Association between urinary phthalates and phthalate metabolites and cancer risk: A systematic review and meta-analysis.

Phthalates, widely utilized in industrial products, are classified as endocrine-disrupting chemicals (EDCs). Although certain phthalate and their metabolites have been implicated in cancer development, the reported findings have exhibited inconsistencies. Therefore, we conducted the comprehensive literature search to assess the association between phthalate and their metabolites and cancer risk by identifying original studies measuring phthalates or their metabolites and reporting their correlation with cancer until July 4, 2023. The Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted and analyzed to estimate the risk. Pooled data from eleven studies, including 3101 cancer patients and 6858 controls, were analyzed using a fixed- or random-effects model based on heterogeneity tests. When comparing extreme categories of different phthalates and their metabolites, we observed a significant association between urinary phthalates and phthalate metabolites (MEHHP, MECPP, DBP and MBzP) and cancer risk. The findings of our meta-analysis reinforce the existing evidence that urinary phthalates and phthalate metabolites is strongly associated with cancer development. Further investigations are warranted to elucidate the underlying mechanisms of this association. These results may offer novel insights into cancer development.

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma.

Paclitaxel is the last choice for the treatment of advanced melanoma as a second-line chemotherapeutic agent, but there are still many cases of intrinsic resistance to paclitaxel in melanoma and the reasons that cause paclitaxel resistance remain unclear. Here, we identified that high expression of SRY-box transcription factor 2 (SOX2) and high ratio of side population (SP) cells reduced the sensitivity to paclitaxel in melanoma cells. The knockout and the induction of SOX2 completely depleted and significantly upregulated the ratios of melanoma SP cells, respectively. These data suggest that SOX2, a pluripotent transcription factor for inducing cancer stem cells in melanoma, is also sufficient and necessary for the induction of melanoma SP cells. ATP-binding cassette (ABC) subfamily C member 1 (ABCC1) is one of ABC transporters which causes SP cells to be resistance to chemotherapeutic agents by efficiently pumping drugs out of cells. The knockout and the induction of ABCC1 significantly increased and decreased the sensitivity of melanoma cells to paclitaxel. High expression of ABCC1 was identified in melanoma cell lines with high expression of SOX2 and in their SP cells. SOX2 was identified to induce ABCC1 transcription. Taken together, SOX2 upregulates SP cells and enhances their chemoresistant ability by increasing ABCC1 expression, which contributes to intrinsic resistance to paclitaxel in melanoma. Our findings will lead to new insights into melanoma biology and therapy resistance, and eventually to new therapeutic targets.

Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance.

Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.

CRL4DCAF2 is required for mature T-cell expansion via Aurora B-regulated proteasome activity.

The proliferation of T cells in peripheral lymphoid tissues requires T cell receptor (TCR)-mediated cell cycle entry. However, the underlying mechanism regulating cell cycle progression in mature T cells is incompletely understood. Here, we have identified an E3 ubiquitin ligase, CRL4DCAF2, as a critical mediator controlling M phase exit in activated T cells. DCAF2 expression is induced upon TCR stimulation and its deficiency attenuates T cell expansion. Additionally, DCAF2 T cell-specific knockout mice display impaired peripheral T cell maintenance and reduced severity of various autoimmune diseases. Continuous H4K20me1 modification caused by DCAF2 deficiency inhibits the induction of Aurkb expression, which regulates 26S proteasome activity during G2/M phase. CRL4DCAF2 deficiency causes M phase arrest through proteasome-dependent mechanisms in peripheral T cells. Our findings establish DCAF2 as a novel target for T cell-mediated autoimmunity or inflammatory diseases.

CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis.

The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. The NEDD8-targeting drug MLN4924, which inactivates cullin ring-finger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. However, the essential role of CRL4DCAF2 in primary myeloid cells remains poorly understood. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse psoriasis models, consistent with the effects of reduced DCAF2 expression in various autoimmune diseases. Using transcriptomic and immunological approaches, we showed that CRL4DCAF2 in dendritic cells (DCs) regulates the proteolytic fate of NIK and negatively regulates IL-23 production. CRL4DCAF2 promoted the polyubiquitination and subsequent degradation of NIK independent of TRAF3 degradation. DCAF2 deficiency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. This study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases.

Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability.

Macrophages, dendritic cells and other innate immune cells are involved in inflammation and host defense against infection. Metabolic shifts in mitochondrial dynamics may be involved in Toll-like receptor agonist-mediated inflammatory responses and immune cell polarization. However, whether the mitochondrial morphology in myeloid immune cells affects anti-tumor immunity is unclear. Here we show that FAM73b, a mitochondrial outer membrane protein, has a pivotal function in Toll-like receptor-regulated mitochondrial morphology switching from fusion to fission. Switching to mitochondrial fission via ablation of Fam73b (also known as Miga2) promotes IL-12 production. In tumor-associated macrophages, this switch results in T-cell activation and enhances anti-tumor immunity. We also show that the mitochondrial morphology affects Parkin expression and its recruitment to mitochondria. Parkin controls the stability of the downstream CHIP-IRF1 axis through proteolysis. Our findings identify mechanisms associated with mitochondrial dynamics that control anti-tumor immune responses and that are potential targets for cancer immunotherapy.

Inhibiting scar formation in vitro and in vivo by adenovirus-mediated mutant Smad4: a preliminary report.

The best characterized signalling pathway employed by transforming growth factor-beta (TGF-ß) is the Smad pathway. We focused on Smad4, because it is essential for the activation of Smad-dependent target genes. We aimed to explore the possibility of inhibiting scar formation after wounding by blocking TGF-ß signalling by means of a gene therapy approach using adenovirus-mediated expression of mutant Smad4. The coding sequence of the dominant-negative mutant Smad4ΔM4, which has a deletion in the linker region of Δ275-322, was introduced by homologous recombination into an adenovirus vector to generate the recombinant vector Ad-ΔM4, which encoded Smad4ΔM4. Mouse fibroblast NIH 3T3 cells were transfected with Ad-ΔM4 and cell proliferation, collagen protein production, and the expression of collagen type I and type III mRNA were evaluated in vitro using a cell proliferation test, western blot analysis, and RT-PCR, respectively. Cell proliferation and the expression of collagen type I and type III mRNA and protein were all inhibited by the transfection of Ad-ΔM4. In vivo, Ad-ΔM4 was applied externally to wounds on rats, and histological examination and quantification of the scars were performed to evaluate the curative effect. The transfection of Ad-ΔM4 successfully inhibited scar formation in rat wounds. In conclusion, Ad-ΔM4 can block the TGF-ß signalling of mouse wound cells effectively. In addition, gene therapy with Ad-ΔM4 can effectively inhibit wound scarring in rats and may potentially be applied to clinical treatment of scars.

Foster replantation of fingertip using neighbouring digital artery in a young child.

UNLABELLED: Reconstruction of an amputated fingertip in a young child demands special techniques for success. We report a 2.5-year-old female patient with an amputated left index fingertip with the vascular defect being too severe to perform the usual replantation. Comparing several methods, we used the neighbouring digital artery as the feeding artery to perform foster replantation. Finally, the patient was satisfied with the appearance and function of her fingers. The clinical case, techniques, results are described and discussed. We consider it a useful technique, especially for those with a rather severe vascular defect. PATIENT: A 2.5-year-old girl suffered a crush amputation of the left index fingertip. Only the flexor tendon of the amputated fingertip was connected to the proximal finger tissue and the blood supply was completely lost (Figure 1). METHODS: The distal amputated fingertip was fixed using Kirschner wire under general anaesthesia. Then, microsurgery operation was carried out immediately to replant this amputated fingertip. Both ulnar and radial digital arteries were avulsed, while the dorsal vein was intact and the digital nerve was also surviving. The integrity of blood vessels was too traumatised to connect to the proximal part. In the case of the distal part of the ulnar artery of the injured index finger, the blood supply was established by anastomosing the distal end of the amputated tip and the radial artery of the middle finger, which was the feeding artery (Figure 2). A 11/0 nylon suture was used. The dorsal vein and digital nerve were repaired by means of microsurgical anastomosis. The wound was covered with the dorsal skin of the middle finger and the palmar skin of the index finger to form a skin pedicle, and then, immobility of the two fingers was maintained to prevent avulsion. RESULT: The index tip obtained good blood supply and survived completely (Figure 3). Detachment of the index and middle finger was performed after 3 weeks, and both of the fingers showed good blood supply (Figure 4). The appearance and function of the index and middle fingers were satisfactory 3 months postoperatively.