Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism.

Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.

Irradiated microparticles suppress prostate cancer by tumor microenvironment reprogramming and ferroptosis.

Immunogenic cell death (ICD) plays a crucial role in triggering the antitumor immune response in the tumor microenvironment (TME). Recently, considerable attention has been dedicated to ferroptosis, a type of ICD that is induced by intracellular iron and has been demonstrated to change the immune desert status of the TME. However, among cancers that are characterized by an immune desert, such as prostate cancer, strategies for inducing high levels of ferroptosis remain limited. Radiated tumor cell-derived microparticles (RMPs) are radiotherapy mimetics that have been shown to activate the cGAS-STING pathway, induce tumor cell ferroptosis, and inhibit M2 macrophage polarization. RMPs can also act as carriers of agents with biocompatibility. In the present study, we designed a therapeutic system wherein the ferroptosis inducer RSL-3 was loaded into RMPs, which were tested in in vitro and in vivo prostate carcinoma models established using RM-1 cells. The apoptosis inducer CT20 peptide (CT20p) was also added to the RMPs to aggravate ferroptosis. Our results showed that RSL-3- and CT20p-loaded RMPs (RC@RMPs) led to ferroptosis and apoptosis of RM-1 cells. Moreover, CT20p had a synergistic effect on ferroptosis by promoting reactive oxygen species (ROS) production, lipid hydroperoxide production, and mitochondrial instability. RC@RMPs elevated dendritic cell (DC) expression of MHCII, CD80, and CD86 and facilitated M1 macrophage polarization. In a subcutaneously transplanted RM-1 tumor model in mice, RC@RMPs inhibited tumor growth and prolonged survival time via DC activation, macrophage reprogramming, enhancement of CD8+ T cell infiltration, and proinflammatory cytokine production in the tumor. Moreover, combination treatment with anti-PD-1 improved RM-1 tumor inhibition. This study provides a strategy for the synergistic enhancement of ferroptosis for prostate cancer immunotherapies.

Gold nanoparticles exhibit anti-osteoarthritic effects via modulating interaction of the "microbiota-gut-joint" axis.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.

Brassica napus cytochrome P450 superfamily: Origin from parental species and involvement in diseases resistance, abiotic stresses tolerance, and seed quality traits.

Cytochromes P450 monooxygenases (CYP450s) constitute the largest enzymic protein family that is widely present in plants, animals, and microorganisms, participate in numerous metabolic pathways, and play diverse roles in development, metabolism, and defense. Rapeseed (Brassica napus) is an important oil crop worldwide and have many versions of reference genome. However, there is no systemically comparative genome-wide analysis of CYP450 family genes in rapeseed and its parental species B. rapa and B. oleracea. In this study, we identified 765, 293 and 437 CYP450 genes in B. napus, B. rapa and B. oleracea, respectively, which were unevenly located in A01-A10 and/or C01-C09 chromosomes in corresponding species. Phylogenetic relationship analysis indicated that 1745 CYP450 proteins from three Brassica species and Arabidopsis were divided into 4 groups. Whole genome duplication (WGD) or segmental duplication resulted in gene expansion of CYP450 family in three Brassica species. There were 33-83 SSR loci in CYP450 genes of three Brassica species, and numerous transcription factor binding sites were identified in their promoters. A total of 459-777 miRNAs were predicted to target 174-426 CYP450 genes in three Brassica species. Based on transcriptome data, BnCYP450s, BrCYP450s and BoCYP450s were differentially expressed in various tissues. There existed numerous BnCYP450 DEGs in response to pathogens and abiotic stresses. Besides, many BnCYP450 DEGs were involved in the regulation of important traits, such as seed germination, seed ALA content, and yellow-seed. The qRT-PCR experiment confirmed the transcriptome analysis results by validating two representative Sclerotinia-responsive BnCYP450 DEGs as an example. Three BnCYP450s genes (CYP707A1, CYP81F1, CYP81H1) might be regulated by seed-specific transcription factors BnTT1 and BnbZIP67 to participate in the development and metabolism of seed coat and embryo by undertaking related metabolic reactions.

Bile acid metabolism regulatory network orchestrates bone homeostasis.

Bile acids (BAs), synthesized in the liver and modified by the gut microbiota, have been widely appreciated not only as simple lipid emulsifiers, but also as complex metabolic regulators and momentous signaling molecules, which play prominent roles in the complex interaction among several metabolic systems. Recent studies have drawn us eyes on the diverse physiological functions of BAs, to enlarge the knowledge about the "gut-bone" axis due to the participation about the gut microbiota-derived BAs to modulate bone homeostasis at physiological and pathological stations. In this review, we have summarized the metabolic processes of BAs and highlighted the crucial roles of BAs targeting bile acid-activated receptors, promoting the proliferation and differentiation of osteoblasts (OBs), inhibiting the activity of osteoclasts (OCs), as well as reducing articular cartilage degradation, thus facilitating bone repair. In addition, we have also focused on the bidirectional effects of BA signaling networks in coordinating the dynamic balance of bone matrix and demonstrated the promising effects of BAs on the development or treatment for pathological bone diseases. In a word, further clinical applications targeting BA metabolism or modulating gut metabolome and related derivatives may be developed as effective therapeutic strategies for bone destruction diseases.

Krüppel-like factors family in health and disease.

Krüppel-like factors (KLFs) are a family of basic transcription factors with three conserved Cys2/His2 zinc finger domains located in their C-terminal regions. It is acknowledged that KLFs exert complicated effects on cell proliferation, differentiation, survival, and responses to stimuli. Dysregulation of KLFs is associated with a range of diseases including cardiovascular disorders, metabolic diseases, autoimmune conditions, cancer, and neurodegenerative diseases. Their multidimensional roles in modulating critical pathways underscore the significance in both physiological and pathological contexts. Recent research also emphasizes their crucial involvement and complex interplay in the skeletal system. Despite the substantial progress in understanding KLFs and their roles in various cellular processes, several research gaps remain. Here, we elucidated the multifaceted capabilities of KLFs on body health and diseases via various compliable signaling pathways. The associations between KLFs and cellular energy metabolism and epigenetic modification during bone reconstruction have also been summarized. This review helps us better understand the coupling effects and their pivotal functions in multiple systems and detailed mechanisms of bone remodeling and develop potential therapeutic strategies for the clinical treatment of pathological diseases by targeting the KLF family.

NIR laser-activated phthalocyanine loaded lipid nanoparticles targeting M2 macrophage for improved photoacoustic imaging-guided photothermal therapy.

The development of novel phototheranostic agents with significant potential in bioimaging-guided therapy is highly desirable for precise tumor therapy. Herein, NIR laser-activated ruthenium phthalocyanine (PcRu) loaded sub-30 nm targeting lipid nanoparticles (α-PcRu-NPs) were fabricated for photoacoustic imaging (PAI)-guided photothermal therapy (PTT). Due to the formation of J-type aggregation of PcRu in the core of the nanostructure, the α-PcRu-NPs exhibited high stability, efficient NIR absorption, reduced singlet oxygen generation, high photothermal activity, and intense photoacoustic signal. With the M2 macrophage target peptide (M2pep) modification and small size of α-PcRu-NPs, in vivo evaluations reveal that α-PcRu-NPs can specifically target and deeply penetrate the tumor foci. Under a high contrast PAI guidance with α-PcRu-NPs (744 nm, 0.35 µW), it also realizes superior photothermal therapy (PTT) for breast cancer under 670 nm laser irradiation (0.5 W/cm2). The prominent therapeutic efficacy of α-PcRu-NP-based PTT not only directly kills tumor cells, but also enhances the immune response by promoting dendritic cell maturation and increasing cytotoxic T cell infiltration. Thus, this work broadens the applications of phthalocyanine derivatives as phototheranostics in the PAI-guided PTT field.

State of the Art in Immersive Interactive Technologies for Surgery Simulation: A Review and Prospective.

Immersive technologies have thrived on a strong foundation of software and hardware, injecting vitality into medical training. This surge has witnessed numerous endeavors incorporating immersive technologies into surgery simulation for surgical skills training, with a growing number of researchers delving into this domain. Relevant experiences and patterns need to be summarized urgently to enable researchers to establish a comprehensive understanding of this field, thus promoting its continuous growth. This study provides a forward-looking perspective by reviewing the latest development of immersive interactive technologies for surgery simulation. The investigation commences from a technological standpoint, delving into the core aspects of virtual reality (VR), augmented reality (AR) and mixed reality (MR) technologies, namely, haptic rendering and tracking. Subsequently, we summarize recent work based on the categorization of minimally invasive surgery (MIS) and open surgery simulations. Finally, the study showcases the impressive performance and expansive potential of immersive technologies in surgical simulation while also discussing the current limitations. We find that the design of interaction and the choice of immersive technology in virtual surgery development should be closely related to the corresponding interactive operations in the real surgical speciality. This alignment facilitates targeted technological adaptations in the direction of greater applicability and fidelity of simulation.

The roles of inflammasomes in cancer.

Inflammation is a key characteristic of all stages of tumor development, including tumor initiation, progression, malignant transformation, invasion, and metastasis. Inflammasomes are an important component of the inflammatory response and an indispensable part of the innate immune system. Inflammasomes regulate the nature of infiltrating immune cells by signaling the secretion of different cytokines and chemokines, thus regulating the anti-tumor immunity of the body. Inflammasome expression patterns vary across different tumor types and stages, playing different roles during tumor progression. The complex diversity of the inflammasomes is determined by both internal and external factors relating to tumor establishment and progression. Therefore, elucidating the specific effects of different inflammasomes in anti-tumor immunity is critical for promoting the discovery of inflammasome-targeting drugs. This review focuses on the structure, activation pathway, and identification methods of the NLRP3, NLRC4, NLRP1 and AIM2 inflammasomes. Herein, we also explore the role of inflammasomes in different cancers and their complex regulatory mechanisms, and discuss current and future directions for targeting inflammasomes in cancer therapy. A detailed knowledge of inflammasome function and regulation may lead to novel therapies that target the activation of inflammasomes as well as the discovery of new drug targets.

Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway.

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.

The Dramatic Role of IFN Family in Aberrant Inflammatory Osteolysis.

Skeletal system has been considered a highly dynamic system, in which bone-forming osteoblasts and bone-resorbing osteoclasts go through a continuous remodeling cycle to maintain homeostasis of bone matrix. It has been well acknowledged that interferons (IFNs), acting as a subgroup of cytokines, not only have crucial effects on regulating immunology but also could modulate the dynamic balance of bone matrix. In the light of different isoforms, IFNs have been divided into three major categories in terms of amino acid sequences, recognition of specific receptors and biological activities. Currently, type I IFNs consist of a multi-gene family with several subtypes, of which IFN-α exerts pro-osteoblastogenic effects to activate osteoblast differentiation and inhibits osteoclast fusion to maintain bone matrix integrity. Meanwhile, IFN-ß suppresses osteoblast-mediated bone remodeling as well as exhibits inhibitory effects on osteoclast differentiation to attenuate bone resorption. Type II IFN constitutes the only type, IFN-γ, which exerts regulatory effects on osteoclastic bone resorption and osteoblastic bone formation by biphasic ways. Interestingly, type III IFNs are regarded as new members of IFN family composed of four members, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, which have been certified to participate in bone destruction. However, the direct regulatory mechanisms underlying how type III IFNs modulate the metabolic balance of bone matrix, remains poorly elucidated. In this review, we have summarized functions of IFN family during physiological and pathological conditions and described the mechanisms by which IFNs maintain bone matrix homeostasis via affecting the osteoclast-osteoblast crosstalk. In addition, the potential therapeutic effects of IFNs on inflammatory bone destruction diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and infectious bone diseases are also well displayed, which are based on the predominant role of IFNs in modulating the dynamic equilibrium of bone matrix.

Stretchable, rapid self-healing guar gum-poly(acrylic acid) hydrogels as wearable strain sensors for human motion detection based on Janus graphene oxide.

Wearable strain sensors have received widespread attention in research fields due to their applications in human motion detection. In this manuscript, the fabrication of functionalized Janus graphene oxide (GO) nanosheets were used by Pickering emulsion template. Polypyrrole (PPy) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) were asymmetrically grafted on the two sides of GO (GO@PPy/PDMAEMA Janus NS), which successfully applied to synthesize Janus NS/guar gum-poly(acrylic acid) (GG-PAA) self-healing nanocomposite hydrogels. The outstandingly improved self-healing efficiency (92.8% for 2 h) and mechanical properties (strength of 4.12 MPa and toughness of 873.8%) of nanocomposite hydrogels were mainly supported by the collaborative effect of reversible electrostatic interactions, multiple hydrogen bonds and metal-ligand coordination. Moreover, the hydrogels exhibited strain sensitivity and could be able to monitor a variety of human motions, which have outstanding application prospects in wearable flexible sensors.