for managing refractory psoriasis plaques, if its side effects can be better controlled. PDL provides optimal outcomes on nail psoriasis compared with other lasers. Although the trails of low-level light/laser therapy (LLLT) are still small, the near infrared (NIR) and visible red light with low energy show promise for treating psoriasis due to its strong penetration and encouraging photobiomodulation. IPL is rarely reported for psoriasis treatment, but PDT-IPL has been found to offer a moderate effect on nail psoriasis. In brief, various phototherapies have been used either in different combinations or as monotherapy. The modality has become a mainstay in the treatment of mild-to-moderate psoriasis without systemic adverse events in today's clinical practice. [ABSTRACT FROM AUTHOR]

Chronic wound infections caused by multidrug-resistant (MDR) bacteria are one of the serious threats to public health due to limited therapeutic options and lengthy care. This investigation combines 5- a minolevulinic acid (ALA), b lue light (BL), and phytochemical c arvacrol, named ABC cocktail or trio-therapy, to efficiently eliminate wound-related MDR pathogens. Both planktonic cells and biofilms of blue light-refractory Escherichia (E.) coli and Klebsiella (K.) pneumoniae succumbed to the trio-therapy partly due to porphyrin accumulations following ALA incubation. ALA either alone or alongside carvacrol could vigorously trigger bursts of reactive oxygen species (ROS) upon blue light irradiation in K. pneumoniae , but not in mammalian cells. The robust antimicrobial activity was extended to polymicrobial biofilms composed of five MDR pathogens (Staphylococcus aureus , E. coli , K. pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa) in vitro and in vivo. Strikingly, polymicrobial biofilm in mouse wounds became readily visible in the presence of ALA owing to the increasing generation of porphyrins that exhibited bright red fluorescence in response to blue light. Thus, ALA not only enhances killing efficacy, but also helps to pinpoint the infections for guiding debridement, precise phototherapy, and timely assessment of treatment effectiveness. Featuring a broadened antimicrobial spectrum and advantages of bacterial/biofilm imaging, the trio-therapy can be used either alone or adjunctive to other wound management modalities to effectively combat MDR bacteria in wounds. • A combination of ALA, blue light (BL), and carvacrol synergically kills multidrug-resistant (MDR) polymicrobial biofilms. • The trio also offers direct visualization of bacterial biofilms in infected wounds and thus precisive treatment. • ALA selectively promotes porphyrin accumulation in bacterial pathogens but not in host cells under the specific treatment. • Carvacrol protects host cells while acting as a "pro-photosensitizer" to enhance BL-mediated bactericidal activity. [ABSTRACT FROM AUTHOR]

Sepsis, a leading cause of mortality in intensive care units worldwide, is often a result of overactive and systemic inflammation following serious infections. We found that mice lacking immediate early responsive gene X-1 (IEX-1) were prone to lipopolysaccharide (LPS) -induced endotoxemia. A nonlethal dose of LPS provoked numerous aberrations in IEX-1 knockout (KO) mice including pancytopenia, increased serum aspartate aminotransferase (AST), and lung neutrophilia, concurrent with liver and kidney damage, followed by death. Given these results, in conjunction with a proven role for IEX-1 in the regulation of reactive oxygen species (ROS) homeostasis during stress, we pre-treated IEX-1 KO mice with Mitoquinone (MitoQ), a mitochondrion-based antioxidant prior to LPS injection. The treatment significantly reduced ROS formation in circulatory cells and protected against pancytopenia and multiple organ failure, drastically increasing the survival rate of IEX-1 KO mice challenged by this low dose of LPS. This study confirms significant contribution of mitochondrial ROS to the etiology of sepsis. [ABSTRACT FROM AUTHOR]

Failure to execute an apoptotic programme is one of the critical steps and a common mechanism promoting tumorogenesis. Immediate early responsive gene 3 (IER3) has been shown to be upregulated in several cancers. IER3 is a stress-induced gene, which upregulation leads to reduction in production of reactive oxygen species (ROS) protecting malignant cells from apoptosis. We observed that malignant lymphocytes from patients with Sézary syndrome (SzS) were resistant to pro-apoptotic dose of tumour necrosis factor-α (TNF-α). The aim of this study was to investigate the role of IER3 in the mechanism of such resistance. CD4+ CD26− lymphocytes from the peripheral blood of patients with SzS and healthy controls were negatively selected using CD4 and CD26 magnetic beads and analysed for expression of TNFR1, TNFR2, IER3 expression, and ROS production in response to TNF-α at an apoptotic dose. Sézary cells with a higher level of IER3 expression retained their viability to TNF-α. IER3 upregulation correlated with a decrease level of intracellular ROS and low TNFR1 expression on malignant cells. Targeting IER3 could be of interest for the development of future therapeutic strategies for patients with SzS. [ABSTRACT FROM AUTHOR]

The present study explores whether photodynamic therapy (PDT)-induced apoptosis can increase the number of tolerogenic regulatory T cells (Treg) and limit collateral tissue damage. BALB/c mice were vaccinated subcutaneously three times with PDT-induced apoptotic or thaw-frozen, necrotic non-infected autologous macrophages (MΦ). Two weeks after the last vaccination, mice were infected intradermally with 10 promastigotes of Leishmania major. Mice that received PDT-induced apoptotic MΦ had fewer parasites and higher numbers of Treg than mice vaccinated with thaw-frozen necrotic MΦ or phosphate-buffered saline (PBS). Interleukin (IL)-4 and IL-6 were significantly suppressed, while IL-10 was increased in mice that received the PDT-induced apoptotic MΦ. The role of Treg in this process was confirmed through Treg transfer from vaccinated to naïve mice. Mice receiving CD4CD25 cells from mice vaccinated with PDT-induced apoptotic MΦ showed smaller lesions 3 weeks after infection and lower parasitic burdens than mice that received Tregs from mice of thaw-frozen necrotic MΦ or PBS groups. These changes were mediated by the depletion of CD3CD8 and NKT cells and increased levels of IL-12p70 and interferon-γ, IL-10, and TGF-β in the cutaneous leishmaniasis lesions. Vaccination with apoptotic MΦ-induced tolerogenic Treg cells that limited collateral tissue damage and diminished parasitic burden. [ABSTRACT FROM AUTHOR]

Abstract: Demonstration of thymic homing dependent on Gαi proteins is one of the keys to determine whether thymic entrance of blood-borne progenitors is a highly selective process. The present study provides compelling evidence of an indispensable role for Gαi proteins in this process. Absence of either Gαi2 or Gαi3 significantly abrogated thymic homing, with an effect of Gαi3 being greater than that of Gαi2. Pertussis toxin treatment that blocks both Gαi2 and Gαi3 almost completely blocked thymic seeding in the thymus. Null mutation of Gαi3 also hindered bone marrow cell development and thus reduced production of pre-thymic progenitors. In contrast, Gαi2 exhibited a more prominent role than Gαi3 in guidance of CD4−CD8− double negative (DN) 1 cell migration and early thymic differentiation. The Gαi-deficiency-induced defects might be compensated for in part via augmented function of thymic stromal cells so that a nearly normal output of mature T cells could be maintained in these Gαi-deficient mice. These studies underscore the importance of Gαi in regulating thymic homing and pre-thymic and early thymocyte differentiation. [Copyright &y& Elsevier]

Polymyxin B (PMB) is often considered as the last line of defense for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP). However, its efficacy is hindered by limited penetration across the blood‐air barrier in the lung due to its low lipid solubility. To simultaneously increase PMB in epithelial lining fluid while suppressing the excessive inflammatory response in the lung, a novel nano‐biomimetic system “Siv‐PMB@G4@MM” is designed and fabricated by encapsulating PMB‐ and anti‐inflammatory Sivelestat (Siv)‐loaded G4 PAMAM dendrimers with macrophage membranes (MM). The Siv‐PMB@G4@MM displayed a superior acidic pH‐responsive release property and can target inflamed lung tissues, greatly increasing the concentrations of PMB and Siv at the infection site. Compared with free drugs, Siv‐PMB@G4@MM demonstrated superior synergistic antibacterial and anti‐inflammatory activities. Moreover, due to the ability of MM to sequester lipopolysaccharide (LPS) and some pro‐inflammatory cytokines, Siv‐PMB@G4@MM further enhanced the anti‐inflammatory potential of Siv. In mouse models of LPS‐induced acute lung injury, pulmonary bacterial infection, and sepsis‐induced pneumonia, Siv‐PMB@G4@MM significantly reduced inflammatory responses and/or bacterial burdens, mitigated neutrophil infiltration and pulmonary edema, and decreased neutrophil extracellular trap (NET) secretion. The highly improved biocompatibility and efficiency of the multifunctional Siv‐PMB@G4@MM presents a promising strategy for the clinical treatment of antibiotic‐resistant bacterial pneumonia. [ABSTRACT FROM AUTHOR]

Demonstrates a key role of IEX-1L in cellular resistance to tumor necrosis factor type alpha (TNF)-induced apoptosis. How IEX-1L protects cells from apoptosis induced by TNF; Role of transcription factors.

Focuses on the ability of the human immunodeficiency virus (HIV)-1 tat protein-treated accessory cells. Suggestions of results; Important role of the HIV infection of accessory cells (ACs); Information on T cells.

The emergence of multidrug-resistant bacteria has become a real threat and we are fast running out of treatment options. A combinatory strategy is explored here to eradicate multidrug-resistant Staphlococcus aureus and Pseudomonas aeruginosa including planktonic cells, established biofilms, and persisters as high as 7.5 log bacteria in less than 30 min. Blue-laser and thymol together rapidly sterilized acute infected or biofilm-associated wounds and successfully prevented systematic dissemination in mice. Mechanistically, blue-laser and thymol instigated oxidative bursts exclusively in bacteria owing to abundant proporphyrin-like compounds produced in bacteria over mammalian cells, which transformed harmless thymol into blue-laser sensitizers, thymoquinone and thymohydroquinone. Photo-excitations of thymoquinone and thymohydroquinone augmented reactive oxygen species production and initiated a torrent of cytotoxic events in bacteria while completely sparing the host tissue. The investigation unravels a previously unappreciated property of thymol as a pro-photosensitizer analogous to a prodrug that is activated only in bacteria. Multidrug-resistant bacteria are a real threat to human health. Here, the authors investigate a combinatory strategy using blue-laser and thymol against Staphylococcus aureus and Pseudomonas aeruginosa. Blue-laser and thymol succesfully sterilized acute infected or biofilm-associated wounds and prevented systematic dissemination in mice. Compared with mammalian cells, bacteria contain abundant proporphyrin-like compounds that transform harmless thymol into blue-laser sensitizers, thymoquinone and thymohydroquinone. Photo-excitation of thymoquinone and thymohydroquinone augmented reactive oxygen species production in bacteria while completely sparing the host tissue. [ABSTRACT FROM AUTHOR]

Bacterial or fungal membrane vesicles, traditionally considered as microbial metabolic wastes, are secreted mainly from the outer membrane or cell membrane of microorganisms. However, recent studies have shown that these vesicles play essential roles in direct or indirect communications among microorganisms and between microorganisms and hosts. This review aims to provide an updated understanding of the physiological functions and emerging applications of bacterial membrane vesicles, with a focus on their biogenesis, mechanisms of adsorption and invasion into host cells, immune stimulatory effects, and roles in the much‐concerned problem of bacterial resistance. Additionally, the potential applications of these vesicles as biomarkers, vaccine candidates, and drug delivery platforms are discussed. [ABSTRACT FROM AUTHOR]

Allergen specific immunotherapy has been shown to be the only effective treatment for long-lasting clinical benefit to IgE-mediated allergic diseases, but a fewer than 5% of patients choose the treatment because of inconvenience and a high risk of anaphylaxis. Recently, epicutaneous allergen-specific immunotherapy (EPIT) has proven effective, yet with limitations owing to strong skin reactions. We demonstrate here safer and faster EPIT, named μEPIT, by delivering powdered allergen and adjuvants into many micropores in the epidermis. We fabricated a microarray patch fractionally coated with a powder mixture of ovalbumin (OVA) model allergen, CpG, and 1,25-dihydroxyvitamin D 3 (VD3). Topical application of the patch onto laser-microperforated skin resulted in a high level of epidermal delivery while greatly minimizing allergen leakage into circulation system as compared to current subcutaneous immunotherapy (SCIT). Moreover, only three times of μEPIT over two weeks could sufficiently inhibit allergen-specific IgE responses in mice suffering OVA-induced airway hyperresponsivness (AHR), which was unattainable by eight times of SCIT over three weeks. Mechanistically, μEPIT preferably enhanced IgG2a production suggesting T H 1-biased immune responses and induced a high level of T-regulatory (Treg) cells against repeated allergen sensitization. The immune tolerance was confirmed by marked reduction in airway wall thickness as well as eosinophil and neutrophil infiltration into the respiratory airway. The μEPIT represents a novel and painless technology to treat IgE-mediated allergic diseases with little local skin reaction and a minimal risk of anaphylaxis. [ABSTRACT FROM AUTHOR]

Development of novel vaccine deliveries and vaccine adjuvants is of great importance to address the dilemma that the vaccine field faces: to improve vaccine efficacy without compromising safety. Harnessing the specific effects of laser on biological systems, a number of novel concepts have been proposed and proved in recent years to facilitate vaccination in a safer and more efficient way. The key advantage of using laser technology in vaccine delivery and adjuvantation is that all processes are initiated by physical effects with no foreign chemicals administered into the body. Here, we review the recent advances in using laser technology to facilitate vaccine delivery and augment vaccine efficacy as well as the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are hallmarked by cytopenia and dysplasia of hematopoietic cells, often accompanied by mitochondrial dysfunction and increases of reactive oxygen species (ROS) within affected cells. However, it is not known whether the increase in ROS production is an instigator or a byproduct of the disease. The present investigation shows that mice lacking immediate early responsive gene X-1 (IEX-1) exhibit lineage specific increases in ROS production and abnormal cytology upon radiation in blood cell types commonly identified in MDS. These affected cell lineages chiefly have the bone marrow as a primary site of differentiation and maturation, while cells with extramedullary differentiation and maturation like B- and T-cells remain unaffected. Increased ROS production is likely to contribute significantly to irradiation-induced thrombocytopenia in the absence of IEX-1 as demonstrated by effective reversal of the disorder after mitoquinone (MitoQ) treatment, a mitochondria-specific antioxidant. MitoQ reduced intracellular ROS production within megakaryocytes and platelets. It also normalized mitochondrial membrane potential and superoxide production in platelets in irradiated, IEX-1 deficient mice. The lineage-specific effects of mitochondrial ROS may help us understand the etiology of thrombocytopenia in association with MDS in a subgroup of the patients. [ABSTRACT FROM AUTHOR]

The current study details efficient lesion-free cutaneous vaccination via vaccine delivery into an array of micropores in the skin, instead of bolus injection at a single site. Such delivery effectively segregated vaccine-induced inflammation, resulting in rapid resolution of the inflammation, provided that distances between any two micropores were sufficient. When the inoculation site was treated by FDA-approved nonablative fractional laser (NAFL) before insertion of a PR8 model influenza vaccine-packaged, biodegradable microneedle array (MNs), mice displayed vigorous antigenuptake, eliciting strong Th1-biased immunity. These animals were completely protected from homologous viral challenges, and fully or partially protected from heterologous H1N1 and H3N2 viral challenges, whereas mice receiving MNs alone suffered from severe illnesses or died of similar viral challenges. NAFL-mediated adjuvanicity was ascribed primarily to dsDNA and other "danger" signals released from laser-damaged skin cells. Thus, mice deficient in dsDNA-sensing pathway, but not Toll like receptor (TLR) or inflammasome pathways, showed poor responses to NAFL. Importantly, with this novel approach both mice and swine exhibited strong protective immunity without incurring any appreciable skin irritation, in sharp contrast to the overt skin irritation caused by intradermal injections. The effective lesion-free cutaneous vaccination merits further clinical studies. [ABSTRACT FROM AUTHOR]

[Display omitted] Nanomedicine has grown structurally complex in order to perform multiple tasks at a time. However, their unsatisfied reliability, uniformity and reproducibility account for the high rates of attrition in translational research. So far, most studies have been one-sidedly focused on the treatment efficacy of inorganic nanoparticles as cancer therapeutics, but overlook their elimination from the body – a key factor in getting regulatory approval. Instead of developing a new drug nanocarrier with uncertain future in medical practice, we therefore choose to leverage the utility of promising and translatable gold nanoclusters (AuNCs) for designing a simple but robust "all-in-one" nanocluster drug delivery system, where the AuNCs not only strengthen the renal clearance of neutral red (NR) as a model drug, but also aid its passive tumor targeting via the enhanced permeability and retention (EPR) effect. More interestingly, NR can stimulate the production of reactive oxygen species (ROS) to suppress tumor growth under ultralow-level radiation with a smartphone's torch (fluence rate: 8 mW/cm2). This finding is especially valuable to low- and middle-income countries lacking resources in healthcare settings. By means of first-principles simulations, we also study in-depth the energies, structural and electronic properties of the AuNCs emitting in the second near-infrared window (NIR-II, 1000–1700 nm). In brief, our model fulfills safety, effectiveness and cost-effectiveness requirements for translational development. [ABSTRACT FROM AUTHOR]

Introduction: The potential for Bacille Calmette-Guerin vaccination to mitigate COVID-19 severity and perhaps infection susceptibility has been hypothesized, attracting global attention given its off-target benefits shown in several respiratory viral infections.Methods: In this retrospective study, patients with laboratory-confirmed COVID-19 from Wuhan Pulmonary Hospital, China were categorized into Bacille Calmette-Guerin‒vaccinated and nonvaccinated groups. Clinical records, demography, laboratory results, and chest computed tomography scans were extracted from electronic medical records and compared between the 2 groups.Results: No adverse events were observed, except for an increased frequency of chills in the Bacille Calmette-Guerin‒vaccinated group compared with that in the unvaccinated group (p=0.014). There were no significant differences in oxygen demand for breathing, computed tomography scans, treatments, or outcomes between the 2 groups. However, Bacille Calmette-Guerin‒vaccinated group had significantly less severe pneumonia (p=0.028) and milder deficiency in liver function, consistent with a lower death rate than in the unvaccinated group.Conclusions: Bacille Calmette-Guerin vaccination received in childhood is associated with less severe COVID-19 pneumonia and milder liver function deficiency in addition to a lower death rate in Bacille Calmette-Guerin‒vaccinated patients than in nonvaccinated individuals. [ABSTRACT FROM AUTHOR]

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to longterm adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of nontoxic photosensitizers with harmless visible light-producing cytotoxic reactive oxygen species. PDT causes apoptosis and necrosis of tumor cells, destruction of the tumor blood supply, and activation of the immune system. The objective of this study was to compare in an animal model of metastatic cancer PDT alone and PDT combined with low-dose cyclophosphamide (CV) a treatment that has been proposed to deplete regulatory T cells (T-regs) and increase the immune response to some tumors. We used J774 tumors (a highly metastatic reticulum cell sarcoma line) and PDT with benzoporphyrin derivative monoacid ring A, verteporfin for injection (BPD; 1-mg/kg injected i.v. followed after 15 mm by 150 J/cm² of 690-nm light). CV (50 or 150 mg/kg i.p.) was injected 48 h before light delivery. PDT alone led to tumor regressions and a survival advantage but no permanent cures were obtained. BPD-PDT in combination with low-dose CV (but not high-dose CV) led to 70% permanent cures. Low-dose CV alone gave no permanent cures but did provide a survival advantage and was shown to reduce CD4+FoxP3+ T-regs in lymph nodes, whereas high-dose CV reduced other lymphocyte classes as well. Cured animals were rechallenged with J774 cells, and the tumors were rejected in 71% of mice. Cured mice had tumor-specific T cells in spleens as determined by a 51Cr release assay. We conclude that low-dose CV depletes T-regs and potentiates BPD-PDT, leading to tumor cures and memory immunity. [ABSTRACT FROM AUTHOR]

The application of NIR‐II emitters for gastrointestinal (GI) tract imaging remains challenging due to fluorescence quenching in the digestive microenvironment. Herein, we report that red‐shifting of the fluorescence emission of Au nanoclusters (AuNCs) into NIR‐II region with improved quantum yields (QY) could be achieved by engineering a protein corona structure consisting of a ribonuclease‐A (RNase‐A) on the particle surfaces. RNase‐A‐encapsulated AuNCs (RNase‐A@AuNCs) displayed emissions at 1050 nm with a 1.9 % QY. Compared to rare earth and silver‐based NIR‐II emitters, RNase‐A@AuNCs had excellent biocompatibility, showing >50‐fold higher sensitivity in GI tract, and migrated homogenously during gastrointestinal peristalsis to allow visualization of the detailed structures of the GI tract. RNase‐A@AuNCs could successfully examine intestinal tumor mice from healthy mice, indicating a potential utility for early diagnosis of intestinal tumors. [ABSTRACT FROM AUTHOR]

The application of NIR‐II emitters for gastrointestinal (GI) tract imaging remains challenging due to fluorescence quenching in the digestive microenvironment. Herein, we report that red‐shifting of the fluorescence emission of Au nanoclusters (AuNCs) into NIR‐II region with improved quantum yields (QY) could be achieved by engineering a protein corona structure consisting of a ribonuclease‐A (RNase‐A) on the particle surfaces. RNase‐A‐encapsulated AuNCs (RNase‐A@AuNCs) displayed emissions at 1050 nm with a 1.9 % QY. Compared to rare earth and silver‐based NIR‐II emitters, RNase‐A@AuNCs had excellent biocompatibility, showing >50‐fold higher sensitivity in GI tract, and migrated homogenously during gastrointestinal peristalsis to allow visualization of the detailed structures of the GI tract. RNase‐A@AuNCs could successfully examine intestinal tumor mice from healthy mice, indicating a potential utility for early diagnosis of intestinal tumors. [ABSTRACT FROM AUTHOR]

Human umbilical cord blood (hUCB)-derived hematopoietic stem cells (HSCs) are an important source for HSCs in allogeneic HSC transplantation, but a limited number and a low efficacy of engraftment greatly restrict their clinical use. Here, we report the ability of photobiomodulation therapy (PBMT) to significantly enhance the engraftment efficacy of hUCB HSCs and progenitor cells (HSPCs). hUCB CD34+ cells were illuminated at a fluence of 2 J/cm2 with a near-infrared light (830 nm) transmitted by an array of light-emitting diodes (LED) prior to infusion of NOD/SCID-IL2Rγ−/− mice. The pre-treatment resulted in a threefold higher of the mean percentage of human CD45+ cells in the periphery of the mice compared to sham-treated CD34+ cells. The enhanced engraftment may result from a PBMT-mediated increase of intracellular reactive oxygen species (ROS) levels and Src protein phosphorylation in CD34+ cells. The two events were causally related as suggested by the finding that elevation of ROS by hydrogen peroxide increased Src phosphorylation, while ROS reduction by N-acetyl cysteine partially reversed the phosphorylation. The investigation demonstrates that PBMT can promote engraftment of hUCB HPSCs, at least in part, via ROS-mediated Src signaling pathway. PBMT can be potentially a safe, convenient, and cost-effective modality to improve hematological reconstitution in patients. [ABSTRACT FROM AUTHOR]

The application of NIR‐II emitters for gastrointestinal (GI) tract imaging remains challenging due to fluorescence quenching in the digestive microenvironment. Herein, we report that red‐shifting of the fluorescence emission of Au nanoclusters (AuNCs) into NIR‐II region with improved quantum yields (QY) could be achieved by engineering a protein corona structure consisting of a ribonuclease‐A (RNase‐A) on the particle surfaces. RNase‐A‐encapsulated AuNCs (RNase‐A@AuNCs) displayed emissions at 1050 nm with a 1.9 % QY. Compared to rare earth and silver‐based NIR‐II emitters, RNase‐A@AuNCs had excellent biocompatibility, showing >50‐fold higher sensitivity in GI tract, and migrated homogenously during gastrointestinal peristalsis to allow visualization of the detailed structures of the GI tract. RNase‐A@AuNCs could successfully examine intestinal tumor mice from healthy mice, indicating a potential utility for early diagnosis of intestinal tumors. [ABSTRACT FROM AUTHOR]

• CS-CDs were rapidly synthesized via microwave method with good water solubility and low toxicity. • CS-CDs had sufficient antibacterial activity against resistant bacteria in vivo. • CS-CDs exerted a good therapeutic effect on acute bloodstream infection. • CS-CDs can rapidly and quantitatively detect the number of bacteria in blood. • It provides a new idea for rapid clinical treatment and monitoring infection degree in patients. Cefminox sodium carbon nanodots were synthesized via a rapid one-step microwave method using cefminox sodium as sole precursor. The prepared cefminox sodium carbon nanodots had good water solubility and the diameter was concentrated at 1.29 ± 0.40 nm with relative uniform. They exhibited fluorescence excitation-dependent property, of which optimal excitation wavelength was ∼ 390 nm, and optimal emission wavelength was ∼ 465 nm. As retained part of the structure and antibacterial properties of cefminox sodium, cefminox sodium carbon nanodots had low biological toxicity and sufficient antibacterial activity against bacteria in vitro. In vivo experiments demonstrated cefminox sodium carbon nanodots could exert a good therapeutic effect on acute bloodstream infection. In the mixed solution (Escherichia coli , blood and cefminox sodium carbon nanodots), the fluorescent intensity exhibited quadratic functional relationship with the concentration of Escherichia coli. The detection concentration range for Escherichia coli was 0.5 × 106 ∼ 1 × 109 CFU/mL, and the detection limit was 3.7 × 105 CFU/mL. It suggested cefminox sodium carbon nanodots can rapidly and quantitatively detect the number of Escherichia coli in blood while effectively treating bloodstream infection. Due to the long period of clinical detection time (about 1–5 days or more) for bacterial counts in the blood of patients, this method provides a new strategy for rapid clinical treatment and effective monitoring of the degree of infection in patients. [ABSTRACT FROM AUTHOR]

Background: Platelets for transfusion become senescent and dysfunctional during storage, resulting in a markedly short shelf life (5 days). We hypothesized that oxidative stress might account for this decline.Study Design and Methods: Human platelets were treated with or without antioxidants before storage, and samples were collected and analyzed at different time points. Platelet senescence was determined by senescence-associated β-galactosidase assay, and senescence-related platelet qualities were also analyzed.Results: Sign of senescence became evident after Day 3 and continued to increase over time. We also found that chemical induction of platelet activation did not affect senescence level, whereas apoptosis inducers showed a stimulative effect on platelet senescence. Moreover, this effect was not prevented by a pan-caspase inhibitor. Meanwhile, cellular and mitochondrial reactive oxygen species were found elevated during storage, and treatments with antioxidants successfully prevented this increase and also mitigated senescence levels of stored platelets. Finally, resveratrol, a natural antioxidant, was utilized as a novel storage additive to safely extend platelet shelf time. We showed that the addition of resveratrol efficiently postponed platelet senescence and ameliorated platelet storage lesion.Conclusions: Platelets during storage became senescent and dysfunctional over time, and we found that oxidative stress might account for this decline. The addition of antioxidants effectively postponed senescence and ameliorated platelet storage lesion, which might provide a valuable reference to future platelet storage methodologies. [ABSTRACT FROM AUTHOR]

Abstract Grass carp (Ctenopharyngodon idellus) hemorrhagic disease (GCHD), caused by grass carp reovirus (GCRV), has given rise to an enormous loss in grass carp industry during the past years. Up to date, vaccination remained to be the most effective way to protect grass carp from GCHD. Oral vaccination is of major interest due to its advantages of noninvasive, time-saving, and easily-operated. The introduction of oral vaccination has profound impact on aquaculture industry because of its feasibility of extensive application for fish in various size and age. However, the main challenge in developing oral vaccine is that antigens are easily degraded and are easy to induce tolerance. Bacillus subtilis (B. subtilis) spores would be an ideal oral vaccine delivery system for their robust specialty, gene operability, safety and adjuvant property. VP4 protein is the major outer capsid protein encoded by GCRV segment 6 (S6), which plays an important role in viral invasion and replication. In this study, we used B. subtilis spores as the oral delivery system and successfully constructed the B. subtilis CotC-VP4 recombinant spores (CotC-VP4 spores) to evaluate its protective efficacy in grass carp. Grass carp orally immunized with CotC-VP4 spores showed a survival rate of 57% and the relative percent survival (RPS) of 47% after the viral challenge. Further, the specific IgM levels in serum and the specific IgZ levels in intestinal mucus were significantly higher in the CotC-VP4 group than those in the Naive group. The immune-related genes including three innate immune-related genes (IL-4/13A, IL-4/13B, CSF1R), four adaptive immune-related genes (BAFF, CD4L, MHC-II, CD8), three inflammation-related genes (IL-1β, TNF-α, TGF-β) and interferon type I (IFN-I) related signaling pathway genes were significantly up-regulated in the CotC-VP4 group. The study demonstrated that the CotC-VP4 spores produced protection in grass carp against GCRV infection, and triggered both innate and adaptive immunity post oral immunization. This work highlighted that Bacillus subtilis spores were powerful platforms for oral vaccine delivery, and the combination of Bacillus subtilis spores with GCRV VP4 protein was a promising oral vaccine. Highlights • Successful construction of Bacillus subtilis spores expressing GCRV VP4 protein. • Recombinant spores showed an effective protection against GCRV infection in fish. • The viral load was reduced after immunization with recombinant spores in fish. • Recombinant spores significantly triggered innate and adaptive immunity of fish. [ABSTRACT FROM AUTHOR]

Live attenuated Bacille Calmette–Guerin (BCG) bacillus is the only licensed vaccine for tuberculosis prevention worldwide to date. It must be delivered intradermally to be effective, which causes severe skin inflammation and sometimes, permanent scars. To minimize the side effects, we developed a novel microneedle array (MNA) that could deliver live attenuated freeze-dried BCG powder into the epidermis in a painless, lesion-free, and self-applicable fashion. The MNA was fabricated with biocompatible and dissolvable hyaluronic acid with a deep cave formed in the basal portion of each microneedle, into which BCG powder could be packaged directly. Viability of BCG vaccine packaged in the caves and the mechanical strength of the powder-laden MNA did not alter significantly before and after more than two months of storage at room temperature. Following insertion of the MNA into the skin, individual microneedle shafts melted away by interstitial fluid from the epidermis and upper dermis, exposing the powder to epidermal tissues. The powder sucked interstitial fluid, dissolved slowly, and diffused into the epidermis in a day against the interstitial fluid influx. Vaccination with BCG-MNA caused no overt skin irritation, in marked contrast to intradermal vaccination that provoked severe inflammation and bruise. While causing little skin irritation, vaccination efficacy of BCG-MNAs was comparable to that of intradermal immunization whether it was evaluated by humoral or cellular immunity. This powder-laden and dissolvable MNA represents a novel technology to sufficiently deliver live attenuated vaccine powders into the skin. [ABSTRACT FROM AUTHOR]

Transdermal delivery of hydrophilic drugs is challenging. This study presents a novel sustained epidermal powder delivery technology (sEPD) for safe, efficient, and sustained delivery of hydrophilic drugs across the skin. sEPD is based on coating powder drugs into high-aspect-ratio, micro-coating channels (MCCs) followed by topical application of powder drug-coated array patches onto ablative fractional laser-generated skin MCs to deliver drugs into the skin. We found sEPD could efficiently deliver chemical drugs without excipients and biologics drugs in the presence of sugar excipients into the skin with a duration of ~ 12 h. Interestingly the sEPD significantly improved zidovudine bioavailability by ~ 100% as compared to oral gavage delivery. sEPD of insulin was found to maintain blood glucose levels in normal range for at least 6 h in chemical-induced diabetes mice, while subcutaneous injection failed to maintain blood glucose levels in normal range. sEPD of anti-programmed death-1 antibody showed more potent anti-tumor efficacy than intraperitoneal injection in B16F10 melanoma models. Tiny skin MCs and ‘bulk’ drug powder inside relatively deep MCCs are crucial to induce the sustained drug release. The improved bioavailability and functionality warrants further development of the novel sEPD for clinical use. [ABSTRACT FROM AUTHOR]

Background: Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion.Methods: To address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration.Results: We detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent S1P normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site.Conclusions: Decreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. [ABSTRACT FROM AUTHOR]

Vascular damage occurs frequently at the injured brain causing hypoxia and is associated with poor outcomes in the clinics. We found high levels of glycolysis, reduced adenosine triphosphate generation, and increased formation of reactive oxygen species and apoptosis in neurons under hypoxia. Strikingly, these adverse events were reversed significantly by noninvasive exposure of injured brain to low-level light (LLL). Low-level light illumination sustained the mitochondrial membrane potential, constrained cytochrome c leakage in hypoxic cells, and protected them from apoptosis, underscoring a unique property of LLL. The effect of LLL was further bolstered by combination with metabolic substrates such as pyruvate or lactate both in vivo and in vitro. The combinational treatment retained memory and learning activities of injured mice to a normal level, whereas other treatment displayed partial or severe deficiency in these cognitive functions. In accordance with well-protected learning and memory function, the hippocampal region primarily responsible for learning and memory was completely protected by combination treatment, in marked contrast to the severe loss of hippocampal tissue because of secondary damage in control mice. These data clearly suggest that energy metabolic modulators can additively or synergistically enhance the therapeutic effect of LLL in energy-producing insufficient tissue-like injured brain. [ABSTRACT FROM AUTHOR]

Surface modified microneedle (MN) arrays are being developed to capture circulating biomarkers from the skin, but inefficiency and unreliability of the current method limit its clinical applications. We describe here that illumination of a tiny area of the skin with hemoglobin-preferably absorbent laser increased the amount of circulating biomarkers in the upper dermis by more than 1000-fold. The hemoglobin-specific light altered the permeability of capillaries leading to extravasation of molecules but not blood cells beneath the skin involved. When specific probe-coated MN arrays were applied into the laser-treated skin, the biomarkers accumulated in the upper dermis were reliably, accurately, and sufficiently captured as early as 15 min of the assay. The maximal binding occurred in 1 h in a manner independent of penetration depth or a molecular mass of the biomarker. With anti-fluorescein isothiocyanate (FITC)-MNs, we were able to measure blood concentrations of FITC in mice receiving FITC intravenously. The sensitivity and accuracy were comparable to those attained by fluorescence spectrophotometer. Likewise, MNs containing influenza hemagglutinin (HA) could detect anti-HA antibody in mice or swine receiving influenza vaccines as effectively as standard immunoassays. The novel, minimally invasive approach holds great promise for measurement of multiple biomarkers by a single array for point-of-care diagnosis. [ABSTRACT FROM AUTHOR]

Fewer antibiotics are available for effective management of bacterial infections to date owing to increasing multiple-drug resistance (MDR). Here, we expand our early success in combination of 405 nm blue light irradiation with phenolic compounds to sufficiently kill blue light-refractory MDR Escherichia coli (E. coli). p-Toluquinone (p-TQ) alongside blue light inactivated 7.3 log 10 E. coli within 6 min, whereas either alone was totally ineffective. A similar killing efficacy was attained with four other pathogens commonly seen in hospital-acquired infections and Enterococcus faecalis (Ef) that don't produce porphyrins-like molecules. The combinatory therapy prevented recurrence of E. coli infection in skin scratch wounds of murine. The bactericidal activity was ascribed to reactive oxygen species (ROS) generation triggered by blue light-mediated excitation of p-TQ, which is less likely to induce resistance because of multi-targeted and non-specific nature of ROS. Remarkably, toxic p-TQ became harmless to mammalian cells after brief exposure to blue light while retaining its bactericidal activity. The opposite effect of blue light on p-TQ activity unravels a novel, simple strategy to detoxify p-TQ and its combination with blue light as a safe and efficacious bactericidal modality for managing MDR bacterial infections. • p-TQ's toxicity to mammalian cells is diminished significantly after brief exposure to blue light. • The detoxified p-TQ retains its broad-spectrum bactericidal activity. • The bactericidal activity is ascribed to robust ROS generation triggered by blue light excitation of p-TQ. [ABSTRACT FROM AUTHOR]

Immunization with radiation-attenuated sporozoites (RAS) via mosquito bites has been shown to induce sterile immunity against malaria in humans, but this route of vaccination is neither practical nor ethical. The importance of delivering RAS to the liver through circulation in eliciting immunity against this parasite has been recently verified by human studies showing that high-level protection was achieved only by intravenous (IV) administration of RAS, not by intradermal (ID) or subcutaneous (SC) vaccination. Here, we report in a murine model that ID inoculation of RAS into laser-illuminated skin confers immune protection against malarial infection almost as effectively as IV immunization. Brief illumination of the inoculation site with a low power 532 nm Nd:YAG laser enhanced the permeability of the capillary beneath the skin, owing to hemoglobin-specific absorbance of the light. The increased blood vessel permeability appeared to facilitate an association of RAS with blood vessel walls by an as-yet-unknown mechanism, ultimately promoting a 7-fold increase in RAS entering circulation and reaching the liver over ID administration. Accordingly, ID immunization of RAS at a laser-treated site stimulated much stronger sporozoite-specific antibody and CD8 + IFN-γ + T cell responses than ID vaccination and provided nearly full protection against malarial infection, whereas ID immunization alone was ineffective. This novel, safe, and convenient strategy to augment efficacy of ID sporozoite-based vaccines warrants further investigation in large animals and in humans. [ABSTRACT FROM AUTHOR]

A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1β and IL-6 but upregulated TNF-α. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT. [ABSTRACT FROM AUTHOR]

The stress-inducible immediate early response gene X-1 (IEX-1) regulates cell proliferation and apoptosis in a cell type and stimulus-dependent manner. The aim of this study was to investigate IEX-1 expression in preeclampsia placenta and human umbilical vein endothelial cells (HUVECs) cultured in the serum isolated from preeclampsia patients, to explore its relationship with the pathogenesis of preeclampsia. Thirty preeclampsia patients with 10 cases in the moderate group, 20 cases in the severe group (PE group) and 20 cases of normal pregnant women (control group) were randomly obtained. Reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that IEX-1 expression was significantly higher in preeclampsia patients than in normal pregnant women ( p < 0.05). There was also a significant difference between moderate and severe preeclampsia ( p < 0.05). IEX-1 protein was mainly present in cytoplasm of placental trophoblast cells and decidual cells. Compared with the normal pregnancy group, IEX-1 in the preeclampsia group was colored more obviously, and the color was strengthened in correlation with the severity of the disease using immunocytochemial method. Flow cytometry and MTT revealed that the serum isolated from preeclampsia patients appeared to promote IEX-1 expression in cytoplasm of HUVECs, inhibited the proliferation and promoted the apoptosis of HUVECs when compared to the serum of normal pregnant women. Our study demonstrates a correlation of IEX-1 expression levels with the severity of preeclampsia. Given a well-known function of IEX-1 in regulation of apoptosis, IEX-1 may be important in the pathogenesis of preeclampsia by regulating placental villous trophoblast and decidual cell apoptosis as well as participation in endothelial cell injury process. [ABSTRACT FROM AUTHOR]

Abstract: An altered redox status and increased lymphocyte apoptosis have been implicated in the development of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between glutathione (GSH) depletion, reactive oxygen species (ROS) and, the progression of apoptosis and their association with SLE severity. Significant low levels of intracellular glutathione, total thiol and altered redox state (GSH/GSSG) were found in SLE patients, in which lymphocyte apoptosis and activated caspase-3 expression in the lymphocytes were remarkably increased. The severity of disease was positively allied with the increased levels of lymphocyte apoptosis and caspase-3, but negatively with the decreased levels of total thiol, depleted intracellular glutathione and altered redox state (GSH/GSSG). The lymphocyte apoptosis and activated caspase-3 expression were negatively associated with intracellular levels of GSH and redox state and positively associated with the elevated levels of multiple oxidative stress markers; ROS and lipid peroxidation measured as malondialdehyde (MDA). These results suggest that GSH depletion and elevated oxidative stress trigger apoptosis and may be coupled with the severity of the disease. [Copyright &y& Elsevier]

Abstract: Immunotherapy for tobacco addiction may offer a safe, alternative treatment if the immunogenicity of the current nicotine vaccines can be improved. We show here that intradermal (ID) immunization induces the production of antibody directed against nicotine (NicAb) at a much higher level than conventional intramuscular (IM) immunization. The magnitude and duration of NicAb production was further increased robustly by non-inflammatory laser vaccine adjuvant (LVA), slightly inflammatory monophosphoryl lipid A (MPL) or a combination of MPL and CpG adjuvants. Consequently, significantly fewer vaccination doses were required to attain a high level of NicAb production for an extended period of time and reduce nicotine entry into the brain in the presence of LVA, MPL or MPL/CpG adjuvant, respectively. Yet, the potency of these adjuvants to augment ID nicotine vaccine immunogenicity came at the expense of local skin reactogenicity, with LVA causing little skin reaction and MPL/CpG stimulating overt skin irritation. These observations underscore a necessity of a balance between optimal adjuvant potency and undesired local reactogenicity. In summary, our study presents a novel approach to significantly improve nicotine vaccine immunogenicity by a combination of safe cutaneous vaccine adjuvants with ID immunization. [Copyright &y& Elsevier]

CD4+ Thl and Th17 cells both can cause autoimmune diseases, either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains poorly understood. Our present investigation shows that null mutation of 1EX-1 promotes differentiation of Thl7 cells but compromises the survival of Thl cells. The differential effect gave rise to a greater number of Thl7 cells, a higher level of IL-17 production, and more severe arthritis in IEX-1 knockout mice than in wild-type mice after immunizations with collagen. IEX-1 deficiency-facilitated Thl7 cell differentiation was mediated by the increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Thl7 induction with ROS scavenger ¿V-acetylcysteine or mitoquinone, a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B cell-activating transcription factor, which may contribute to increased IL-17 production in the absence of IEX-1, in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the cytokine milieu. [ABSTRACT FROM AUTHOR]

Abstract: Full-surface laser ablation has been shown to efficiently disrupt stratum corneum and facilitate transcutaneous drug delivery, but it is frequently associated with skin damage that hampers its clinic use. We show here that a safer ablative fractional laser (AFL) can sufficiently facilitate delivery of not only patch-coated hydrophilic drugs but also protein vaccines. AFL treatment generated an array of self renewable microchannels (MCs) in the skin, providing free paths for drug and vaccine delivery into the dermis while maintaining integrity of the skin by quick healing of the MCs. AFL was superior to tape stripping in transcutaneous drug and vaccine delivery as a much higher amount of sulforhodamine B (SRB), methylene blue (MB) or a model vaccine ovalbumin (OVA) was recovered from AFL-treated skin than tape-stripped skin or control skin after patch application. Following entry into the MCs, the drugs or OVA diffused quickly to the entire dermal tissue via the lateral surface of conical-shaped MCs. In contrast, a majority of the drugs and OVA remained on the skin surface, unable to penetrate into the dermal tissue in untreated control skin or tape stripping-treated skin. Strikingly, OVA delivered through the MCs was efficiently taken up by epidermal Langerhans cells and dermal dendritic cells in the vicinity of the MCs or transported to the draining lymph nodes, leading to a robust immune response, in sharp contrast to a weak, though significant, immune response elicited in tape stripping group or a basal immune response in control groups. These data support strongly that AFL is safe and sufficient for transcutaneous delivery of drugs and vaccines. [Copyright &y& Elsevier]

Background: The stress-inducible immediate early response gene X-1 (IEX-1) regulates cell proliferation and apoptosis in a cell type and stimulus-dependent manner. The aim of this study was to investigate IEX-1 expression and its role in apoptosis of ovarian epithelial tumors for potential use in clinical diagnosis and therapy. Methods: IEX-1 expression was examined in paraffin-embedded specimens from 77 patients with epithelial ovarian tumors using immunohistochemistry. Correlation between IEX-1 expression and other clinicopathological parameters was evaluated. Apoptosis of tumor cells was detected by terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL). Results: IEX-1 expression was significantly lower in ovarian cancers compared to cystadenomas and borderline tumors ( p < .05). The expression was significantly associated with FIGO stage and histological grade ( p < .05), but not with age, histological type, or residual tumor ( p > .05). A positive correlation was also observed between IEX-1 expression and apoptotic index ( p < .01) or survival ( p == .005). Conclusion: With the development of epithelial ovarian tumors from benign to malignant, IEX-1 expression is decreased, concomitant with a decreased rate of cell apoptosis. Thus, IEX-1 is pro-apoptotic in the development of epithelial ovarian cancer. The pro-apoptotic activity may take part in restraining tumor growth at the early stage of ovarian epithelial cancer, whereas its decreased expression probably contributes to the abnormal survival advantage for malignant cancer. Altered IEX-1 expression can potentially be a new predictor of the malignant transformation and a prognostic indicator for cancer therapy. [ABSTRACT FROM AUTHOR]

Egress of lymphocytes from lymphoid tissues is a complex process in which Gαi-mediated signals play a decisive role. We show here that although FTY720, an agonist of the sphingosine 1-phosphate (S1P)(1) receptor, induces S1P(1) receptor internalization sufficiently in the presence or absence of Gαi2 or Gαi3, the drug blocks egress of wild-type (WT) and Gαi3-deficent T cells, but not Gαi2-deficient T cells, in both WT and Gαi2-deficient hosts. Intravital imaging of lymph nodes revealed that all three groups of T cells approached and engaged cortical sinusoids similarly in the presence or absence of FTY720. The cells also entered and departed the sinus at an almost identical frequency in the absence of the drug. However, after engagement of the sinus, most WT and Gαi3-deficient T cells retracted and migrated back into the parenchyma in FTY720-treated animals, due to a failure of the cells to establish adhesion on the sinus, whereas Gαi2-deficient T cells adhered firmly on the sinus, which prevented their retraction, facilitating their transmigration of the lymphatic endothelial barrier. These data confirm egress of Gαi2-/- T cells independent of S1P-mediated chemotaxis and failure of FTY720 to close lymphatic stromal channels and argue for the first time, to our knowledge, that FTY720 induces lymphopenia in part by impairing T cell adhesion to the sinus in a manner dependent on Gαi2. [ABSTRACT FROM AUTHOR]

Background: Development of a potent vaccine adjuvant without introduction of any side effects remains an unmet challenge in the field of the vaccine research. Methodology/Principal Findings: We found that laser at a specific setting increased the motility of antigen presenting cells (APCs) and immune responses, with few local or systemic side effects. This laser vaccine adjuvant (LVA) effect was induced by brief illumination of a small area of the skin or muscle with a nondestructive, 532 nm green laser prior to intradermal (i.d.) or intramuscular (i.m.) administration of vaccines at the site of laser illumination. The pre-illumination accelerated the motility of APCs as shown by intravital confocal microscopy, leading to sufficient antigen (Ag)-uptake at the site of vaccine injection and transportation of the Ag-captured APCs to the draining lymph nodes. As a result, the number of Ag+ dendritic cells (DCs) in draining lymph nodes was significantly higher in both the 1° and 2° draining lymph nodes in the presence than in the absence of LVA. Laser-mediated increases in the motility and lymphatic transportation of APCs augmented significantly humoral immune responses directed against a model vaccine ovalbumin (OVA) or influenza vaccine i.d. injected in both primary and booster vaccinations as compared to the vaccine itself. Strikingly, when the laser was delivered by a hair-like diffusing optical fiber into muscle, laser illumination greatly boosted not only humoral but also cell-mediated immune responses provoked by i.m. immunization with OVA relative to OVA alone. Conclusion/Significance: The results demonstrate the ability of this safe LVA to augment both humoral and cell-mediated immune responses. In comparison with all current vaccine adjuvants that are either chemical compounds or biological agents, LVA is novel in both its form and mechanism; it is risk-free and has distinct advantages over traditional vaccine adjuvants. [ABSTRACT FROM AUTHOR]

The article presents a study regarding safe and effective hemoglobin-based oxygen carrier (HBOC) as a substitute for erythrocyte transfusion. It says that HBOC ideally would provide oxygen transport to vital tissues and organs after major hemorrhage in which its clinical application has been hindered due the effects of nitric oxide scavenging. An analysis of the hemodynamic effects of the infusion of PolyHeme to awake healthy lambs and mice, and anesthetized mice is made. The analysis obtained a cumulative dose-tension response through sequential addition of PolyHeme. Results of the study show that animal testings of HBOCs having endothelial dysfunction can offer a more sensitive indication of potential vasoconstrictor effects.

G protein-coupled receptors (GPCRs) convey extracellular stimulation into dynamic intracellular action, leading to the regulation of cell migration and differentiation. T lymphocytes express Gαi2 and Gαi3, two members of the Gαi/o protein family, but whether these two Gαi proteins have distinguishable roles guiding T cell migration remains largely unknown because of a lack of member-specific inhibitors. This study details distinct Gαi2 and Gαi3 effects on chemokine receptor CXCR3-mediated signaling. Our data showed that Gαi2 was indispensable for T cell responses to three CXCR3 ligands, CXCL9, CXCL10, and CXCL11, as the lack of Gαi2 abolished CXCR3-stimulated migration and guanosine 5′-3-O-(thio)triphosphate (GTPγS) incorporation. In sharp contrast, T cells isolated from Gαi3 knock-out mice displayed a significant increase in both GTPγS incorporation and migration as compared with wild type T cells when stimulated with CXCR3 agonists. The increased GTPγS incorporation was blocked by Gαi3 protein in a dose-dependent manner. Gαi3-mediated blockade of Gαi2 activation did not result from Gαi3 activation, but instead resulted from competition or steric hindrance of Gαi2 interaction with the CXCR3 receptor via the N terminus of the second intracellular loop. A mutation in this domain abrogated not only Gαi2 activation induced by a CXCR3 agonist but also the interaction of Gαi3 to the CXCR3 receptor. These findings reveal for the first time an interplay of Gαi proteins in transmitting G protein-coupled receptor signals. This interplay has heretofore been masked by the use of pertussis toxin, a broad inhibitor of the Gαi/o protein family. [ABSTRACT FROM AUTHOR]

IEX-1 (immediate early response gene X-1) is a stress-inducible gene. Its overexpression can suppress or enhance apoptosis dependent on the nature of stress, yet the polypeptide does not possess any of the functional domains that are homologous to those present in well characterized effectors or inhibitors of apoptosis. This study using sequence-targeting mutagenesis reveals a transmembrane-like integrated region of the protein to be critical for both pro-apoptotic and anti-apoptotic functions. Substitution of the key hydrophobic residues with hydrophilic ones within this region impairs the capacity IEX-1 to positively and negatively regulate apoptosis. Mutations at N-linked glycosylation and phosphorylation sites or truncation of the C terminus of IEX-1 also abrogated its potential to promote cell survival. However, distinguished from the transmembrane-like domain, these mutants preserved pro-apoptotic activity of IEX-1 fully. On the contrary, mutation of nuclear localization sequence, despite its importance in apoptosis, did not impede IEX-1-mediated cell survival. Strikingly, all the mutants that lose their anti-apoptotic ability are unable to prevent acute increases in production of intracellular reactive oxygen species (ROS) at the initial onset of apoptosis, whereas those mutants that can sustain anti-death function also control acute ROS production as sufficiently as wild-type IEX-1, These findings suggest a critical role of IEX-1 in regulation of intracellular ROS homeostasis, providing new insight into the mechanism underlying IEX-1-mediated cell survival. [ABSTRACT FROM AUTHOR]

Inhibition of apoptosis or abnormal cell survival can result in tumorigenesis by facilitating the insurgence of various mutations. Immediate-early response gene X-1 (IEX-1), protects T cells from apoptosis induced by the ligation of Fas or the T-cell receptor (TCR)/CD3 complex in Eµ-IEX-1 mice that direct the gene expression in both T and B cell lineages under the control of the Eµ enhancer. Consistent with a biased effect of IEX-1 towards T cells, Eµ-IEX-1 mice selectively developed T-cell lymphomas in the spleen, when they aged, which may be associated with increased levels of IEX-1 phosphorylation in T cells compared to B cells. The lymphomas were single positive (CD4+CD8-, CD4-CD8+), double positive (CD4+CD8+), or double negative (CD4-CD8-) T cells. They resulted from aberrantly clonal expansions of T cells expressing a specific TCR, as suggested by the TCR repertoire analysis using a panel of monoclonal antibodies recognizing TCR Vß chain, as well as by TCR ß gene rearrangements. The study provides, for the first time, unambiguous evidence of the oncogenic potential of IEX-1 in a cell-specific manner. The animal model may help our understanding of peripheral T-cell lymphoma development.Oncogene (2003) 22, 6845-6851. doi:10.1038/sj.onc.1206707 [ABSTRACT FROM AUTHOR]

Provides information on a study that examined how transcription factors Nf-κB/rel proteins, p53 and c-Myc coordinarily control immediate early response gene X-1 expression. Results and discussion; Materials and methods used.

Examines the apoptosis, immune responses, and autoimmune disease in transgenic mice. Observation on the expression of Immediate Early response gene X-1 (IEX-1); Effect of transgenic expression of IEX-1 on apoptosis in activated cells, immune response, and accumulation of T cells; Role of IEX-1 in regulating T cell homeostasis.

The article presents a research related to pulmonary surfactant–biomimetic nanoparticles which potentiate heterosubtypic influenza immunity. Topics discussed include Type I interferons (IFN-Is) as the chief immune mediators for protective immunity against viral infections, activation of stimulator of interferon genes (STING) and challenge in delivery of STING agonists into the cytosol of alveolar epithelial cells (AECs) without breaching the integrity of the pulmonary surfactant (PS) layer.