NIR-Ⅱ成像引导的精准光动力治疗通过干扰糖代谢重编程增强肿瘤饥饿治疗

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy-Dglucose(2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy(PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle(Ln NP) cores was constructed and combined with mesoporous silicon shells loaded with2DG and photosensitizer chlorin e6(Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared(NIR-II, 1000–1700 nm) window from the Ln NPs was used to monitor the accumulation of nanomaterials in tumors.Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system.

Activation of autophagy by in situ Zn^(2+) chelation reaction for enhanced tumor chemoimmunotherapy

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment.Although autophagy is involved in activating tumor immunity,the synergistic role of autophagy in ICD remains elusive and challenging.Herein,we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion(Zn^(2+))-doped,disulfiram(DSF)-loaded mesoporous silica nanoparticles(DSF@Zn-DMSNs).Upon pH-sensitive biodegradation of DSF@Zn-DMSNs,Zn2+and DSF are coreleased in the mildly acidic tumor microenvironment,leading to the formation of toxic Zn2+chelate through an in situ chelation reaction.Consequently,this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns(DAMPs)but also activates autophagy,which mediates the amplified release of DAMPs to enhance ICD.In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy,thus enhancing immunotherapy by promoting the infiltration of T cells.This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.

Destroying pathogen-tumor symbionts synergizing with catalytic therapy of colorectal cancer by biomimetic protein-supported single-atom nanozyme

The crucial role of intratumoral bacteria in the progression of cancer has been gradually recognized with the development of sequencing technology.Several intratumoral bacteria which have been identified as pathogens of cancer that induce progression,metastasis,and poor outcome of cancer,while tumor vascular networks and immunosuppressive microenvironment provide shelters for pathogens localization.Thus,the mutually-beneficial interplay between pathogens and tumors,named“pathogentumor symbionts”,is probably a potential therapeutic site for tumor treatment.Herein,we proposed a destroying pathogen-tumor symbionts strategy that kills intratumoral pathogens,F.nucleatum,to break the symbiont and synergize to kill colorectal cancer(CRC)cells.This strategy was achieved by a groundbreaking protein-supported copper single-atom nanozyme(BSA-Cu SAN)which was inspired by the structures of native enzymes that are based on protein,with metal elements as the active center.BSA-Cu SAN can exert catalytic therapy by generating reactive oxygen species(ROS)and depleting GSH.The in vitro and in vivo experiments demonstrate that BSA-Cu SAN passively targets tumor sites and efficiently scavenges F.nucleatum in situ to destroy pathogentumor symbionts.As a result,ROS resistance of CRC through elevated autophagy mediated by F.nucleatum was relieved,contributing to apoptosis of cancer cells induced by intracellular redox imbalance generated by BSA-Cu SAN.Particularly,BSA-Cu SAN experiences renal clearance,avoiding long-term systemic toxicity.This work provides a feasible paradigm for destroying pathogen-tumor symbionts to block intratumoral pathogens interplay with CRC for antitumor therapy and an optimized trail for the SAN catalytic therapy by the clearable protein-supported SAN.

Microbial treatment in chronic constipation

Chronic functional constipation is a kind of common intestinal disease that occurs in children, adults and elderly people. This disease not only causes great influence to physiological function, but also results in varying degrees of psychological barriers. At present, constipation treatments continue to rely on traditional methods such as purgative therapy and surgery. However, these approaches can disrupt intestinal function. Recent research between intestinal diseases and gut microbiota has gradually revealed a connection between constipation and intestinal flora disturbance, providing a theoretical basis for microbial treatment in chronic constipation. Microbial treatment mainly includes probiotic preparations such as probiotics, prebiotics, synbiotics and fecal microbiota transplantation(FMT). Due to its safety, convenience and curative effect, probiotic preparations have been widely accepted, especially gradually developed FMT with higher curative effects. Microbial treatment improves clinical symptoms, promotes the recovery of intestinal flora, and has no complications during the treatment process. Compared with traditional treatments, microbial treatment in chronic constipation has advantages, and is worthy of further promotion from clinical research to clinical application.

Dysbiosis of gut microbiota was closely associated with psoriasis

Psoriasis is an autoimmune disease and gut microbiota participate in the establishment of intestinal immunity. This study was performed to identify the fecal microbial composition of psoriasis patients, and investigated the influence of subgroup(type and severity) on the fecal microbial composition, and to define the key microbiota in the pathogenesis of psoriasis. Fecal samples from 35 psoriasis patients and 27 healthy controls were sequenced by 16 S rRNA and then analyzed by informatics methods. We found that the microbiota of the psoriasis group differed from that of the heathy group. The relative abundances of Firmicutes and Bacteroidetes were inverted at the phylum level, and 16 kinds of phylotype at the genus level were found with significant difference. No microbial diversity and composition alteration were observed among the four types of psoriasis. The microbiota of psoriasis patients in the severe state differs from those of psoriasis patients with more mild conditions and also the healthy controls. The veillonella in fecal microbiota showed a positive relationship with h-CRP in blood. This research proved that psoriasis patients have a significant disturbed microbiota profiles. Further study of psoriasis based on microbiota may provide novel insights into the pathogenesis of psoriasis and more evidence for the prevention and treatment of psoriasis.

Alterations in intestinal microbiota of colorectal cancer patients receiving radical surgery combined with adjuvant CapeOx therapy

An intricate relationship exists and interactions occur between gut microbiota and colorectal cancer(CRC).Radical surgery combined with adjuvant chemotherapy(AC) serves as the mainstream therapeutic scheme for most CRC patients.The current research was conducted to assess the effect of surgery or chemotherapy on gut microbiota.Forty-three CRC patients who received radical surgery and AC were enrolled.Fecal samples were collected preoperatively,postoperatively,and after the first to fifth cycles of postoperative chemotherapy.The microbial community of each sample was analyzed using high throughput 16S rRNA amplicon sequencing.Compared with preoperative samples,fecal samples collected postoperatively exhibited a significant decrease of obligate anaerobes,tumor-related bacteria,and butyric acid-producing bacteria.However,a significant increase of some conditional pathogens was observed.In addition,the AC regimen(CapeOx) was found to alter intestinal microbiota dramatically.In particular,several changes were observed after chemotherapy including an increase of pathogenic bacteria,the "rebound effect" of chemotherapy-adapted bacteria,the shift of lactate-utilizing microbiota from Veillonella to Butyricimonas and Butyricicoccus,as well as the decrease of probiotics.Both radical surgery and CapeOx chemotherapy exert a non-negligible effect on the gut microbiota of CRC patients.Microbiota-based intervention may be beneficial for patients during postoperative clinical management.

Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome

Accumulating evidence suggests that ketogenic diets(KDs)mediate the rise of circulating ketone bodies and exert a potential antiinflammatory effect;however,the consequences of this unique diet on colitis remain unknown.We performed a series of systematic studies using a dextran sulfate sodium(DSS)animal model of inflammatory colitis.Animals were fed with a KD,low-carbohydrate diet(LCD),or normal diet(ND).Germ-free mice were utilized in validation experiments.Colon tissues were analyzed by transcriptome sequencing,RT2 profiler PCR array,histopathology,and immunofluorescence.Serum samples were analyzed by metabolic assay kit.Fecal samples were analyzed by 16S rRNA gene sequencing,liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD.Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia,whereas the opposite was observed for Escherichia/Shigella.After colitis induction,the KD protected intestinal barrier function,and reduced the production of R0Ryt+CD3_group 3 innate lymphoid cells(ILC3s)and related inflammatory cytokines(IL-17a,IL-18,IL-22,Ccl4).Finally,fecal microbiota transplantation into germ-free mice revealed that the KD-mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota.Taken together,our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment,and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.

Ketogenic diet for human diseases:the underlying mechanisms and potential for clinical implementations

The ketogenic diet(KD)is a high-fat,adequate-protein,and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies.The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade,subject to emerging evidence of the promising therapeutic potential of the KD for various diseases,besides epilepsy,from obesity to malignancies.In this review,we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases,and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels.We emphasize that the KD may function through multiple mechanisms,which remain to be further elucidated.The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed.We suggest that,with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action,randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade in colorectal cancer

Given that only a subset of patients with colorectal cancer(CRC)benefit from immune checkpoint therapy,efforts are ongoing to identify markers that predict immunotherapeutic response.Increasing evidence suggests that microbes influence the efficacy of cancer therapies.Fusobacterium nucleatum induces different immune responses in CRC with different microsatellite-instability(MSI)statuses.Here,we investigated the effect of F.nucleatum on anti-PD-L1 therapy in CRC.We found that high F.nucleatum levels correlate with improved therapeutic responses to PD-1 blockade in patients with CRC.Additionally,F.nucleatum enhanced the antitumor effects of PD-L1 blockade on CRC in mice and prolonged survival.Combining F.nucleatum supplementation with immunotherapy rescued the therapeutic effects of PD-L1 blockade.Furthermore,F.nucleatum induced PD-L1 expression by activating STING signaling and increased the accumulation of interferon-gamma(IFN-γ)^(+)CD8^(+)tumor-infiltrating lymphocytes(TILs)during treatment with PD-L1 blockade,thereby augmenting tumor sensitivity to PD-L1 blockade.Finally,patient-derived organoid models demonstrated that increased F.nucleatum levels correlated with an improved therapeutic response to PD-L1 blockade.These findings suggest that F.nucleatum may modulate immune checkpoint therapy for CRC.

Fecal microbiota transplantation: standardization or diversification?

Call for standardization of fecal microbiota transplantation(FMT)The gut microbiota plays an important role in human health and disease.Dysbiosis is often recognized in patients with diseases of the digestive and other systems(Blaser,2019;Li et al.,2018b;Qin et al.,2018).FMT refers to the administration of fecal material containing distal gut microbiota from a healthy person(donor)to a patient(recipient)to restore the gut microecology of the recipient(Kelly et al.,2015).Clinical guidelines have strongly recommended FMT for the treatment of relapsed or refractory Clostridium difficile infection(CDI)(Mullish et al.,2018).FMT has also shown potential clinical benefits in many other diseases related to dysbiosis,including inflammatory bowel disease(IBD),irritable bowel syndrome(IBS),functional constipation(FC),liver diseases,metabolic syndrome,autism,and cancer(Huang et al.,2018;Li et al.,2018a;Zhang et al.,2018).Because of its broad curative potential,FMT has become a topic of great interest.More than 3,000 published articles have reported treatment of different diseases with FMT,and over 380 FMT trials have been registered on the ClinicalTrials.gov website.

Targeting TM4SF1 exhibits therapeutic potential via inhibition of cancer stem cells

Dear Editor,Cancer stem cells(CSCs)are thought to be responsible for cancer initiation,growth,recurrence,metastasis,and drug resistance.1 Therefore,targeting CSCs is an effective therapeutic approach for cancer.2 However,there are few CSC-specific targets with functional extracellular domains for the development of antibody drugs.3 Our published paper demonstrated that transmembrane 4 L six family member 1(TM4SF1)coupled discoidin domain receptor tyrosine kinase 1(DDR1)under collagen I stimulation activated JAK2-STAT3 signaling.This noncanonical DDR1 signaling sustained the manifestation of CSC traits by inducing SOX2 and NANOG expression and drove multiorgan metastases.

Correction To: Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade in colorectal cancer

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/S41392-021-00795-x,published online 19 November 2021 In this article^(1) Qing Wei should have been denoted as a corresponding author along with Huanlong Qin,but was inadvertently removed during the production process.The original article has been corrected.

Fluid balance in major abdominal surgery deserves more exploration

Professor Myles and his team have published their latest study entitled"Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery"in the New England Journal of Medicine(1).This international study enrolled 2,983 patients undergoing major abdominal surgery in seven countries.