Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice

Sepsis-induced liver injury(SILI)is an important cause of septicemia deaths.BaWeiBaiDuSan(BWBDS)was extracted from a formula of Panax ginseng C.A.Meyer,Lilium brownie F.E.Brown ex Miellez var.viridulum Baker,Polygonatum sibiricum Delar.ex Redoute,Lonicera japonica Thunb.,Hippophae rhamnoides Linn.,Amygdalus Communis Vas,Platycodon grandiflorus(Jacq.)A.DC.,and Cortex Phelloderdri.Herein,we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota.BWBDS protected mice against SILI,which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity.BWBDS selectively promoted the growth of Lactobacillus johnsonii(L.johnsonii)in cecal ligation and puncture treated mice.Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects.Notably,L.johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity,increasing interleukin-10+M2 macrophage production and enhancing intestinal integrity.Furthermore,heat inactivation L.johnsonii(HI-L.johnsonii)treatment promoted macrophage anti-inflammatory activity and alleviated SILI.Our findings revealed BWBDS and gut microbiota L.johnsonii as novel prebiotic and probiotic that may be used to treat SILI.The potential underlying mechanism was at least in part,via L.johnsonii-dependent immune regulation and interleukin-10+M2 macrophage production.

Myricetin inhibits interferon-γ-induced programmed death ligand-1 and indoleamine 2,3-dioxygenase 1 expression in lung cancer cells

OBJECTIVE Programmed death ligand-1(PD-L1)and indoleamine 2,3-dioxygenase 1(IDO1)are immune checkpoints which can be induced by interferon-γ(IFN-γ)in the tumor microenvironment,leading to immune escape of tumors.Myricetin(MY)is a flavonoid distributed in many edible and medicinal plants.The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells.METHODS Expressions of PD-L1 and major histocompatibility complex-I(MHC-I)were evaluated by flow cytometry and Western blotting,and the expression of IDO1 was measured by Western blotting.qRT-PCR was used to detect their mRNA levels.The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1.Molecular docking analysis,Western blotting and immunofluorescence were used for mechanism study.RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells,while didn't show obvious effect on the expression of MHC-I.In addition,MY restored the survival,proliferation,CD69 expression and interleukin-2(IL-2)secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system.Mechanistically,IFN-γup-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis,which was targeted and inhibited by MY.CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression,supporting the potential of MY in anti-tumor immunotherapy.

A platinum@polymer-catechol nanobraker enables radio-immunotherapy for crippling melanoma tumorigenesis, angiogenesis, and radioresistance

Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis,angiogenesis,and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression.Interdicting melanoma intrinsic growth signals,including the blockade of PD-L1 and mTOR signaling concurrently,cooperative with radiotherapy may provide a vigorous repertoire to alleviate the tumor encumbrance.Thence,we design a three-pronged platinum@polymer-catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody(aPD-L1)for impeding the melanoma-PD-1-driven aggression and maximizing the melanoma eradication.The aPD-L1 collaborated with TAK228 restrains melanoma cell-intrinsic PD-1:PD-L1 tumorigenic interaction via blocking melanoma-PD-L1 ligand and the melanoma-PD-1 receptor-driven mTOR signaling;corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic hypoxia-inducible factor 1-alpha is conducive to preventing tumorigenesis and angiogenesis,respectively.Further,high-Z metal platinum sensitizing TAK228-enhanced radiotherapy confers the nanobraker on remarkable tumoricidal efficacy.Hereto,the customized three-pronged nanobrakers efficiently suppress melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy.Such an ingenious tactic may provide substantial benefits to clinical melanoma patients.

Nanoengineered sonosensitive platelets for synergistically augmented sonodynamic tumor therapy by glutamine deprivation and cascading thrombosis

Ultrasound(US)-activated sonodynamic therapy(SDT)stands for a distinct antitumor modality because of its attractive characteristics including intriguing noninvasiveness,desirable safety,and high tissue penetration depth,which,unfortunately,suffers from compromised therapeutic efficacy due to cancer cell-inherent adaptive mechanisms,such as glutathione(GSH)neutralization response to reactive oxygen species(ROS),and glutamine addictive properties of tumors.In this work,we developed a biological sonosensitive platelet(PLT)pharmacytes for favoring US/GSH-responsive combinational therapeutic of glutamine deprivation and augmented SDT.The amino acid transporter SLC6A14 blockade agentα-methyl-DL-tryptophan(α-MT)-loaded and MnO_(2)-coated porphyrinic metal-organic framework(MOF)nanoparticles were encapsulated in the PLTs through the physical adsorption of electrostatic attraction and the intrinsic endocytosis of PLTs.When the sonosensitive PLT pharmacytes reached tumor sites through their natural tendencies to TME,US stimulated the PLTs-loaded porphyrinic MOF to generate ROS,resulting in morphological changes of the PLTs and the release of nanoparticles.Subsequently,intracellular high concentration of GSH and extracellular spatio-temporal controlled US irradiation programmatically triggered the release ofα-MT,which enabled the synergistically amplified SDT by inducing amino acid starvation,inhibiting mTOR,and mediating ferroptosis.In addition,US stimulation achieved the targeted activation of PLTs at tumor vascular site,which evolved from circulating PLTs to dendritic PLTs,effectively blocking the blood supply of tumors through thrombus formation,and revealing the encouraging potential to facilitate tumor therapeutics.

IR780/Gemcitabine-conjugated metal-phenolic network enhanced photodynamic cancer therapy

Photodynamic therapy (PDT) is a clinically approved cancer treatment that uses energy of light to generate active substances that cause damage to the cancer. Photosensitizers are employed to absorb light and generate toxic reactive oxygen species (ROS) to damage biomolecules like DNA. At the same time, some chemotherapy drugs like nucleotide analogues can provide mechanism-guided promotion in the treatment efficacy of PDT. However, the photosensitizer and chemotherapy drugs used in PDT is usually organic molecules, which suffers from bad solubility, fast clearance, and acute toxicity. To achieve targeted treatment, a reasonable delivery system is necessary. Therefore, we reported a metal-phenolic network where IR780 and gemcitabine were coupled chemically to overcome these shortcomings. The enhanced PDT effects can be realized by the promoted cell death both in vitro and in vivo. Moreover, the synergistic therapy also induced T-cell mediated anti-tumor immune response, which was significant for the inhibition of distant tumor growth. This work expanded the biomedical application of metal-phenolic materials and contribute to the wider application of photodynamic cancer therapy.

Genome engineering of the human gut microbiome

The human gut microbiome,a complex ecosystem,significantly influences host health,impacting crucial aspects such as metabolism and immunity.To enhance our comprehension and control of the molecular mechanisms orchestrating the intricate interplay between gut commensal bacteria and human health,the exploration of genome engineering for gut microbes is a promising frontier.Nevertheless,the complexities and diversities inherent in the gut microbiome pose substantial challenges to the development of effective genome engineering tools for human gut microbes.In this comprehensive review,we provide an overview of the current progress and challenges in genome engineering of human gut commensal bacteria,whether executed in vitro or in situ.A specific focus is directed towards the advancements and prospects in cargo DNA delivery and high-throughput techniques.Additionally,we elucidate the immense potential of genome engineering methods to enhance our understanding of the human gut microbiome and engineer the microorganisms to enhance human health.

A"three musketeers"tactic for inclining interferon-γ as a comrade-in-arm to reinforce the synergistic-tumoricidal therapy

Interferon-γ(IFN-γ),secreted by activated T cells predominantly,plays a crucial performance in the tumoricidal immune response.Unfortunately,a high level of IFN-γseverely ignites the immunosuppressive response,especially by increasing the expression of immune checkpoint programmed death-ligand 1(PD-L1)and immunoregulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1).Herein,we have explored a versatile IFN-γ-nano-integrator(aPD-L1-SH@Ce6@NLG919-PEG,simplified as CNDP)to establish a positive anti-tumor feedback loop to amplify the IFN-γ-mediated tumoricidal effect.In this nanointegrator,photosensitizer chlorin e6(Ce6)mediates photodynamic therapy(PDT)to re-shape immunogenicity and activate the adaptive immune response,followed by the secretion of high-level IFN-γto struggle tumor cells.IDO-1 inhibitor(NLG919)afterwards mitigates the immunosuppressive behavior of IFN-γby neutralizing the function of IDO-1.To turn“waste”into wealth,anti-PD-L1(aPD-L1)antibodies are technically integrated into the nano-integrator to propel the precise attack of breast cancer through ascending PD-L1 blockade.Together,this“three musketeers”nano-integrator tumoricidal tactic may give a unique insight into the clinical anti-tumor therapy.

One step synthesis of efficient red emissive carbon dots and their bovine serum albumin composites with enhanced multi-photon fluorescence for in vivo bioimaging

Efficient red emissive carbon dots(CDs)in aqueous solutions are very scarce for high performance bioimaging applications.In this work,we report a one-step solvothermal treatment to synthesize pure red emissive CDs(FA-CDs)from citric acid and urea in formic acid without complicated purification procedures.Photoluminescence quantum yield(PLQY)of 43.4%was observed in their dimethyl sulfoxide solutions.High PLQY up to 21.9%in aqueous solutions was achieved in their bovine serum albumin(BSA)composites(FA-CDs@BSA)with significantly enhanced multiphoton fluorescence.The strong surface electron-withdrawing structure of FA-CDs caused by the high content of C=O groups contributes for their pure red emission.Owing to the significantly enhanced single and multi-photon red fluorescence and enlarged particle sizes after composing with BSA,in vivo tumor imaging and two-photon fluorescence imaging of blood vessels in mouse ear have been realized via intravenous injection of FA-CDs@BSA aqueous solutions.

Biomimetic Recognition-Based Bioorthogonal Host-Guest Pairs for Cell Targeting and Tissue Imaging in Living Animals

Bioconjugation methods offer very important tools in studying biological systems.Synthetic host-guest pairs provide an alternative and complementary conjugation method to bioorthogonal reactions and biological association pairs.Nevertheless,macrocyclic hosts that can be used for in situ capture are limited and often rely on extremely high binding affinities.Herein,we report an alternative bioorthogonal host-guest pair that relies on highly selective molecular recognition in water.The host,namely amide naphthotube,possesses a biomimetic cavity with inward-directing hydrogen bonding sites and shows selective and strong binding to the guest(2-phenyl pyrimidine)even in biological media.Through anchoring the tetraphenyl ethylene-modi fied hosts to cell surfaces,the bioorthogonal host-guest pair can be applied in cell surface recognition,cell-cell interactions,and tissue imaging in mice.The bioorthogonality is originated from the high binding selectivity of the biomimetic macrocyclic host,which is different from other known host-guest pairs that have been applied in biological systems.This research provides a new noncovalent bioconjugation tool and a new concept for designing bioorthogonal host-guest pairs for biological applications.

Building on the backbone of CD47-based therapy in cancer:Combination strategies,mechanisms,and future perspectives

Described as a“don't eat me”signal,CD47 becomes a vital immune checkpoint in cancer.Its interaction with signal regulatory protein alpha(SIRPa)prevents macrophage phagocytosis.In recent years,a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer effect.Latest clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies,indicating the combination strategy as a general trend of the future.In this review,clinical and preclinical cases about the current combination strategies targeting CD47 are collected,their underlying mechanisms of action are discussed,and ideas from future perspectives are shared.

超声激活的金属多酚配位纳米抗生素在体内抗耐药菌治疗中的应用

抗生素的滥用引发了漫延全球的抗生素耐药危机.多重耐药细菌的出现对人类生命健康构成了极大的威胁.此外,传统抗生素在体内杀死病原菌的同时,对人体正常微生物菌群的破坏也增加了导致其他感染和疾病的风险.因此,新型抗生素的研发显得日益紧迫.在本文中,我们合成了一种超声激活的金属多酚配位纳米抗生素(PEG-P18-Ag NPs),其可在感染部位被选择性激活,从而避免了对体内正常微生物群体的影响.实验证实PEG-P18-Ag NPs在未激活时不具有抗菌活性.经超声激活后,其可引起大量活性氧物种(ROS)的产生,从而杀死多种多重耐药菌及生物膜.通过RNA测序技术,本文进一步证实PEG-P18-Ag NPs对细菌细胞的细胞膜、核糖体、染色质及鞭毛等结构造成了严重损伤.总之,本研究合成了一种靶向体内耐药菌的新型抗生素,可实现广谱、快速和可控的抗多重耐药菌治疗.

CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Author correction to‘Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsisinduced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice'[Acta Pharmaceutica Sinica B 13(2023)1164-1179]

The authors regret that there were some picture errors in Fig.7C and Supporting Information Fig.S10B owing to the negligence of the picture typesetting and careless mistakes.In Fig.7C,the H&E picture of PBS+Lipo+CLP group was the inverted picture of CLP group in Fig.5G.In Fig.7C,the H&E picture of Clo-Lipo+CLP group was zoom-in picture of L johnsoni+CLP group in Fig.8F.In Fig.SI0B,the H&E picture of ileum in CLP group was zoom-in picture of Anti-IL-10R+CLP group in Fig.S11C.The authors revise the H&E picture of liver in PBS+Lipo+CLP group and the H&E picture of liver in Clo-Lipo+CLP group in Fig.7C.Also,the H&E picture of ileum in CLP group of Fig.S10B have been revised.The correct figures are presented as below.