Butein, a potential drug for the treatment of bone cancer pain through bioinformatic and network pharmacology.

Bone cancer pain is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus database and differentially expressed gene extraction was performed. DEGs integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map 2.0 database for drug prediction. Moreover, butein has good drug-likeness properties. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A, which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP.

Biosynthesis of Vanillin by Rational Design of Enoyl-CoA Hydratase/Lyase.

Vanillin holds significant importance as a flavoring agent in various industries, including food, pharmaceuticals, and cosmetics. The CoA-dependent pathway for the biosynthesis of vanillin from ferulic acid involved feruloyl-CoA synthase (Fcs) and enoyl-CoA hydratase/lyase (Ech). In this research, the Fcs and Ech were derived from Streptomyces sp. strain V-1. The sequence conservation and structural features of Ech were analyzed by computational techniques including sequence alignment and molecular dynamics simulation. After detailed study for the major binding modes and key amino acid residues between Ech and substrates, a series of mutations (F74W, A130G, A130G/T132S, R147Q, Q255R, ΔT90, ΔTGPEIL, ΔN1-11, ΔC260-287) were obtained by rational design. Finally, the yield of vanillin produced by these mutants was verified by whole-cell catalysis. The results indicated that three mutants, F74W, Q147R, and ΔN1-11, showed higher yields than wild-type Ech. Molecular dynamics simulations and residue energy decomposition identified the basic residues K37, R38, K561, and R564 as the key residues affecting the free energy of binding between Ech and feruloyl-coenzyme A (FCA). The large changes in electrostatic interacting and polar solvating energies caused by the mutations may lead to decreased enzyme activity. This study provides important theoretical guidance as well as experimental data for the biosynthetic pathway of vanillin.

Gangliosides play important roles in the nervous system by regulating ion concentrations.

Gangliosides are important components of the neuronal cell membrane and play a vital role in the development of neurons and the brain. They participate in neurotransmission and are considered as the structural basis of learning and memory. Gangliosides participate in several and important physiological processes, such as cell differentiation, cell signaling, neuroprotection, nerve regeneration and apoptosis. The stability of ion concentration in excitable cells is particularly important in the maintenance of a steady state of cells and in the regulation of physiological functions. Ion concentration has been found to be related to the ganglioside's regulation in many neurological diseases, and several studies have found that they can stabilize intracellular ion concentration by regulating ion channels, which highlights their important regulatory role in neuronal excitability and synaptic transmission. Gangliosides can influence some forms of ion transport, by directly binding to ion transporters or through indirect binding and activation of transport proteins via appropriate signaling pathways. Therefore, the important and special role of gangliosides in the homeostasis of ion concentration is becoming a hot topic in the field and a theoretical basis in promoting help gangliosides use as key drugs for the treatment of nervous system diseases.

Identification of a novel protective human monoclonal antibody, LXY8, that targets the key neutralizing epitopes of staphylococcal enterotoxin B.

Staphylococcal enterotoxin B (SEB), one of the exotoxins produced by Staphylococcus aureus, is the key toxin that causes poisoning reactions and toxic shock syndrome. In the current research work, a novel human antibody named LXY8 was screened from a human phage display antibody library, and LXY8 blocked the interaction between SEB and the T cell receptor (TCR). The binding activity between LXY8 and SEB was 0.525 nM. Furthermore, LXY8 could effectively inhibit the SEB-induced activation of peripheral blood mononuclear cells and release of cytokines. In the BALB/c mouse model, LXY8 effectively neutralized SEB toxicity in vivo. Finally, based on computer-guided molecular modeling, we designed a series of SEB mutation sites; these sites facilitated the determination of the key residues (i.e.176EFNN179) of SEB recognized by LXY8. The research revealed that the 176EFNN179 residues of SEB are important for specific antibody-antigen recognition. The results may be helpful for the development of antibody-based therapy for SEB-induced toxic shock syndrome.

Siglec1 enhances inflammation through miR-1260-dependent degradation of IκBα in COPD.

It has been documented that sialic acid-binding Ig-like lectin 1 (Siglec1) is a cell surface protein with a variety of functions in the immune system. In the present study, we evaluated whether Siglec1 plays a role in chronic obstructive pulmonary disease (COPD). Results show that the expression of Siglec1 was increased in the lung of COPD rats, and that Siglec1 overexpression greatly enhanced the expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and IL-6 in cigarette smoke extract (CSE)-treated NR8383 cells, a rat lung-derived macrophage cell line. Notably, the proinflammatory effect of Siglec1 was totally inhibited by overexpression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Importantly, Siglec1 overexpression increased miR-1260, which then degraded IκBα through its 3' untranslated region (3'UTR). Further study demonstrated that miR-1260 inhibitor attenuated inflammation in CSE-induced rat COPD lung and in CSE-treated NR8383 cells. Finally, the inhibitory effect of miR-1260 on inflammation was totally lost when IκBα was inhibited. In summary, the present study demonstrated that Siglec1 exerts its proinflammatory effects through increasing miR-1260, leading to decreased expression of IκBα.

A novel hexamerin with an unexpected contribution to the prophenoloxidase activation system of the Chinese oak silkworm, Antheraea pernyi.

Hexamerin was originally identified as a storage protein but later confirmed to be involved in many physiological processes. In the present study, we cloned and characterized a novel hexamerin complementary DNA sequence from the Chinese oak silkworm, Antheraea pernyi (Ap-hexamerin), which shows high homology with reported insect methionine-rich hexamerins. The tissue distribution and time course of expression demonstrated that Ap-hexamerin was predominantly synthesized in the fat body and the expression level was significantly increased in response to the microbial challenge, suggesting the relevance of Ap-hexamerin to immune responses. In further immune functional studies, Ap-hexamerin was confirmed to take part in the upregulation of prophenoloxidase (PPO) activation in A. pernyi haemolymph triggered by pathogen-associated molecular patterns (PAMPs). Additional molecular interaction analysis revealed that Ap-hexamerin is capable of binding the PAMPs used in the phenoloxidase assay, suggesting hexamerin in A. pernyi may positively regulate haemolymph PPO activation, acting as a pattern recognition protein.

Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation.

Human Cav1.3 (hCav1.3) is of great interest as a potential target for Parkinson's disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav1.2 (hCav1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav1.3. In this study, we describe the selectivity mechanism of PYTs for hCav1.2 and hCav1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson's disease.

Enhanced interaction between SEC2 mutant and TCR Vß induces MHC II-independent activation of T cells via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways.

SEC2, a major histocompatibility complex class II (MHC II)-dependent T-cell mitogen, binds MHC II and T-cell receptor (TCR) Vßs to induce effective co-stimulating signals for clonal T-cell expansion. We previously characterized a SEC2 mutant with increased recognition of TCR Vßs, ST-4, which could intensify NF-κB signaling transduction, leading to IL-2 production and T-cell activation. In this study, we found that in contrast to SEC2, ST-4 could induce murine CD4+ T-cell proliferation in a Vß8.2- and Vß8.3-specific manner in the absence of MHC II+ antigen-presenting cells (APCs). Furthermore, although IL-2 secretion in response to either SEC2 or ST-4 stimulation was accompanied by up-regulation of protein kinase Cθ (PKCθ), inhibitor of κB (IκB), α and ß IκB kinase (IKKα/ß), IκBα, and NF-κB in mouse splenocytes, only ST-4 could activate CD4+ T cells in the absence of MHC II+ APCs through the PKCθ/NF-κB signaling pathway. The PKCθ inhibitor AEB071 significantly suppressed SEC2/ST-4-induced T-cell proliferation, CD69 and CD25 expression, and IL-2 secretion with or without MHC II+ APCs. Further, SEC2/ST-4-induced changes in PKCθ/NF-κB signaling were significantly relieved by AEB071 in a dose-dependent manner. Using Lck siRNA, we found that Lck controlled SEC2/ST-4-induced phosphorylation of PKCθ. We also demonstrated that the IL-2R/STAT5 pathway is essential for SEC2/ST-4-induced T-cell activation. Collectively, our data demonstrate that an enhanced ST-4-TCR interaction can compensate for lack of MHC II and stimulate MHC II-free CD4+ T-cell proliferation via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways. Compared with SEC2, intensified PKCθ/NF-κB and IL-2R/STAT5 signals induced by ST-4 lead to enhanced T-cell activation. The results of this study will facilitate better understanding of TCR-based immunotherapies for cancer.

A mutant of the Buthus martensii Karsch antitumor-analgesic peptide exhibits reduced inhibition to hNav1.4 and hNav1.5 channels while retaining analgesic activity.

Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Buthus martensii Karsch, has been proved to possess analgesic and antitumor activities. Trp38, a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology-modeling analyses. Therefore, an AGAP mutant, W38G, was generated, and effects of both AGAP and the mutant W38G were examined by whole-cell patch clamp techniques on the sodium channels hNav1.4 and hNav1.5, which were closely associated with the biotoxicity of skeletal and cardiac muscles, respectively. The data showed that both W38G and AGAP inhibited the peak currents of hNav1.4 and hNav1.5; however, W38G induced a much weaker inhibition of both channels than AGAP. Accordingly, W38G exhibited much less toxic effect on both skeletal and cardiac muscles than AGAP in vivo The analgesic activity of W38G and AGAP were verified in vivo as well, and W38G retained analgesic activity similar to AGAP. Inhibition to both Nav1.7 and Nav1.8 was involved in the analgesic mechanism of AGAP and W38G. These findings indicated that Trp38 was a key amino acid involved in the biotoxicity of AGAP, and the AGAP mutant W38G might be a safer alternative for clinical application because it retains the analgesic efficacy with less toxicity to skeletal and cardiac muscles.

A novel expression vector for the improved solubility of recombinant scorpion venom in Escherichia coli.

Recombinant scorpion anti-excitation peptide (rANEP) has previously been expressed using the pET32a system and purified via affinity chromatography. However, rANEP is expressed in BL21(DE3) cells as an inclusion body, and the affinity tag can not be removed. To overcome this problem, we used a variety of protein, DsbA, MBP, TrxA, intein, and affinity tags in fusion and co-expression to achieve soluble and functional rANEP without any affinity tag. In the pCIT-ANEP expression vector, the highest soluble expression level was approximately 90% of the total cellular proteins in E. coli, and the rANEP was cleaved by the intein protein and subsequently purified to obtain rANEP, which had the same activity as the natural ANEP. The purity of rANEP obtained using this method was over 95%, with a quantity of 5.1 mg from of purified rANEP from 1 L of culture. This method could expand the application of the soluble expression of disulfide-rich peptides in E. coli.

Staphylococcal enterotoxin C2 mutant drives T lymphocyte activation through PI3K/mTOR and NF-ĸB signaling pathways.

Staphylococcal enterotoxin C2 (SEC2), a superantigen, causes rapid clonal expansion of lymphocytes and secretion of T cell growth factors, leading to a severe inflammatory response within tissues. Although previous studies have shown that ST-4, a SEC2 mutant with enhanced recognition of Vß regions of T-cell receptors (TCRVß), can activate an increased number of T cells and produce more cytokines than SEC2. However, the signaling mechanisms of SEC2/ST-4-mediated immune activation have not been addressed. In this study, we showed that the phosphatidylinositide-3-kinase (PI-3K) inhibitor LY294002, mammalian target of rapamycin (mTOR) inhibitor rapamycin, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor Bay11-7085 could suppress SEC2/ST-4-induced proliferation, CD69/CD25 expression, cell-cycle progression, and IL-2 production in BALB/c mouse splenocytes. In addition, we observed significantly upregulated expression of p70S6K, cyclin E, cyclin D3, and NF-ĸB/p65, but downregulated expression of p27kip during SEC2/ST-4-driven T cells activation. However, SEC2/ST-4-induced changes in cell cycle and PI3K/mTOR signaling were significantly relieved by either LY294002 or rapamycin, and the induction of NF-ĸB/p65 induced was significantly downregulated by Bay11-7085. Moreover, we found that IL-2 secretion was positively associated with p65 expression in a time- and dose-dependent manner. Taken together, our findings demonstrate the involvement of PI3K/mTOR and NF-κB signaling pathways in SEC2/ST-4-induced T cell activation. ST-4 intensifies PI3K/mTOR and NF-ĸB signaling transduction, ultimately leading to enhance T cell activation. These results provide a theoretical mechanism for future immunotherapy using ST-4.

Analgesic-antitumor peptide inhibits the migration and invasion of HepG2 cells by an upregulated VGSC ß1 subunit.

Analgesic-antitumor peptide (AGAP), one of the scorpion toxin polypeptides, has been shown to have an antitumor activity. Recombinant AGAP (rAGAP) was shown to affect the migration and invasion of HepG2 cells via a voltage-gated sodium channel (VGSC) ß1 subunit. The VGSC ß1 subunit was validated as a cell adhesion molecule (CAM) in human hepatocellular carcinoma (HCC) cell lines. rAGAP suppresses the migration and invasion of HepG2 cells but has no significant effect of human liver HL7702 cells without ß1 subunit expression. rAGAP inhibits the migration and invasion of the cells when the VGSC ß1 subunit is overexpressed in HL7702 cells. To explain these findings, VGSC ß1 subunit messenger RNA (mRNA) and protein levels were measured. The ß1 subunit protein level was upregulated in a dose-dependent manner following treatment with rAGAP while there was no significant change in the mRNA level, so rAGAP might be an active component of the VGSC ß1 subunit.

The Functional Property Changes of Muscular Na(v)1.4 and Cardiac Na(v)1.5 Induced by Scorpion Toxin BmK AGP-SYPU1 Mutants Y42F and Y5F.

Scorpion toxins are invaluable therapeutic leads and pharmacological tools which influence the voltage-gated sodium channels. However, the details were still unclear about the structure-function relationship of scorpion toxins on VGSC subtypes. In the previous study, we reported one α-type scorpion toxin Bmk AGP-SYPU1 and its two mutants (Y5F and Y42F) which had been demonstrated to ease pain in mice acetic acid writhing test. However, the function of Bmk AGP-SYPU1 on VGSCs is still unknown. In this study, we examined the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNa(v)1.4 and hNa(v)1.5 heterologously expressed CHO cell lines by using Na⁺-specialized fluorescent dye and whole-cell patch clamp. The data showed that BmK AGP-SYPU1 displayed as an activator of hNa(v)1.4 and hNa(v)1.5, which might indeed contribute to its biotoxicity to muscular and cardiac system and exhibited the functional properties of both the α-type and ß-type scorpion toxin. Notably, Y5F mutant exhibited lower activatory effects on hNa(v)1.4 and hNa(v)1.5 compared with BmK AGP-SYPU1. Y42F was an enhanced activator and confirmed that the conserved Tyr42 was the key amino acid involved in bioactivity or biotoxicity. These data provided a deep insight into the structure-function relationship of BmK AGP-SYPU1, which may be the guidance for engineering α-toxin with high selectivity on VGSC subtypes.

NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways.

The purposes of this study are to investigate the antitumor activities of NSK-01105, a novel sorafenib derivative, in in vitro and in vivo models, and explore the potential mechanisms. The effects of NSK-01105 on proliferation and apoptosis of prostate cancer cells were established by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blot analysis. Two xenograft tumor models were used to verify the therapeutic effect of NSK-01105 in vivo. NSK-01105 exhibited broad-spectrum antitumor activity, particularly in prostate cancer cells. Characterization of apoptosis morphology was observed, and the percentage of apoptosis-positive cells significantly increased after NSK-01105 treatment for 24 h. Furthermore, a significant increase of the "sub-G1" population in LNCaP and PC-3 cells after NSK-01105 treatment was determined by cell cycle analysis. Tumor growth was significantly suppressed by once daily oral 30 mg/kg dose of NSK-01105 with the inhibition rates of 63.82% in LNCaP models and 64.29% in PC-3 models, respectively. The activation of Raf-1 kinase and epidermal growth factor receptor was downregulated by NSK-01105 at 10 µmol/L. Consequently, the dual inhibitions of Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways were observed by Western blot analysis. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors by inhibiting cell proliferation and inducing apoptosis. NSK-01105 appears to be a promising orally active anticancer drug and deserves further investigation.

Mechanism study on pH-responsive cyclodextrin capped mesoporous silica: effect of different stalk densities and the type of cyclodextrin.

Cyclodextrin (CD)-capped mesoporous silica nanoparticles (MSN) with pH-responsive properties were synthesized, but little research has been carried out to evaluate the impact of critical factors such as the stalk density and the type of CD on the pH-responsive release behavior. Here, the effect of different stalk densities on the pH-responsive release behavior was investigated. Either too low or too high density of the grafted p-anisidine stalk could result in poor cargo release, and the optimum stalk density for MSN was measured by thermal analysis, and found to be approximately 8.7 stalks nm(-2). To achieve effective release control, the CD capes, α-CD and ß-CD, were also investigated. Isothermal titration calorimetry (ITC) analysis was employed to determine the formation constants (Kf) of the two CD with p-anisidine at different pH values. The results obtained showed that the complex of ß-CD with p-anisidine had excellent pH-responsive behavior as it exhibited the largest changed formation constant (ΔKf) in different pH media. Furthermore, the pH-responsive mechanism between CD and p-anisidine molecules was investigated through ITC and a molecular modeling study. The release of antitumor drug DOX presents a significant prospect toward the development of pH-responsive nanoparticles as a drug delivery vehicle.

AGAP, a new recombinant neurotoxic polypeptide, targets the voltage-gated calcium channels in rat small diameter DRG neurons.

A previous study showed that antitumor-analgesic peptide (AGAP), a novel recombinant polypeptide, which had been expressed in Escherichia coli, exhibits analgesic and antitumor effects in mice. In the present study, we investigated the underlying analgesic mechanism of AGAP. The effect of AGAP on voltage-gated calcium channels (VGCCs) was assessed in acutely isolated rat dorsal root ganglia (DRG) neurons using the whole-cell patch clamp technique. The results showed that AGAP potently inhibited VGCCs, especially high-voltage activated (HVA) calcium channels. AGAP inhibited HVA and T-type calcium currents in a dose-dependent manner, but had no significant effect on their dynamic functions in rat small-diameter DRG neurons. AGAP inhibited N- and L-type calcium currents at 78.2% and 57.3%, respectively. Thus, the present study demonstrates that AGAP affects calcium currents through the inhibition of N-, L- and T-type channels in DRG neurons, explaining the potential mechanisms of antinociception.

RVG-peptide-linked trimethylated chitosan for delivery of siRNA to the brain.

In this work, a peptide derived from the rabies virus glycoprotein (RVG) was linked to siRNA/trimethylated chitosan (TMC) complexes through bifunctional PEG for efficient brain-targeted delivery of siRNA. The physiochemical properties of the complexes, such as siRNA complexing ability, size and ζ potential, morphology, serum stability, and cytotoxicity, were investigated prior to studying the cellular uptake, in vitro gene silencing efficiency, and in vivo biodistribution. The RVG-peptide-linked siRNA/TMC-PEG complexes showed increased serum stability, negligible cytotoxicity, and higher cellular uptake than the unmodified siRNA/TMC-mPEG complexes in acetylcholine receptor positive Neuro2a cells. The potent knockdown of BACE1, a therapeutic target in Alzheimer's disease, demonstrated the gene silencing efficiency. In vivo imaging analysis showed significant accumulation of Cy5-siRNA in the isolated brain of mice injected with RVG-peptide-linked complexes. Therefore, the RVG-peptide-linked TMC-PEG developed in this study can be used as a potential carrier for delivery of siRNA to the brain.

The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol.

OBJECTIVE: To explore the suitable application of MCM-41 (Mobil Composition of Matter number forty-one)-type and MCM-48-type mesoporous silica in the oral water insoluble drug delivery system. METHODS: Cilostazol (CLT) as a model drug was loaded into synthesized MCM-48 (Mobil Composition of Matter number forty-eight) and commercial MCM-41 by three common methods. The obtained MCM-41, MCM-48 and CLT-loaded samples were characterized by means of nitrogen adsorption, thermogravimetric analysis, ultraviolet-visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and powder X-ray diffractometer. RESULTS: It was found that solvent evaporation method was preferred according to the drug loading efficiency and the maximum percent cumulative drug dissolution. MCM-48 with 3D cubic pore structure and MCM-41 with 2D long tubular structure are nearly spherical particles in 300-500 nm. Nevertheless, the silica carriers with similar large specific surface areas and concentrating pore size distributions (978.66 m(2)/g, 3.8 nm for MCM-41 and 1108.04 m(2)/g, 3.6 nm for MCM-48) exhibited different adsorption behaviors for CLT. The maximum percent cumulative drug release of the two CLT/silica solid dispersion (CLT-MCM-48 and CLT-MCM-41) was 63.41% and 85.78% within 60 min, respectively; while in the subsequent 12 h release experiment, almost 100% cumulative drug release were both obtained. In the pharmacokinetics aspect, the maximum plasma concentrations of CLT-MCM-48 reached 3.63 mg/L by 0.92 h. The AUC0-∞ values of the CLT-MCM-41 and CLT-MCM-48 were 1.14-fold and 1.73-fold, respectively, compared with the commercial preparation. CONCLUSION: Our findings suggest that MCM-41-type and MCM-48-type mesoporous silica have great promise as solid dispersion carriers for sustained and immediate release separately.

Current trends in gas-synergized phototherapy for improved antitumor theranostics.

Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field.

Erratum: Author correction to "Immune-awakening Saccharomyces-inspired nanocarrier for oral target delivery to lymph and tumors" [Acta Pharmaceutica Sinica B 12 (2022) 4501-4518].

[This corrects the article DOI: 10.1016/j.apsb.2022.04.018.].