An NIR-II-enhanced nanozyme to promote wound healing in methicillin-resistant Staphylococcus aureus infections.

Deep tissue bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infections, pose challenges to clinical therapy due to their low debridement efficiency and relapsing. Molybdenum disulfide (MoS2) is used in the antibacterial field as a classic photothermal agent (NIR-I) with good biocompatibility. However, due to its limited NIR-I tissue penetration ability and single treatment mode, MoS2 has poor therapeutic effects on deep tissue infection. Herein, we prepared a defect-type hybrid 2H-MoS2 nanozyme (MoWS2) using hydrothermal method fabricate the MoWS2 composite, which is a new antibacterial strategy involving photothermal and enzyme catalysis, and further enhances the activity of the nanozyme through overheating. The regulation of 2H-MoS2 defects through tungsten ion doping endows MoWS2 with better near-infrared two-region absorption (NIR-II) and enzyme catalytic performance. Antibacterial activity experiments in vitro have shown that MoWS2 can achieve efficient bactericidal activity and biofilm clearance through hyperthermia and reactive oxygen species (ROS). Deep MRSA infection experiments have shown that MoWS2 rapidly removes bacteria from subcutaneous infected tissues through photothermal therapy (PTT) and chemodynamic therapy (CDT), accelerates the dissipation of abscesses, and promotes the healing of infected wounds. Additionally, the versatile treatment mode of MoWS2 was further confirmed through tissue sectioning and immunofluorescence staining analysis. Overall, these results provide a feasible approach for achieving efficient treatment of deep tissue infections through tungsten ion doping to regulate defective 2H-MoS2. STATEMENT OF SIGNIFICANCE: The photothermal effect of MoS2 nanosheets in the NIR-I (650-900 nm) window in anti-MRSA therapy is considered to be highly reliable and efficient in PTA. However, most of the developed PPT therapies or antimicrobial systems based on PTT therapies developed with 1T-MoS2 have in vivo sterilization temperatures of more than 55°C, which have the risk of damaging the normal tissues of the skin. In this study, we prepared W@MoS2 with a good photothermal effect (36.9%) in the NIR-II window and good peroxidase-like activity. The combined effect of PTT and CDT has a stronger bactericidal effect while avoiding high-temperature damage, which makes the W@MoS2 material more advantageous in terms of antimicrobial effect.

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance.

Immune checkpoint inhibitors (ICIs) have been extensively used in immunological therapy primarily due to their ability to prolong patient survival. Although ICIs have achieved success in cancer treatment, the resistance of ICIs should not be overlooked. Ferroptosis is a newly found cell death mode characterized by the accumulation of reactive oxygen species (ROS), glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, which has been demonstrated to be beneficial to immunotherapy and combining ferroptosis and ICIs to exploit new immunotherapies may reverse ICIs resistance. Exosomes act as mediators in cell-to-cell communication that may regulate ferroptosis to influence immunotherapy through the secretion of biological molecules. Thus, utilizing exosomes to target ferroptosis has opened up exciting possibilities for reversing ICIs resistance. In this review, we summarize the mechanisms of ferroptosis improving ICIs therapy and how exosomes regulate ferroptosis through adjusting iron metabolism, blocking the ROS accumulation, controlling ferroptosis defense systems, and influencing classic signaling pathways and how engineered exosomes target ferroptosis and improve ICIs efficiency.

Exosomal non-coding RNA: A new frontier in diagnosing and treating pancreatic cancer: A review.

Pancreatic cancer is the most fatal malignancy worldwide. Once diagnosed, most patients are already at an advanced stage because of their highly heterogeneous, drug-resistant, and metastatic nature and the lack of effective diagnostic markers. Recently, the study of proliferation, metastasis, and drug resistance mechanisms in pancreatic cancer and the search for useful diagnostic markers have posed significant challenges to the scientific community. Exosomes carry various biomolecules (DNA, non-coding RNAs (ncRNAs), proteins, and lipids) that mediate communication between tumors and other cells. ncRNAs can be transported through exosomes to numerous relevant receptor cells and regulate local epithelial-mesenchymal transition (EMT) in tumor tissue, proliferation, drug resistance, and the establishment of pre-metastatic ecological niches in distant organs. In summary, exosomal ncRNAs promote tumor cell proliferation, invasion, and metastasis through multiple EMT, immunosuppression, angiogenesis, and extracellular matrix remodeling pathways. Moreover, we discuss the significant therapeutic significance of exosomal ncRNAs as PC biomarkers.

Tumour-associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy.

Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

Effect of bone mass density and alveolar bone resorption on stress in implant restoration of free-end edentulous posterior mandible: Finite element analysis of double-factor sensitivity.

BACKGROUND: Osseous condition of the mandible was regarded as a key factor influencing stability of implants in the early stage. Finite element analysis was used to assess the effect of bone mass density and alveolar bone resorption (double factors) on stress in a four-unit implant restoration of a free-end edentulous posterior mandible. METHODS: A 3D finite element model was constructed for a single-sided free-end edentulous mandible (from mandibular first premolar to mandibular second molar) containing threaded dental implants. Mandible sensitivity modes were constructed with different alveolar bone resorption levels for normal conditions as well as mild, moderate and severe periodontitis, respectively. Based on the mass density of cancellous bone for four types of bones as the sensitivity parameter, two implant design modes were constructed: Model A (four-unit fixed bridge supported by three implants, implant positions were 34, 36 and 37) and model B: 34 × 36, 37 (37: a single implant crown) (34 × 36: three-unit fixed bridge supported by two implants, implant positions were 34 and 36). A total of 32 sensitivity-based finite element models, grouped in two groups, were constructed. Stress distribution and maximum von Mises stress on cortical bone and cancellous bone around the implant, as well as the surface of implant were investigated by using ABAQUS when vertical loading and 45° oblique loading were applied, respectively. RESULTS: When vertical loading was applied on the implant, maximum von Mises stress on the cortical bone around the implant was assessed to be 4.726 MPa - 13.15 MPa and 6.254 MPa - 13.79 MPa for groups A and B, respectively; maximum stress on the cancellous bone around the implant was 2.641 MPa - 3.773 MPa and 2.864 MPa - 4.605 MPa, respectively; maximum stress on the surface of implant was 14.7 MPa - 21.17 MPa and 21.64 MPa - 30.70 MPa, respectively. When 45° oblique loading was applied on the implant restoration, maximum von Mises stress on the cortical bone around the implant was assessed to be 42.08 MPa - 92.71 MPa and 50.84 MPa - 102.5 MPa for groups A and B, respectively; maximum stress on the cancellous bone around the implant was 4.88 MPa - 25.95 MPa and 5.227 MPa - 28.43 MPa, respectively; maximum stress on the surface of implant was 77.91 MPa - 124.8 MPa and 109.2 MPa - 150.7 MPa, respectively. Stress peak on the cortical bone and that on cancellous bone around the implant increased and decreased with the decrease in bone mass density, respectively. Stress peak on alveolar bone increased with alveolar bone resorption when oblique loading was applied. CONCLUSION: 1. Both alveolar bone resorption and bone mass density (double factors) are critical to implant restoration. Bone mass density may exhibit a more pronounced impact than alveolar bone resorption. 2. From the biomechanical perspective, types I and II bones are preferred for implant restoration, while implantation should be considered carefully in the case of type III bones, or those with less bone mass density accompanied by moderate to severe alveolar bone loss. 3. Splinting crowns restoration is biomechanically superior to single crown restoration.

On the road to colorectal cancer development: crosstalk between the gut microbiota, metabolic reprogramming, and epigenetic modifications.

An increasing number of studies have reported the role of gut microbes in colorectal cancer (CRC) development, as they can be influenced by dietary metabolism and mediate alterations in host epigenetics, ultimately affecting CRC. Intake of specific dietary components can affect gut microbial composition and function, and their metabolism regulates important epigenetic functions that may influence CRC risk. Gut microbes can regulate epigenetic modifications through nutrient metabolism, including histone modification, DNA methylation, and noncoding RNAs. Epigenetics, in turn, determines the gut microbial composition and thus influences the risk of developing CRC. This review discusses the complex crosstalk between metabolic reprogramming, gut microbiota, and epigenetics in CRC and highlights the potential applications of the gut microbiota as a biomarker for the prevention, diagnosis, and therapy of CRC.

Akkermansia muciniphila: a potential booster to improve the effectiveness of cancer immunotherapy.

Cancer immunotherapy has emerged as a groundbreaking method of treating malignancies. However, cancer immunotherapy can only benefit a small percentage of patients, and the numerous side effects that might develop during treatment reduce its effectiveness or even put patients' lives in jeopardy. Surprisingly, the gut microbiome Akkermansia muciniphila (A. muciniphila) can significantly inhibit carcinogenesis and improve anti-tumor effects, thus increasing the effectiveness of cancer immunotherapy and decreasing the likelihood of side effects. In this review, we focus on the effects of A. muciniphila on the human immune system and the positive impacts of A. muciniphila on cancer immunotherapy, which can build on strengths and improve weaknesses of cancer immunotherapy. The potential clinical applications of A. muciniphila on cancer immunotherapy are also proposed, which have great prospects for anti-tumor therapy.

Progress of gut microbiome and its metabolomics in early screening of colorectal cancer

Gut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC (AU)

The huge potential of targeting copper status in the treatment of colorectal cancer

Colorectal cancer (CRC) commonly leads to cancer deaths and is often diagnosed at advanced stages. It also faces difficulties due to the poor results of conventional treatments such as surgery, chemotherapy, and radiotherapy. Copper is a mineral nutrient whose intrinsic properties have a two-way effect on the production and treatment of cancer. Copper's redox properties allow it to be used in developing anti-cancer drugs, while its potential toxicity leads to oxidative stress and even cancer. Copper status is closely related to colorectal tumors’ proliferation and metastasis. The study of the mechanisms of copper homeostasis, cuproplasia, and cuproptosis due to altered copper status plays a crucial role in developing anticancer drugs. Therefore, targeting alteration of copper status becomes a potential option for treating colorectal cancer. This review summarizes the mechanisms by which altered copper status causes CRC progression and emphasizes the potential of regulating copper status in treating CRC (AU)

Intratumoural microbiota: from theory to clinical application.

Cancer is a major cause of high morbidity and mortality worldwide. Several environmental, genetic and lifestyle factors are associated with the development of cancer in humans and result in suboptimal treatment. The human microbiota has been implicated in the pathophysiological process of cancer and has been used as a diagnostic, prognostic and risk assessment tool in cancer management. Notably, both extratumoural and intratumoural microbiota are important components of the tumor microenvironment, subtly influencing tumorigenesis, progression, treatment and prognosis. The potential oncogenic mechanisms of action of the intratumoural microbiota include induction of DNA damage, influence on cell signaling pathways and impairment of immune responses. Some naturally occurring or genetically engineered microorganisms can specifically accumulate and replicate in tumors and then initiate various anti-tumor programs, ultimately promoting the therapeutic effect of tumor microbiota and reducing the toxic and side effects of conventional tumor treatments, which may be conducive to the pursuit of accurate cancer treatment. In this review, we summarise evidence revealing the impact of the intratumoural microbiota on cancer occurrence and progress and potential therapeutic and diagnostic applications, which may be a promising novel strategy to inhibit tumor development and enhance therapeutic efficacy. Video Abstract.

The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target.

Heat shock protein 70 (HSP70) is a highly conserved protein composed of nucleotide-binding domains (NBD) and C-terminal substrate binding domain (SBD) that can function as a "molecular chaperone". HSP70 was discovered to directly or indirectly play a regulatory role in both internal and external apoptosis pathways. Studies have shown that HSP70 can not only promote tumor progression, enhance tumor cell resistance and inhibit anticancer effects but also induce an anticancer response by activating immune cells. In addition, chemotherapy, radiotherapy and immunotherapy for cancer may be affected by HSP70, which has shown promising potential as an anticancer drug. In this review, we summarized the molecular structure and mechanism of HSP70 and discussed the dual effects of HSP70 on tumor cells and the possibility and potential methods of using HSP70 as a target to treat cancer.

Influence of different implant designs on replacement of four teeth of the posterior free-end edentulism: Three-dimensional finite element analysis and clinic case validation.

BACKGROUND: With periodontal disease having an increasing incidence, mandibular free-end edentulism caused by periodontitis is clinically more common. Finite element analysis and clinical case reports were used to evaluate the influence of different designs on the load distribution of implant prosthesis in mandibular posterior free-end edentulism. METHOD: A finite element model of a mandible with posterior free-end edentulism was established. Considering the implant position and selection of single crown repair or splint repair, four designs were conducted including model A: 3435 × 37(four-unit fixed bridge supported by three implants, implant positions were 34, 35, 37); model B: 34,35 × 37, (34: a single implant crown) (35 ×37: three-unit fixed bridge supported by two implants, implant positions were 35, 37); model C: 34 × 3637(four-unit fixed bridge supported by three implants, implant positions were 34, 36, 37); and model D: 34 × 36, 37(37: a single implant crown)(34 ×36: three-unit fixed bridge supported by two implants, implant positions were 34, 36). Stress distribution and the Von Mises stress value of the implants, the crown and the bone around the implants were analyzed at vertical and 45° inclined load. RESULTS: Stress in the cortical bone was mainly concentrated around the implant neck, and maximum Von Mises stress (MVMS) of the four models was 11.6-16.1 MPa at vertical load and 61.74-96.49 MPa at 45° inclined load. Stress in the cancellous bone was concentrated around the implant base, and MVMS of four models was 3.075-3.899 MPa at vertical load and 5.021-6.165 MPa at 45° inclined load. Stress of the restoration crowns was mainly concentrated in the connector of the bridge, and MVMS of four models was 23.38-26.28 MPa at vertical load and 53.14-56.35 MPa at 45° inclined load. Stress of the implant interface was mainly concentrated on the surface of the smaller implants near the bridge, and MVMS of four models was 21.12-33.25 MPa at vertical load and 83.73-138.7 MPa at 45° inclined load. CONCLUSION: There was favorable stress distribution of the four models at vertical load and 45° inclined load. Design of a three-unit fixed bridge combined with a partial crown may be an available option for devising patient treatment plans with mandibular free-end edentulism.

Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.

Metastasis, the spread of a tumor or cancer from the primary site of the body to a secondary site, is a multi-step process in cancer progression, accounting for various obstacles in cancer treatment and most cancer-related deaths. Metabolic reprogramming refers to adaptive metabolic changes that occur in cancer cells in the tumor microenvironment (TME) to enhance their survival ability and metastatic potential. Stromal cell metabolism also changes to stimulate tumor proliferation and metastasis. Metabolic adaptations of tumor and non-tumor cells exist not only in the TME but also in the pre-metastatic niche (PMN), a remote TME conducive for tumor metastasis. As a novel mediator in cell-to-cell communication, small extracellular vesicles (sEVs), which have a diameter of 30-150 nm, reprogram metabolism in stromal and cancer cells within the TME by transferring bioactive substances including proteins, mRNAs and miRNAs (microRNAs). sEVs can be delivered from the primary TME to PMN, affecting PMN formation in stroma rewriting, angiogenesis, immunological suppression and matrix cell metabolism by mediating metabolic reprogramming. Herein, we review the functions of sEVs in cancer cells and the TME, how sEVs facilitate PMN establishment to trigger metastasis via metabolic reprogramming, and the prospective applications of sEVs in tumor diagnosis and treatment. Video Abstract.

Progress of gut microbiome and its metabolomics in early screening of colorectal cancer.

Gut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.

The huge potential of targeting copper status in the treatment of colorectal cancer.

Colorectal cancer (CRC) commonly leads to cancer deaths and is often diagnosed at advanced stages. It also faces difficulties due to the poor results of conventional treatments such as surgery, chemotherapy, and radiotherapy. Copper is a mineral nutrient whose intrinsic properties have a two-way effect on the production and treatment of cancer. Copper's redox properties allow it to be used in developing anti-cancer drugs, while its potential toxicity leads to oxidative stress and even cancer. Copper status is closely related to colorectal tumors' proliferation and metastasis. The study of the mechanisms of copper homeostasis, cuproplasia, and cuproptosis due to altered copper status plays a crucial role in developing anticancer drugs. Therefore, targeting alteration of copper status becomes a potential option for treating colorectal cancer. This review summarizes the mechanisms by which altered copper status causes CRC progression and emphasizes the potential of regulating copper status in treating CRC.

Intratumoral microbiota: A new force in diagnosing and treating pancreatic cancer.

Pancreatic cancer is an increasingly growing source of cancer-related deaths and is often diagnosed at advanced stages. Its treatment is difficult because of the poor results of conventional treatments, such as surgery, chemotherapy, and radiotherapy. Microbiota and their products can regulate the microenvironment of pancreatic tumors, the biological behavior of pancreatic cancer cells, and the functionality of the immune system. Promising results have been achieved in treating pancreatic cancer by regulating microbiota. However, intratumoral microbiota is still in its infancy as a new field of discovery for pancreatic cancer. This review summarizes the mechanisms by which intratumoral microbiota causes pancreatic cancer tumorigenesis, progression, and metastasis and demonstrates their significant potential in diagnosing and treating pancreatic cancer. Additionally, we present an outlook on the future of intratumoral microbiota in treating pancreatic cancer.

Effects of Long Non-Coding RNAs Induced by the Gut Microbiome on Regulating the Development of Colorectal Cancer.

Although an imbalanced gut microbiome is closely associated with colorectal cancer (CRC), how the gut microbiome affects CRC is not known. Long non-coding RNAs (lncRNAs) can affect important cellular functions such as cell division, proliferation, and apoptosis. The abnormal expression of lncRNAs can promote CRC cell growth, proliferation, and metastasis, mediating the effects of the gut microbiome on CRC. Generally, the gut microbiome regulates the lncRNAs expression, which subsequently impacts the host transcriptome to change the expression of downstream target molecules, ultimately resulting in the development and progression of CRC. We focused on the important role of the microbiome in CRC and their effects on CRC-related lncRNAs. We also reviewed the impact of the two main pathogenic bacteria, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, and metabolites of the gut microbiome, butyrate, and lipopolysaccharide, on lncRNAs. Finally, available therapies that target the gut microbiome and lncRNAs to prevent and treat CRC were proposed.

The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications

Colorectal cancer (CRC) is the third most common cancer in the world today, and its incidence and mortality rates are increasing every year. The ease of proliferation and metastasis of CRC has long been an important reason for its high mortality rate. Exosomes serve as key mediators that mediate communication between tumor cells and various other cells. Non-coding RNAs (ncRNAs) have been shown to play a key role in apoptosis, immunosuppression and proliferation metastasis in cancer. ncRNAs are loaded on exosomes and initiate the onset of metastasis by promoting epithelial-mesenchymal transition (EMT) at the primary site of the tumor. Meanwhile, exosome-derived ncRNAs construct a pre-metastatic niche (PMN) for CRC metastasis by forming an inflammatory microenvironment in distant organs, immunosuppression, and promoting angiogenesis and remodeling of the extracellular matrix. Here, we summarize the specific mechanisms associated with exosome-derived ncRNAs promoting local invasion and metastasis in CRC. Finally, we focus on their value for clinical application in future CRC diagnosis and treatment (AU)

Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is highly immune tolerant. Although there is immune cell infiltration in PDAC tissues, most of the immune cells do not function properly and, therefore, the prognosis of PDAC is very poor. Galectins are carbohydrate-binding proteins that are intimately involved in the proliferation and metastasis of tumor cells and, in particular, play a crucial role in the immune evasion of tumor cells. Galectins induce abnormal functions and reduce numbers of tumor-associated macrophages (TAM), natural killer cells (NK), T cells and B cells. It further promotes fibrosis of tissues surrounding PDAC, enhances local cellular metabolism, and ultimately constructs tumor immune privileged areas to induce immune evasion behavior of tumor cells. Here, we summarize the respective mechanisms of action played by different Galectins in the process of immune escape from PDAC, focusing on the mechanism of action of Galectin-1. Galectins cause imbalance between tumor immunity and anti-tumor immunity by coordinating the function and number of immune cells, which leads to the development and progression of PDAC.

Nanomaterial-Based Drug Delivery Systems: A New Weapon for Cancer Immunotherapy.

Cancer immunotherapy, a major breakthrough in cancer treatment, has been successfully applied to treat a number of tumors. However, given the presence of factors in the tumor microenvironment (TME) that impede immunotherapy, only a small proportion of patients achieve a good clinical response. With the ability to increase permeability and cross biological barriers, nanomaterials have been successfully applied to deliver immunotherapeutic agents, thus realizing the anti-cancer therapeutic potential of therapeutic agents. This has driven a wave of research into systems for the delivery of immunotherapeutic agents, which has resulted in widespread interest in nanomaterial-based drug delivery systems. Nanomaterial-based drug delivery systems are able to overcome the challenges from TME and thus achieve good results in cancer immunotherapy. If it can make a breakthrough in improving biocompatibility and reducing cytotoxicity, it will be more widely used in clinical practice. Different types of nanomaterials may also have some subtle differences in enhancing cancer immunotherapy. Moreover, delivery systems made of nanomaterials loaded with drugs, such as cytotoxic drugs, cytokines, and adjuvants, could be used for cancer immunotherapy because they avoid the toxicity and side effects associated with these drugs, thereby enabling their reuse. Therefore, further insights into nanomaterial-based drug delivery systems will provide more effective treatment options for cancer patients.