The Role of the Gut Microbiome in Neuroinflammation and Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating adverse effects caused by chemotherapy drugs such as paclitaxel, oxaliplatin and vincristine. It is untreatable and often leads to the discontinuation of cancer therapy and a decrease in the quality of life of cancer patients. It is well-established that neuroinflammation and the activation of immune and glial cells are among the major drivers of CIPN. However, these processes are still poorly understood, and while many chemotherapy drugs alone can drive the activation of these cells and consequent neuroinflammation, it remains elusive to what extent the gut microbiome influences these processes. In this review, we focus on the peripheral mechanisms driving CIPN, and we address the bidirectional pathways by which the gut microbiome communicates with the immune and nervous systems. Additionally, we critically evaluate literature addressing how chemotherapy-induced dysbiosis and the consequent imbalance in bacterial products may contribute to the activation of immune and glial cells, both of which drive neuroinflammation and possibly CIPN development, and how we could use this knowledge for the development of effective treatment strategies.

Characterization of Human Engraftment and Hemophagocytic Lymphohistiocytosis in NSG-SGM3 Neonate Mice Engrafted with Purified CD34+ Hematopoietic Stem Cells.

Immunodeficient mice bearing human immune systems, or "humanized" chimeric mice, are widely used in basic research, along with the preclinical stages of drug development. Nonobese diabetic-severe combined immunodeficiency (NOD-SCID) IL2Rγnull (NSG) mice expressing human stem cell factor, granulocyte-macrophage colony stimulating factor, and interleukin-3 (NSG-SGM3) support robust development of human myeloid cells and T cells but have reduced longevity due to the development of fatal hemophagocytic lymphohistiocytosis (HLH). Here, we describe an optimized protocol for development of human immune chimerism in NSG-SGM3 mice. We demonstrate that efficient human CD45+ reconstitution can be achieved and HLH delayed by engraftment of neonatal NSG-SGM3 with low numbers of human umbilical cord-derived CD34+ hematopoietic stem cells in the absence of preconditioning irradiation.

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-ß (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection.

RATIONALE: Severe viral respiratory infections are often characterised by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain poorly understood. OBJECTIVES: To identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. METHODS: Preclinical murine models of influenza A virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESULTS: Oxidised cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte/macrophage infiltration to the lung during influenza A virus (IAV) and SARS-CoV-2 infection. Both IAV and SARS-CoV-2 infection upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidised cholesterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of Gpr183 or treatment with a GPR183 antagonist reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist significantly attenuated the severity of SARS-CoV-2 infection and viral loads. Analysis of single-cell RNA-sequencing data on bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed that CH25H, CYP7B1 and GPR183 are significantly upregulated in macrophages during COVID-19. CONCLUSION: This study demonstrates that oxysterols drive inflammation in the lung via GPR183 and provides the first preclinical evidence for the therapeutic benefit of targeting GPR183 during severe viral respiratory infections.

Discovery of Methyl (5 Z)-[2-(2,4,5-Trioxopyrrolidin-3-ylidene)-4-oxo-1,3-thiazolidin-5-ylidene]acetates as Antifungal Agents against Potato Diseases.

Synthesis, isomerism, and fungicidal activity against potato diseases of new (5 Z)-[2-(2,4,5-trioxopyrrolidin-3-ylidene)-4-oxo-1,3-thiazolidin-5-ylidene]acetate derivatives with 1,3-thiazolidine-4-one and pyrrolidine-2,3,5-trione moieties linked by an exocyclic C═C bond were described. Their structures were clearly confirmed by spectroscopic and spectrometric data (Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance, and mass spectrometry), elemental analysis, and X-ray diffraction crystallography. A bioassay for antifungal activity in vitro against Phytophthora infestans, Fusariun solani, Alternaria solani, Rhizoctonia solani, and Colletotrichum coccodes demonstrated that 2,4,5-trioxopyrrolidin-1,3-thiazolidine derivatives exhibited a relatively broad spectrum of antifungal activity. One of the compounds showed considerable activity against all of the strains; in the case of F. solani, P. infestans, and A. solani, it possesses comparable or better fungicidal efficacy than the positive control Consento. Consequently, this compound is a promising fungicidal candidate for plant protection.