Neurotrophins and neural stem cells in posttraumatic brain injury repair.

Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood-brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.

Small Mitochondria-Targeting Fluorophore with Multifunctional Therapeutic Activities against Prostate Cancer via the HIF1α/OATPs Pathway.

Prostate cancer (PCa) is considered to be the most prevalent malignancy in males worldwide. Abiraterone is a 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor that has been approved for use in patients with prostate cancer. However, several negative aspects, such as drug resistance, toxicity, and lack of real-time monitoring of treatment responses, could appear with long-term use. Therefore, the development of anticancer agents with specific targeting to avoid side effects is imperative. Here, we used MHI-148, a type of heptamethine cyanine (HC) near-infrared fluorescence dye (NIRF), as a prototype structure to synthesize two theranostic agents, Abi-DZ-1 and Abi-783. The new compound Abi-DZ-1 retained the excellent photophysical characteristics and NIRF imaging property of MHI-148, and it could preferentially accumulate in prostate cancer cells but not in normal prostate epithelial cells via the HIF1α/organic anion-transporting polypeptides axis. NIRF imaging using Abi-DZ-1 selectively identified tumors in mice bearing PCa xenografts. Moreover, Abi-DZ-1 treatment significantly retarded the tumor growth in both a cell-derived xenograft model and a patient-derived tumor xenograft model. This finding demonstrated that Abi-DZ-1 may hold promise as a potential multifunctional theranostic agent for future tumor-targeted imaging and precision therapy. Constructing theranostic agents using the NIRF dye platform holds great promise in accurate therapy and intraoperative navigation.

LRRC8A Is a Promising Prognostic Biomarker and Therapeutic Target for Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor of the digestive system with increasing morbidity and mortality. The lack of sensitive and reliable biomarkers is one of the main reasons for the poor prognosis. Volume-regulated anion channels (VRAC), which are ubiquitously expressed in the vertebrate cell membrane, are composed of leucine-rich repeat-containing 8A (LRRC8A) and four other homologous family members (LRRC8B-E). VRAC heterogeneous complex is implicated in each of the six "hallmarks of cancer" and represents a novel therapeutic target for cancer. In this study, LRRC8A was speculated to be a promising prognostic biomarker and therapeutic target for PAAD based on a series of bioinformatics analyses. Additional cell experiments and immunohistochemical assays demonstrated that LRRC8A can affect the prognosis of PAAD and is correlated to cell proliferation, cell migration, drug resistance, and immune infiltration. Functional analysis indicated that LRRC8A influences the progression and prognosis of patients with PAAD by the regulation of CD8+ T cells immune infiltration. Taken together, these results can help in the design of new therapeutic drugs for patients with PAAD.

The Application of [68Ga]-Labeled FAPI-04 PET/CT for Targeting and Early Detection of Pancreatic Carcinoma in Patient-Derived Orthotopic Xenograft Models.

[18F]FDG as a probe of PET/CT is a radiolabeled glucose analogue taken up by most cells, but its batch activity is limited. [68Ga]FAPI-04 is a promising alternative based on a fibroblast activation protein-specific inhibitor (FAPI) labeled with radiotracer FAP. Here, a series of databases suggested that FAP expression was significantly different in pancreatic cancer compared to normal tissue. The FAP-positive fibroblasts were evaluated around the tumor cells and the stroma. A patient-derived orthotopic xenograft (PDOX) model of pancreatic adenocarcinoma (PDAC) exhibits significantly higher quantitative uptake of [68Ga]FAPI-04 (P < 0.05) than [18F]FDG PET/CT in various organs. Because of relatively high (T/M) ratios, the [68Ga]FAPI-04 is excellent for B-mode ultrasound, NIRF, and PET/CT. Thus, [68Ga]FAPI-04 PET displayed a better tumor specificity and can be a potential application for the early detection of pancreatic cancer.

Lipocalin 2 may be a key factor regulating the chemosensitivity of pancreatic cancer to gemcitabine.

Owing to the high heterogeneity of pancreatic cancer, patient-derived xenografts (PDX) can compensate for the defects of cell line-derived xenografts (CDX) and also better preserve the heterogeneity and tumor microenvironment of primary tumors. Further, gemcitabine, which is used for the treatment of various cancers, is prone to tumor drug resistance, and this limits its sustained efficacy. Therefore, in this study, our objective was to screen appropriate individual therapeutic drugs for pancreatic cancer. To this end, we established pancreatic cancer PDX models from different patients and screened gemcitabine sensitivity regulatory molecules via high-throughput transcriptome sequencing and bioinformatics analysis. Based on the results obtained, gemcitabine was identified as the most suitable chemotherapeutic drug in a variety of PDX models. Additionally, our results indicated that Lipocalin 2 (LCN 2) may play an important role in the sensitivity of pancreatic cancer to gemcitabine treatment. Thus, the study provides a new potential intervention target for the treatment of pancreatic cancer in clinical practice.

Development of a colloidal gold immunochromatographic strip for the rapid detection of pefloxacin in grass carp with a novel pretreatment method.

A rapid colloidal gold immunochromatography assay (GICA) for the detection of pefloxacin (PEF) was established and optimized. The anti-PEF monoclonal antibody (mAb) was used to target PEF as a colloidal gold-mAb conjugate. The mAb belonged to the IgG2b subtype, lambda light chain, the affinity constant (Ka) was 5.21 × 109 L·mol-1, and its half maximal inhibitory concentration (IC50) was 0.23 ng·mL-1. No obvious cross-reactivity (CR) was observed with other common fluoroquinolone antibiotics, including ciprofloxacin (CIP), norfloxacin (NOR), lomefloxacin (LOM) and ofloxacin (OFL). The visual limit of detection (vLOD) of the optimized GICA was 2 ng·g-1 under the conventional pretreatment method, and the assay was completed in 15 min. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) was employed to confirm the performance of the strip. In addition, a novel pretreatment was established and compared with conventional pretreatment. Without the removal of organic solvents, the novel pretreatment method reduced the sample pretreatment time (more than 10 min). The vLOD of the optimized GICA was also 2 ng·g-1 when applying the novel pretreatment method. In conclusion, the proposed PEF-GICA could detect samples containing PEF rapidly and accurately, and the novel pretreatment method saved the time of sample pretreatment and improved the efficiency of detection.

Monoamine oxidase A drives neuroendocrine differentiation in prostate cancer.

Neuroendocrine transdifferentiation (NED) of prostate cancer (PCa) is the main cause of failure of androgen receptor inhibitor treatment. However, the molecular mechanisms underlying the development of NEPC, especially treatment-induced NEPC, remain unclear. Emerging evidence indicates that elevated monoamine oxidase A (MAOA) contribute to the proliferation, cell stemness, and bone metastasis in PCa. Here, we generated an enzalutamide-induced NED cell model to assess the role of MAOA during NED. Overall, MAOA expression was significantly increased upon Enz long-term exposure and was required for neuroendocrine marker expression. In particular, Enz was found to induce NED via the MAOA/mTOR/HIF-1α signaling axis. Further analyses revealed that the MAOA inhibitor clorgyline(CLG) may bring multiple benefits to CRPC patients, including better therapeutic effect and delays NED. These findings suggest that MAOA may be an important target for the development of anti-NED therapies, thereby providing a novel strategy for the combined application of CLG and AR inhibitors in the clinic.

Screening of an individualized treatment strategy for an advanced gallbladder cancer using patient-derived tumor xenograft and organoid models.

Gallbladder cancer is a highly aggressive malignancy with poor sensitivity to postoperative radiotherapy or chemotherapy; therefore, the development of individualized treatment strategies is paramount to improve patient outcomes. Both patient-derived tumor xenograft (PDX) and patient-derived tumor organoid (PDO) models derived from surgical specimens can better preserve the biological characteristics and heterogeneity of individual original tumors, display a unique advantage for individualized therapy and predicting clinical outcomes. In this study, PDX and PDO models of advanced gallbladder cancer were established, and the consistency of biological characteristics between them and primary patient samples was confirmed using pathological analysis and RNA-sequencing. Additionally, we tested the efficacy of chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitors using these two models. The results demonstrated that gemcitabine combined with cisplatin induced significant therapeutic effects. Furthermore, treatment with immune checkpoint inhibitors elicited promising responses in both the humanized mice and PDO immune models. Based on these results, gemcitabine combined with cisplatin was used for basic treatment, and immune checkpoint inhibitors were applied as a complementary intervention for gallbladder cancer. The patient responded well to treatment and exhibited a clearance of tumor foci. Our findings indicate that the combined use of PDO and PDX models can guide the clinical treatment course for gallbladder cancer patients to achieve individualized and effective treatment.

Advances in neuroendocrine prostate cancer research: From model construction to molecular network analyses.

Prostate cancer is the most common cancer among men and has a high incidence and associated mortality worldwide. It is an androgen-driven disease in which tumor growth is triggered via ligand-mediated signaling through the androgen receptor (AR). Recent evidence suggests that the widespread use of effective AR pathway inhibitors may increase the occurrence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant; however, mechanisms controlling NEPC development remain to be elucidated. Various preclinical models have recently been developed to investigate the mechanisms driving the NEPC differentiation. In the present study, we summarized strategies for the development of NEPC models and proposed a novel method for model evaluation, which will help in the timely and accurate identification of NEPC by virtue of its ability to recapitulate the heterogeneity of prostate cancer. Moreover, we discuss the origin and the mechanism of NEPC. The understanding of the regulatory network mediating neuroendocrine differentiation presented in this review could provide valuable insights into the identification of novel drug targets for NEPC as well as into the causes of antiandrogenic drug resistance.

Application of Organoid Models in Prostate Cancer Research.

Complex heterogeneity is an important characteristic in the development of prostate cancer (PCa), which further leads to the failure of known therapeutic options. PCa research has been hampered by the current in vitro model systems that cannot fully reflect the biological characteristics and clinical diversity of PCa. The tumor organoid model in three-dimensional culture retains the heterogeneity of primary tumor tissues in vitro well and enables high-throughput screening and genome editing. Therefore, the establishment of a PCa organoid model that recapitulates the diverse heterogeneity observed in clinical settings is of great significance for the study of PCa. In this review, we summarize the culture conditions, establishments, and limitations of PCa organoids and further review their application for the study of pathogenesis, drug screening, mechanism of drug resistance, and individualized treatment for PCa. Additionally, we look forward to other potential developmental directions of PCa organoids, such as the interaction between prostate cancer tumor cells and their microenvironment, clinical individualized treatments, heterogeneous transformation model, tumor immunotherapy, and organoid models combined with liquid biopsy. Through this, we provide more effective preclinical experimental schemes using the PCa organoid model.

Bisphenol S promotes fat storage in multiple generations of Caenorhabditis elegans in a daf-16/nhr-49 dependent manner.

Bisphenol S (BPS) has been gradually used in all kinds of productions. Our previous study has demonstrated that BPS increases the obesogenic effects of a high-glucose diet through regulating lipid metabolism in Caenorhabditis elegans (C. elegans). Whether the effects pass on to the next generations remains uncovered. In the present study, C. elegans was selected as the model organism to investigate the effects of BPS on lipid metabolism in multiple generations. Oil Red O staining and triglyceride assays showed that multi-generational exposure to BPS in C. elegans significantly increased the fat accumulation in wild type worms, while not in the daf-16 gene-deficient worms. In addition, BPS affected the expressions of fat-7 and acs-2 in four generations of C. elegans. Furthermore, BPS promotes fat storage in C. elegans of multiple generations by the daf-16/nhr-49-mediated signaling pathway.

Strategies for the Construction of Mouse Models With Humanized Immune System and Evaluation of Tumor Immune Checkpoint Inhibitor Therapy.

Immunotherapy has been used as a first-line treatment for a variety of advanced tumors, allowing remarkable progress to be made in cancer treatment. Nonetheless, only a small number of patients can benefit from immune checkpoint inhibitor monotherapy. To improve the effect of immunotherapy, the underlying mechanism of combination therapy was investigated in the context of an intact human tumor immune microenvironment using mice with a human immune system (HIS) bearing human tumors. Herein, we summarize and discuss strategies for the development and use of HIS mice models in tumor immunotherapies. Most importantly, this review proposes a method of t11umor identification and classification in HIS mice based on the tumor-infiltrating lymphocytes and PD-L1 expression, and according to this classification, we propose different combination treatment strategies that can be utilized to enhance the effect of immunotherapy. Thus, we provide effective experimental schemes for tumor immunotherapy in HIS mice models.

Intestinal microbiota: A potential target for enhancing the antitumor efficacy and reducing the toxicity of immune checkpoint inhibitors.

Accumulating evidence suggests that the intestinal microbiota is associated with the antitumor efficacy of immune checkpoint inhibitors (ICIs) and the occurrence of immune-related adverse events (irAEs) following ICI treatment. However, the mechanisms underlying these interactions remain unclear. Recent technological advances have allowed more extensive investigation into the interplay between the intestinal microbiota and the tumor immune microenvironment. Breakthroughs by two research groups revealed that Bifidobacterium enhanced the efficacy of ICIs via the stimulator of interferon genes (STING) and adenosine 2A receptor (A2AR) signaling pathways, highlighting the molecular mechanisms through which the intestinal microbiota modulates immunotherapy. In this review, we summarize recent findings related to the potential role and mechanisms of the gut microbiota in ICI therapy, available microbiota-targeting strategies, and ongoing clinical trials. Further we discuss the associated challenges that remain in this field of research. The current review aims to evaluate the potential of the intestinal microbiota in maximizing the antitumor efficacy of ICIs while minimizing their toxic effects and guiding the development of more specific treatment regimens.

Bisphenol S increases the obesogenic effects of a high-glucose diet through regulating lipid metabolism in Caenorhabditis elegans.

Bisphenol S (BPS), a structural analog of Bisphenol A (BPA), has been widely used as a substitute for epoxy resin, food packaging materials, and other products due to the limited application of BPA. Studies in vivo and in vitro have indicated that BPA could induce fat accumulation like an obesogen. The main goal of this study was to investigate the role and mechanism of BPS in lipid metabolism using Caenorhabditis elegans (C. elegans) as a model. Results showed that both the overall fat deposition and the triglyceride level were significantly increased in a non-monotonically increasing trend, and the low dose of BPS (0.01 µM) exhibited a stronger influence. Additionally, BPS enhanced fat synthesis depending on daf-16, fat-5, fat-6 and fat-7, and inhibited fatty acid oxidation via nhr-49 and acs-2. This study further indicate that fat accumulation induced by BPS requires nhr-49, which also mediated the nuclear hormone signaling pathway.

Establishment and characterization of patient-derived xenografts for hormone-naïve and castrate-resistant prostate cancers to improve treatment modality evaluation.

Prostate cancer (PC) is a heterogeneous disease characterized by variable morphological patterns. Thus, establishing a patient-derived xenograft (PDX) model that retains the key features of the primary tumor for each type of PC is important for appropriate evaluation. In this study, we established PDX models of hormone-naïve (D17225) and castration-resistant (B45354) PC by implanting fresh tumor samples, obtained from patients with advanced PC under the renal capsule of immune-compromised mice. Supplementation with exogenous androgens shortened the latent period of tumorigenesis and increased the tumor formation rate. The PDX models exhibited the same major genomic and phenotypic features of the disease in humans and maintained the main pathological features of the primary tumors. Moreover, both PDX models showed different outcomes after castration or docetaxel treatment. The hormone-naïve D17225 PDX model displayed a range of responses from complete tumor regression to overt tumor progression, and the development of castrate-resistant PC was induced after castration. The responses of the two PDX models to androgen deprivation and docetaxel were similar to those observed in patients with advanced PC. These new preclinical PC models will facilitate research on the mechanisms underlying treatment response and resistance.

Mediated Imaging and Improved Targeting of Farnesylthiosalicylic Acid Delivery for Pancreatic Cancer via Conjugation with Near-Infrared Fluorescence Heptamethine Carbocyanine Dye.

S-trans-trans-Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that exhibits desirable anticancer property and currently undergoing clinical trials for pancreatic cancer (PC). However, its poor water solubility and low bioavailability have severely hampered clinical applications. A strategy to improve FTS bioavailability is to develop a suitable drug delivery method. Here, we use a near-infrared fluorescence (NIRF) heptamethine carbocyanine (HC) dye conjugated with FTS (to produce FTS-148) as a drug delivery system to enhance FTS bioavailability. We further investigate its tumor-targeting functions. FTS-148 displayed better bioavailability and photophysical property and selective recognition of cancer cells. FTS-148 significantly reduced PC cell proliferation, and more effective than FTS in restricting tumor growth both in a cell-derived xenograft (CDX) model and a patient-derived tumor xenograft (PDX) model. FTS-148 can specifically recognize PC cells in mice subcutaneous models or rabbit orthotopic models and allows real-time monitoring of the therapeutic effects by NIRF optical imaging. FTS-148 treatment significantly reduced Ras expression in PC cells and increased tumor tissue apoptosis. In short, FTS conjugated with HC dye had enhanced bioavailability and tumor-targeting property. It provides a potential agent for imaging and therapy of PC.

Toxicity and multigenerational effects of bisphenol S exposure to Caenorhabditis elegans on developmental, biochemical, reproductive and oxidative stress.

Bisphenol A (BPA) is a typical endocrine disruptor. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of BPA. However, it does not mean that BPS is a safe substitute due to the lack of effective evaluation of BPS. In this study, the clinical model of Caenorhabditis elegans (C. elegans) was used to study the effects of BPS on the locomotion behavior, growth, reproduction, lifespan and antioxidant system. Our study found that C. elegans exposed to 0.01 µM BPS could have significantly inhibited locomotion behavior and growth, as well as damaged reproductive and antioxidant systems and lifespan. It is interesting to note that in multi-generational exposure studies, we found that BPS exhibits complex genotoxicity. With the transmission to the offspring, BPS showed more significant inhibition of the head thrashes of the nematode, while the effect on the body bends and body length was gradually weakened. The effect of BPS on the brood size shows different rules according to different concentrations and offsprings. Therefore, the safety of BPS still needs further evaluation, especially the multi-generational genotoxicity.

Patient-derived bladder cancer xenograft models reveal VEGF and CDK4 enhancing tumor metastasis behavior.

New strategies to treat advanced bladder cancer are urgently required. A patient-derived xenograft (PDX) model has become a useful tool to evaluate chemotherapeutics and investigate personalized cancer treatment options. In this study, fresh human bladder cancer specimens (C09303 and C21391) were transplanted subcutaneously into nude mice to establish PDX models. These models well retained pathological characteristics and molecular markers of the original tumor. Primary cells derived from C09303 were cultured and perfused into the bladders of nude mice to establish orthotopic xenograft models. Evident signals of lung and kidney metastases were detected by whole-body optical imaging. Gemcitabine displayed a significant therapeutic effect on the subcutaneous or orthotopic xenograft tumors of C09303. In vitro, matrigel invasion assays showed that C09303 primary culture cells are remarkably invasive. To study the metastatic properties of C09303, we sequenced the genomes of C09303 and C21391, and found that the expression of VEGF and CDK4 was significantly upregulated, and VEGF-knockdown or CDK4-knockdown C09303 cells showed attenuated invasiveness and migration. This PDX model revealed that VEGF and CDK4 enhanced tumor metastasis behavior, suggesting them as novel molecular therapeutic targets. This framework provides a tool for research on metastasis mechanism and individualized treatment for bladder cancer.

NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye.

Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 109/cm2 tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide 68Ga (68Ga-MHI-148) for PET tracing. We applied the dual-modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and 68Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of 68Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm × 0.3 cm) and rabbits (1.2 cm × 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC.

Insights into Macrophage Autophagy in Latent Tuberculosis Infection: Role of Heat Shock Protein 16.3.

Tuberculosis (TB) is a major bacterial infectious disease worldwide that is predominantly caused by Mycobacterium tuberculosis (Mtb). The comorbidity of multiple drug-resistant TB strains with HIV and diabetes is widespread. In the presence of these diseases, host immunity is weakened, allowing the recovery of dormant bacilli and leading to recurrent TB infection. As an important component of the host innate and adaptive immune responses, macrophage autophagy plays a significant role in protecting the host against TB. However, dormant bacilli can escape from autophagosomes and/or suppress autophagy, thus surviving within the host for an extended period of time, although the underlying mechanism remains elusive. Heat shock protein 16.3 (Hsp16.3, HspX, Rv2031c, and Acr) is one of the immunodominant proteins expressed during latent TB infection (LTBI). It may help maintain the protein stability and long-term viability of Mtb by inhibiting macrophage autophagy, resulting in LBTI. In this review, we discuss how dormant bacilli escape from autophagosomes, and we focus on the role of Hsp16.3 in regulating macrophage autophagy in LTBI so as to provide a firm basis for further studies. Hsp16.3 may represent a potential biomarker of LTBI and novel pharmacological target for anti-tubercular drugs.