Structural Basis of the Mechanisms of Action and Immunity of Lactococcin A, a Class IId Bacteriocin.

Lactococcin A (LcnA), a class IId bacteriocin, induces membrane leakage and cell death by specifically binding to the membrane receptor-mannose phosphotransferase system (man-PTS), as is the case for pediocin-like (class IIa) bacteriocins. The cognate immunity protein of bacteriocins, which protects the producer cell from its own bacteriocin, recognizes and binds to the bacteriocin-man-PTS complex, consequently blocking membrane leakage. We previously deciphered the mode of action and immunity of class IIa bacteriocins. Here, we determined the structure of the ternary complex of LcnA, LciA (i.e., the immunity protein), and its receptor, i.e., the man-PTS of Lactococcus lactis (ll-man-PTS). An external loop on the membrane-located component IIC of ll-man-PTS was found to prevent specific binding of the N-terminal region of LcnA to the site recognized by pediocin-like bacteriocins. Thus, the N-terminal ß-sheet region of LcnA recognized an adjacent site on the extracellular side of ll-man-PTS, with the LcnA C-terminal hydrophobic helix penetrating into the membrane. The cytoplasmic cleft formed within the man-PTS Core and Vmotif domains induced by embedded LcnA from the periplasmic side is adopted by the appropriate angle between helices H3 and H4 of the N terminus of LciA. The flexible C terminus of LciA then blocks membrane leakage. To summarize, our findings reveal the molecular mechanisms of action and immunity of LcnA and LciA, laying a foundation for further design of class IId bacteriocins. IMPORTANCE Class IId (lactococcin-like) bacteriocins and class IIa (pediocin-like) bacteriocins share a few similarities: (i) both induce membrane leakage and cell death by specifically binding the mannose phosphotransferase system (man-PTS) on their target cells, and (ii) cognate immunity proteins recognize and bind to the bacteriocin-man-PTS complex to block membrane leakage. However, class IId bacteriocins lack the "pediocin box" motif, which is typical of class IIa bacteriocins, and basically target only lactococcal cells; in contrast, class IIa bacteriocins target diverse bacterial cells, but not lactococcal cells. We previously solved the structure of class IIa bacteriocin-receptor-immunity ternary complex from Lactobacillus sakei. Here, we determined the structure of the ternary complex of class IId bacteriocin LcnA, its cognate immunity protein LciA, and its receptor, the man-PTS of Lactococcus lactis. By comparing the interactions between man-PTS and class IIa and class IId bacteriocins, this study affords some clues to better understand the specificity of bacteriocins targeting the mannose phosphotransferase system.

Dietary polyphenol oleuropein and its metabolite hydroxytyrosol are moderate skin permeable elastase and collagenase inhibitors with synergistic cellular antioxidant effects in human skin fibroblasts.

Oleuropein (OLE) and hydroxytyrosol (HT) are dietary polyphenols with skin beneficial effects but their effects on skin-ageing-related enzymes are not clear. Herein, we evaluated their inhibitory effects on elastase and collagenase. OLE and HT (62.5-1 000 µM) showed moderate anti-elastase and anti-collagenase effects (5.1-26.3%, 5.8-12.2% and 12.6-31.0%, 11.6-31.9% inhibition, respectively). Combinations of OLE and HT (1:1 ratio) exerted synergistic inhibitory effects on elastase, which were supported by their combination index (CI), kinetic assay and computational docking. Moreover, HT (100 µM) reduced hydrogen peroxide (H2O2)-induced cytotoxicity and reactive oxygen species (ROS) in human dermal fibroblast cells by 21.8 and 15.2%, respectively. In addition, combinations of OLE and HT (6.25/6.25-100/100 µM) exerted synergistic cytoprotective effects by reducing ROS levels by 7.6-37.3% with CIs of 0.17-0.44, respectively. The findings from this study support the cosmeceutical activities of OLE and HT but further research is warranted to evaluate their anti-skin-ageing effects using in vivo models.

Fibroblast growth factor inducible 14 signaling facilitates anti-dsDNA IgG penetration into mesangial cells.

Anti-double-stranded DNA (dsDNA) antibodies induce renal damage in patients with systemic lupus erythematosus by triggering fibrotic processes in kidney cells. However, the precise mechanism underlying penetration of anti-dsDNA immunoglubolin G (IgG) into cells remains unclear. This study was designed to investigate the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible 14 (Fn14) signaling on anti-dsDNA IgG penetration into cells. Mesangial cells were cultured in vitro, and stimulated with TWEAK and anti-dsDNA IgG. The results revealed that TWEAK dose-dependently enhanced cellular internalization of anti-dsDNA IgG and the expression of high-mobility group box 1 (HMGB1). In addition, TWEAK and anti-dsDNA IgG synthetically downregulate suppressor of cytokine signaling 1, and induce the expression of various fibrotic factors. Furthermore, inhibition of HMGB1 attenuates the enhancement effect of TWEAK on anti-dsDNA IgG internalization. The TWEAK upregulation of HMGB1 involves the nuclear factor-κB and phosphatidylinositide 3-kinase/protein kinase B pathways. Therefore, TWEAK/Fn14 signaling contributes to the penetration of anti-dsDNA IgG and relevant fibrotic processes in mesangial cells.

ApSerpin-ZX from Agapanthus praecox, is a potential cryoprotective agent to plant cryopreservation.

Cryopreservation-induced cell death is regarded as an important problem faced by cryobiologists. Oxidative stress and programmed cell death are detrimental to cell survival. Serine protease inhibitors (serpins) inhibit pro-cell-death proteases and play a pro-survival role in excessive cell death induced by abiotic stress. In this study, ApSerpin-ZX was isolated from Agapanthus praecox and characterized as a protective protein in plant cryopreservation. The mRNA level of ApSerpin-ZX was elevated under abiotic stress, such as salt, osmosis, oxidative, cold, and cryoinjury. The purified recombinant protein expressed in E. coli was added to the plant vitrification solution and used for A. praecox embryogenic callus cryopreservation. The concentration of 0.6-4.8 mg∙L-1 of ApSerpin-ZX protein was beneficial to the survival of cryopreserved embryogenic callus of A. praecox. The most effective concentration was 1.2 mg∙L-1, which elevated the survival by 37.15%. Subsequently, the cryopreservation procedure with 1.2 mg∙L-1 of ApSerpin-ZX protein was regarded as the treated group, compared to standard procedure, to determine the physiological mechanism of ApSerpin-ZX protein on cryopreserved cell. The MDA and H2O2 contents were significantly decreased in the treated group, along with reduced OH· generation activity in the recovery stage. After the addition of ApSerpin-ZX, the POD and CAT activities keep increased, while SOD activity increased only after dehydration. Besides, the caspase-1-like and caspase-3-like activities were lower than the standard procedure. This study indicated that ApSerpin-ZX was a potential cryoprotective agent that alleviated oxidative stress and cell death induced by cryopreservation.

A novel WO3/graphene composite using poly(ionic liquid) as a linker for enhanced supercapacitive performance.

WO3 has attracted widespread attention as an important semiconductor for supercapacitors. However, applications of WO3 are limited by its poor performance regarding capacitance and conductivity. In this paper, a novel method is presented for preparing a WO3/reduced graphene oxide (RGO) composite, based on poly(ionic liquid) (PIL) as a linker. PIL enables a tight contact between WO3 and graphene to exploit the excellent electrical conductivity of graphene. Results of the morphology for the as-prepared WO3/PIL/RGO composite indicate that the WO3 nanoparticles are distributed uniformly on the surface of the RGO. The WO3/PIL/RGO electrode displays a much higher specific capacitance, 316 F g-1 at 1 A g-1, than that of the pure WO3 electrode. Furthermore, WO3/PIL/RGO also has good rate and long cycling performance for supercapacitors, making it a promising electrode material.

Blood-Brain Barrier Permeable Chitosan Oligosaccharides Interfere with ß-Amyloid Aggregation and Alleviate ß-Amyloid Protein Mediated Neurotoxicity and Neuroinflammation in a Dose- and Degree of Polymerization-Dependent Manner.

It is proven that ß-amyloid (Aß) aggregates containing cross-ß-sheet structures led to oxidative stress, neuroinflammation, and neuronal loss via multiple pathways. Therefore, reduction of Aß neurotoxicity via inhibiting aggregation of Aß or dissociating toxic Aß aggregates into nontoxic forms might be effective therapeutic methods for Alzheimer's disease (AD) treatment. This study was designed to explore interference of chitosan oligosaccharides (COS) on ß-(1-42)-amyloid protein (Aß42) aggregation and Aß42-induced cytotoxicity. Here it was demonstrated that COS showed good blood-brain barrier (BBB) penetration ability in vitro and in vivo. The experimental results showed that COS efficiently interfered with Aß42 aggregation in dose- and degree of polymerization (DP)-dependent manners, and COS monomer with DP6 showed the best effect on preventing conformational transition into ß-sheet-rich structures. Based on the binding affinity analysis by microscale thermophoresis (MST), it was confirmed that COS could directly bind with Aß42 in a DP-dependent manner. Our findings demonstrated that different performance of COS monomers with different DPs against Aß42 assembly was, to some extent, attributable to their different binding capacities with Aß42. As a result, COS significantly ameliorated Aß42-induced cytotoxicity. Taken together, our studies would point towards a potential role of COS in treatment of AD.

Chitosan Oligosaccharides Coupling Inhibits Bacterial Biofilm-Related Antibiotic Resistance against Florfenicol.

The formation of bacterial biofilms has increased the resistance of bacteria to various environmental factors and is tightly associated with many persistent and chronic bacterial infections. Herein we design a strategy conjugating florfenicol, an antibiotic commonly used in the treatment of streptococcus, with the antimicrobial biomaterial, chitosan oligosaccharides. The results demonstrated that the florfenicol-COS conjugate (F-COS) efficiently eradicated the mature Streptococcus hyovaginalis biofilm, apparently inhibiting drug resistance to florfenicol. A quantity of 250 µg/mL F-COS showed effective inhibitory activity against planktonic cells and biofilm of the bacteria, and a 4-fold improvement of the F-COS compared to unmodified florfenicol was observed. Furthermore, the conjugate showed a broad-spectrum activity against both Gram-positive and Gram-negative bacteria. It suggested that F-COS might have a potential for application in the treatment of biofilm-related infections.

Altered levels of focal adhesion and extracellular matrix-receptor interacting proteins were identified in Hailey-Hailey disease by quantitative iTRAQ proteome analysis.

Benign chronic familial pemphigus or Hailey-Hailey disease (HHD, OMIM 169600) is a rare, autosomal dominant blistering skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. To date, the proteomic changes in skin lesions from HHD patients has not been reported yet. In this study, a sample of skin lesions from HHD patients was collected for isobaric tags for relative and absolute quantitation to analyze proteome changes compared with unaffected individuals. The 134 differentially expressed proteins were assigned to at least one Gene Ontology term, and 123 annotated proteins with significant matches were assigned to 187 known metabolic or signaling pathways listed in the Kyoto Encyclopedia of Genes and Genomes. Most of the altered proteins in skin lesions of HHD patients were enriched in pathways involved in the PI3K-Akt signaling, focal adhesion, extracellular matrix (ECM)-receptor interaction, and protein digestion and absorption, such as collagen family members, microfibril-associated glycoprotein 4 and plakophilin. The changes of proteins related to cell adhesion, ECM-receptor interaction, and protein folding and glycosylation suggested that strategy targeted to alter cell junction and extracellular microenvironment might provide a potential treatment for HHD.

Synthesis and Evaluation of a Chitosan Oligosaccharide-Streptomycin Conjugate against Pseudomonas aeruginosa Biofilms.

Microbial biofilms are considerably more resistant to antibiotics than planktonic cells. It has been reported that chitosan coupling with the aminoglycoside antibiotic streptomycin dramatically disrupted biofilms of several Gram-positive bacteria. This finding suggested the application of the covalent conjugate of antimicrobial natural polysaccharides and antibiotics on anti-infection therapy. However, the underlying molecular mechanism of the chitosan-streptomycin conjugate (CS-Strep) remains unclear and the poor water-solubility of the conjugate might restrict its applications for anti-infection therapy. In this study, we conjugated streptomycin with water-soluble chitosan oligosaccharides (COS). Unlike CS-Strep, the COS-streptomycin conjugate (COS-Strep) barely affected biofilms of tested Gram-positive bacteria. However, COS-Strep efficiently eradicated established biofilms of the Gram-negative pathogen Pseudomonas aeruginosa. This activity of COS-Strep was influenced by the degree of polymerization of chitosan oligosaccharide. The increased susceptibility of P. aeruginosa biofilms to antibiotics after conjugating might be related to the following: Suppression of the activation of MexX-MexY drug efflux pump system induced by streptomycin treatment; and down-regulation of the biosynthesis of biofilm exopolysaccharides. Thus, this work indicated that covalently linking antibiotics to chitosan oligosaccharides was a possible approach for the development of antimicrobial drugs against biofilm-related infections.

Conjugation of Inulin Improves Anti-Biofilm Activity of Chitosan.

Bacteria biofilm helps bacteria prevent phagocytosis during infection and increase resistance to antibiotics. Staphylococcus aureus is a Gram-positive pathogenic bacterium and is tightly associated with biofilm-related infections, which have led to great threat to human health. Chitosan, the only cationic polysaccharide in nature, has been demonstrated to have antimicrobial and anti-biofilm activities, which, however, require a relative high dosage of chitosan. Moreover, poor water solubility further restricts its applications on anti-infection therapy. Inulins are a group of polysaccharides produced by many types of plants, and are widely used in processed foods. Compared to chitosan, inulin is very soluble in water and possesses a mild antibacterial activity against certain pathogenic bacteria. In order to develop an effective strategy to treat biofilm-related infections, we introduce a method by covalent conjugation of inulin to chitosan. The physicochemical characterization of the inulin⁻chitosan conjugate was assayed, and the anti-biofilm activity was evaluated against S. aureus biofilm. The results indicated that, as compared to chitosan, this novel polysaccharide⁻polysaccharide conjugate significantly enhanced activities against S. aureus either in a biofilm or planktonic state. Of note, the conjugate also showed a broad spectrum anti-biofilm activity on different bacteria strains and low cellular toxicity to mammalian cells. These results suggested that chitosan conjugation of inulin was a viable strategy for treatment against biofilm-related infections. This finding may further spread the application of natural polysaccharides on treatments of infectious disease.

The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.

Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis.

Alleviative effect of ciliary neurotrophic factor analogue on high fat-induced hepatic steatosis is partially independent of the central regulation.

Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high-fat diet-fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat-induced hepatic steatosis. The rat model of fatty liver was induced by a high-fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05-0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT-1 and PPARα, and decreased SREBP-1c, FAS and SCD-1 in steatotic HepG2 cells. But the production of nitric oxide and 8-isoPGF2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat-induced hepatic steatosis.

2940-nm Er:YAG fractional laser enhanced the effect of topical drug for psoriasis.

We observed the promoting effects of the 2940-nm erbium:YAG (Er:YAG) fractional laser in topical drug delivery for psoriasis. A total of five (four males and one female) recalcitrant psoriasis patients were given laser treatment eight times at 1-week intervals with the following parameters: 5-11% spot density and 100-µm energy depth. The psoriatic skin lesions on the left knee and the corresponding lesions at the right ones of each psoriasis patient were randomly divided into two groups: laser + topical drug group (L) and drug alone group (D). The psoriatic lesions in both groups were treated with the same topical treatment (calcipotriol ointment). The corresponding psoriatic lesions in the L group received extra 2940-nm Er:YAG laser irradiation before topical treatment. The photos of psoriatic lesions were taken before each treatment. The final photos were obtained from the patients at the seventh day after the final treatment. Drug alone or in combination with laser Er:YAG both reduced psoriatic lesions. However, with the increase in the number of treatments, increasing differences were observed between the treatment and the control sides. The therapeutic outcomes in the L groups were better than those in the D groups. Psoriasis area and severity index (PASI) scores for five cases of both groups were decreased. However, the scores in the L groups were lower than those in the D groups. The use of 2940 nm Er:YAG promoted the absorption of topical drugs for psoriasis, improving the therapeutic effect.

Upregulated MicroRNA-25 Mediates the Migration of Melanoma Cells by Targeting DKK3 through the WNT/ß-Catenin Pathway.

Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion and proliferation of melanoma cells in vitro; however, overexpression of miR-25 markedly increased melanoma cell invasion and proliferation. Moreover, we observed Dickkopf-related protein 3 (DKK3) as a direct target of miR-25 in vitro. Upregulation of DKK3 partially attenuated the oncogenic effect of miR-25 on melanoma cells. Ectopic expression of miR-25 in melanoma cells induced ß-catenin accumulation in nuclear and inhibited TCF4 (T cell factor 4) activity, as well as the expression of c-Myc and Cyclin D1. In a nude xenograft model, miR-25 upregulation significantly increased A375 melanoma growth. In summary, miR-25 is upregulated in melanoma and promotes melanoma cell proliferation and invasion, partially by targeting DKK3. These results were indicated that miR-25 may serve as a potential target for the treatment of melanoma in the future.

Uric acid lowering effect of Tibetan Medicine RuPeng15 powder in animal models of hyperuricemia.

OBJECTIVE: To evaluate the influence of the Tibetan medicine RuPeng15 powder (RPP15) on uric acid levels, and explore its possible mechanisms of action in hyperuricemic animal models. METHODS: Hyperuricemic mice were generated by orally administering yeast extract paste twice daily (30 g/kg) for 8 days, to mimic human hyperuricemia induced by high-protein diets. Hyperuricemic rats were generated by intraperitoneal injection of 250 mg/kg potassium oxonate to each animal 1 h before the last oral administration of test compounds, which raised the serum uric acid level by inhibiting the decomposition of uric acid. Levels of uric acid and creatinine in serum and urine were detected by the phosphotungstic acid and picric acid methods respectively, and the activity of xanthine oxidase (XOD) was assayed using a commercial test kit. RESULTS: RPP15 (0.4, 0.8, 1.2 g/kg) significantly decreased the level of serum uric acid in healthy rats (P < 0.05). Furthermore, hyperuricemic rats treated with RPP15 (0.4, 0.8, 1.2 g/kg) had lower serum uric acid levels (P < 0.05), accompanied by lower urine uric acid (P < 0.05). For the hyperuricemic mice, the levels of uric acid in the serum decreased significantly (P < 0.05) and the activity of XOD in the liver was restored to normal levels after treatment with RPP15 (P < 0.05). CONCLUSION: RPP15 (0.4, 0.8, 1.2 g/kg) demonstrated an anti-hyperuricemic effect on both healthy and hyperuricemic animals, and the mechanism is most likely associated with inhibiting the activity of XOD.

Unveiling the inverse antimicrobial impact of a hetero-chitooligosaccharide on Candida tropicalis growth and biofilm formation.

Chitosan and chitooligosaccharide (COS) are renowned for their potent antimicrobial prowess, yet the precise antimicrobial efficacy of COS remains elusive due to scant structural information about the utilized saccharides. This study delves into the antimicrobial potential of COS, spotlighting a distinct hetero-chitooligosaccharide dubbed DACOS. In contrast to other COS, DACOS remarkably fosters the growth of Candida tropicalis planktonic cells and fungal biofilms. Employing gradient alcohol precipitation, DACOS was fractionated, unveiling diverse structural characteristics and differential impacts on C. tropicalis. Notably, in a murine model of systemic candidiasis, DACOS, particularly its 70 % alcohol precipitates, manifests a promotive effect on Candida infection. This research unveils a new pathway for exploring the intricate nexus between the structural attributes of chitosan oligosaccharides and their physiological repercussions, underscoring the imperative of crafting chitosan and COS with meticulously defined structural configurations.

High molecular weight chitosan oligosaccharide exhibited antifungal activity by misleading cell wall organization via targeting PHR transglucosidases.

The fungal cell wall is an ideal target for the design of antifungal drugs. In this study we used an analog of cell wall polymer, a highly deacetylated high molecular-weight chitosan oligosaccharide (HCOS), to test its effect against pathogenic Candida strains. Results showed that HCOS was successfully incorporated into the dynamic cell wall organization process and exhibited an apparent antifungal activity against both plankton and mature fungal biofilm, by impairing the cell wall integrity. Unexpectedly, mechanistic studies suggested that HCOS exerts its activity by interfering with family members of PHR ß-(1,3)-glucanosyl transferases and affecting the connection and assembly of cell wall polysaccharides. Furthermore, HCOS showed great synergistic activity with different fungicides against Candida cells, especially those in biofilm. These findings indicated HCOS has a great potential as an antifungal drug or drug synergist and proposed a novel antifungal strategy with structure-specific oligosaccharides mimicking cell wall polysaccharide fragments.

Therapeutic effects of a recombinant mutant of the human ciliary neurotrophic factor in a mouse model of metabolic syndrome.

Metabolic syndrome (MS) is highly prevalent in developed countries and becoming a serious worldwide public health issue. In this study, we established a MS model by feeding male C57BL/6J mice with a high-fat diet (10%) for 18.5 weeks, studied the therapeutic effects of a recombinant mutant of the human ciliary neurotrophic factor (rhmCNTF) 0.1 (C-0.1) or 0.3 (C-0.3) mg x kg(-1) per day subcutaneously or pair feeding (PF, which mice were restricted to the same amount of food as eaten by C-0.3 treated mice) in MS mice. After 10 days treatment, rhmCNTF reduced obesity related indices, ameliorated glucose and lipid metabolism abnormality, and enhanced insulin sensitivity. In addition, liver function and antioxidant ability of MS mice were improved by rhmCNTF. Pair feeding revealed the same effects as C-0.3 on obesity related indices and insulin sensitivity, but aggravated hepatic steatosis and hepatic function. The results suggest that rhmCNTF could serve as an effective therapeutic agent for MS and related diseases.

Short-Term Efficacy and Safety of IL-17, IL-12/23, and IL-23 Inhibitors Brodalumab, Secukinumab, Ixekizumab, Ustekinumab, Guselkumab, Tildrakizumab, and Risankizumab for the Treatment of Moderate to Severe Plaque Psoriasis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis. OBJECTIVE: To compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA). METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA). RESULTS: This meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80 mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA = 93.0%). Brodalumab 210 mg ranked the highest in short-term achievement of PASI 100 (SUCRA = 85.0%). Secukinumab 300 mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA = 98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45 mg compared with placebo. Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA = 4.5%). Guselkumab 50 mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA = 25.9%). Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA = 10.7%). CONCLUSIONS: IL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.

Serum levels of adipokines and cytokines in psoriasis patients: a systematic review and meta-analysis.

PURPOSE: To evaluate the association of serum levels of adipokines and cytokines with psoriasis. MATERIALS AND METHODS: A comprehensive literature search was performed in PubMed, ScienceDirect and Web of Science for the available relevant studies published before December 1, 2016. Differences in serum marker levels between patients and controls were pooled as standardized mean differences (SMDs) with 95% confidence interval to combine the effect estimations. We also conducted stratified analysis, meta-regression analysis and sensitivity analysis. RESULTS: Sixty-three studies containing 2876 psoriasis patients and 2237 healthy controls were included in this meta-analysis. The pooled serum levels of TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-18, IL-22, chemerin, lipocalin-2, resistin, sE-selectin, fibrinogen and C3 were higher in psoriasis patients compared with healthy controls (all P < 0.05). In contrast, adiponectin levels were lower. Serum levels of IL-1ß, IL-4, IL-10, IL-12, IL-17, IL-21, IL-23, visfatin and omentin were not significantly different between psoriasis patients and controls (all P > 0.05). However, increased serum levels of IL-17 correlated with psoriasis in men. For other biomarkers, age, gender and psoriasis area and severity index did not explain the differences in effect size between the studies. CONCLUSIONS: Serum levels of TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-18, IL-22, chemerin, lipocalin-2, resistin, sE-selectin, fibrinogen, complement 3, and adiponectin correlate with psoriasis and can be used as potential biomarkers for psoriasis and response to the treatment. Future studies are needed to identify additional players involved in the pathogenesis of psoriasis and to fully decipher the underlying mechanism.