Factors Affecting Postoperative Complications of Suction-Curettage by Arthroscopic Shaver for Bromhidrosis.

BACKGROUND: Suction-curettage by arthroscopic shaver is the most effective treatment for bromhidrosis; however, postoperative complications require wound management and exhibit a high risk of hypertrophic scarring. We investigated factors affecting postoperative complications. METHODS: We retrospectively evaluated data for 215 patients (430 axillae) with bromhidrosis treated with suction-curettage by arthroscopic shaver between 2011 and 2019. Cases followed for less than 1 year were excluded. Complications of hematoma or seroma, epidermis decortication, skin necrosis, and infection were recorded. Multinomial logistic analysis was used to calculate odds ratios and corresponding 95% confidence intervals for the complication of the surgery, adjusting for relevant statistically significant variables. RESULTS: Complications occurred in 52 axillae (12.1%). Epidermis decortication occurred in 24 axillae (5.6%), with a significant difference for age (P < 0.001). Hematoma occurred in 10 axillae (2.3%) with a significant difference in tumescent infiltration use (P = 0.039). Skin necrosis occurred in 16 axillae (3.7%) with a significant difference for age (P = 0.001). Infection occurred in 2 axillae (0.5%). Severe scarring occurred in 15 axillae (3.5%), with complications related to more severe skin scarring (P < 0.05). CONCLUSION: Older age was a risk factor for complications. Use of tumescent infiltration resulted in good postoperative pain control and less hematoma. Patients with complications presented with more severe skin scarring, but none experienced limited range of motion after massage.

In Utero Cell Treatment of Hemophilia A Mice via Human Amniotic Fluid Mesenchymal Stromal Cell Engraftment.

Hemophilia is a genetic disorder linked to the sex chromosomes, resulting in impaired blood clotting due to insufficient intrinsic coagulation factors. There are approximately one million individuals worldwide with hemophilia, with hemophilia A being the most prevalent form. The current treatment for hemophilia A involves the administration of clotting factor VIII (FVIII) through regular and costly injections, which only provide temporary relief and pose inconveniences to patients. In utero transplantation (IUT) is an innovative method for addressing genetic disorders, taking advantage of the underdeveloped immune system of the fetus. This allows mesenchymal stromal cells to play a role in fetal development and potentially correct genetic abnormalities. The objective of this study was to assess the potential recovery of coagulation disorders in FVIII knockout hemophilia A mice through the administration of human amniotic fluid mesenchymal stromal cells (hAFMSCs) via IUT at the D14.5 fetal stage. The findings revealed that the transplanted human cells exhibited fusion with the recipient liver, with a ratio of approximately one human cell per 10,000 mouse cells and produced human FVIII protein in the livers of IUT-treated mice. Hemophilia A pups born to IUT recipients demonstrated substantial improvement in their coagulation issues from birth throughout the growth period of up to 12 weeks of age. Moreover, FVIII activity reached its peak at 6 weeks of age, while the levels of FVIII inhibitors remained relatively low during the 12-week testing period in mice with hemophilia. In conclusion, the results indicated that prenatal intrahepatic therapy using hAFMSCs has the potential to improve clotting issues in FVIII knockout mice, suggesting it as a potential clinical treatment for individuals with hemophilia A.

Lipofundin mediates major inhibition of intravenous propofol on phorbol myristate acetate and Escherichia coli-induced neutrophil extracellular traps.

BACKGROUND: Neutrophil extracellular traps (NETs) consist of chromatin DNA networks that are studded with cytosolic and granular antimicrobial proteins to trap or kill an infected microorganism. A lipid emulsion, the solvent of pure propofol for intravenous application, is given to clinical patients who require intravenous feeding of fatty acids and fat for energy. Intravenous propofol is widely used to sedate critically ill patients. Both intravenous propofol and its lipid emulsion have immunomodulatory activity. However, the role of lipid emulsion of intravenous propofol on NET induction remains unclear. METHODS: In this study, neutrophils were stimulated with phorbol myristate acetate (PMA) or Escherichia coli (E. coli) in the absence or presence of intravenous propofol (Propofol-Lipuro®), its solvent lipid emulsion (Lipofundin) or pure propofol, and NETs were stained with SYTOX Green for visualization and quantification. Total HOCl was determined by measuring the taurine-chloramine complex, and intracellular HOCl was evaluated with BioTracker™ TP-HOCl 1 dye. RESULTS: PMA-induced NETs were not efficiently inhibited when Propofol-Lipuro® was added after PMA stimulation. Clinically relevant concentrations of Lipofundin exerted a significant reduction in PMA-induced NETs and total reactive oxidative species (ROS), which was comparable to that observed for Propofol-Lipuro®. Lipofundin transiently reduced intracellular HOCl production and the phosphorylation level of extracellular regulated kinase (p-ERK) but did not scavenge HOCl. Moreover, Lipofundin decreased E. coli-induced NETs in a ROS-independent pathway, similar to Propofol-Lipuro®. CONCLUSIONS: All data agree that Lipofundin, the major component of Propofol-Lipuro®, inhibits intracellular HOCl and p-ERK to suppress PMA-induced NET formation but reduces E.coli-induced NETs in a ROS-independent pathway.

Multi-Staged Surgeries for Coexisting Facial Asymmetry and Strabismus in Parry-Romberg Syndrome.

ABSTRACT: Parry-Romberg syndrome (PRS) is a rare disorder resulting in disfiguring facial asymmetry. Ocular manifestations can result in complex strabismus. There were limited reports on the treatment of PRS with coexisting strabismus. We present a multistaged surgical approach to manage the facial asymmetry and strabismus.

Factors Affecting the Efficacy of Suction Curettage Using an Arthroscopic Shaver for Bromhidrosis.

BACKGROUND: Suction-curettage using an arthroscopic shaver is the most effective surgical treatment for bromhidrosis; however, information regarding the procedure is limited. This study investigated the factors that affect the efficacy of suction-curettage. PATIENTS AND METHODS: We retrospectively evaluated data for 215 patients (430 axillae) with bromhidrosis treated with suction-curettage using an arthroscopic shaver between 2011 and 2019. RESULTS: Excellent or good efficacy with improved malodor was achieved in 418 axillae (97.21%). Secondary suction-curettage was performed for 11 (2.56%), with excellent results. Efficacy and need for secondary suction-curettage were not associated with age, sex, shaving time, and tumescent infiltration use. Complications were observed in 52 (12.09%) axillae, including hematoma or seroma, epidermis decortication, skin necrosis, and infections; 10 (2.33%) required local debridement for wounds. Complications showed a significant difference with respect to age (p < .001). Pain scores on postoperative Day 2 were significantly lower for patients treated using tumescent infiltration than those for the others (1.65 ± 0.84 vs 4.57 ± 1.16; p < .001). CONCLUSION: The results suggest that 7 to 15 minutes of suction curettage using an arthroscopic shaver is sufficient to achieve good efficacy for bromhidrosis with few complications. Older age was a risk factor for complications, and tumescent infiltration use achieved good postoperative pain control. LEVELS OF EVIDENCE: II.

The Effects of Combining Progressive Tension Sutures, Closed Drain, and Fibrin Sealant in Abdominoplasty Wound After Deep Inferior Epigastric Perforator Flap Harvesting.

BACKGROUND: This study is a retrospective review to compare combining progressive tension sutures, closed drain, and fibrin sealant effects on seroma formation, postoperative drainage volume, and hospital stay for abdominoplasty after deep inferior epigastric artery perforator (DIEP) flap. We ever published a 0% seroma rate in abdominoplasty after DIEP flap using progressive tension sutures and closed drain. Massive abdominal wound drainage caused delayed drain removal and increased hospital stay and medical costs. METHODS: We retrospectively evaluated 54 abdominoplasty patients between December 2013 and September 2017; 43 patients used fibrin glue and 11 used progressive tension sutures and closed drain. RESULTS: Abdominal drainage for the first 3 postoperative days was 84.65 ± 52.95 mL in the fibrin group, with total drainage of 127.70 ± 125.50 mL and 214.45 ± 104.35 mL in the no fibrin group, with total drainage of 350.45 ± 213.58 mL. Drains were removed on postoperative day 6.21 ± 1.44 in the fibrin group and day 9.64 ± 1.96 in the no fibrin group. The association of the first 3 days and total drainage volumes with the drain removal day significantly differed in the fibrin and no fibrin groups. Hospital stay was 9.88 ± 3.55 and 12.45 ± 5.22 days in the fibrin and no fibrin group, respectively, with borderline significant differences. CONCLUSIONS: Donor site abdominoplasty after DIEP flap combining progressive tension sutures, closed drainage, and fibrin glue can prevent seroma occurrence, reduce postoperative abdominal drainage and need for blood transfusion, and achieve early removal of the abdominal drain, shorter hospital stay, and lower medical cost.

Flavopereirine Inhibits Autophagy via the AKT/p38 MAPK Signaling Pathway in MDA-MB-231 Cells.

Autophagy is a potential target for the treatment of triple negative breast cancer (TNBC). Because of a lack of targeted therapies for TNBC, it is vital to find optimal agents that avoid chemoresistance and metastasis. Flavopereirine has anti-proliferation ability in cancer cells, but whether it regulates autophagy in breast cancer cells remains unclear. A Premo™ Tandem Autophagy Sensor Kit was used to image the stage at which flavopereirine affects autophagy by confocal microscopy. A plasmid that constitutively expresses p-AKT and siRNA targeting p38 mitogen-activated protein kinase (MAPK) was used to confirm the related signaling pathways by Western blot. We found that flavopereirine induced microtubule-associated protein 1 light chain 3 (LC3)-II accumulation in a dose- and time-dependent manner in MDA-MB-231 cells. Confocal florescent images showed that flavopereirine blocked autophagosome fusion with lysosomes. Western blotting showed that flavopereirine directly suppressed p-AKT levels and mammalian target of rapamycin (mTOR) translation. Recovery of AKT phosphorylation decreased the level of p-p38 MAPK and LC3-II, but not mTOR. Moreover, flavopereirine-induced LC3-II accumulation was partially reduced in MDA-MB-231 cells that were transfected with p38 MAPK siRNA. Overall, flavopereirine blocked autophagy via LC3-II accumulation in autophagosomes, which was mediated by the AKT/p38 MAPK signaling pathway.

Closed incision negative pressure therapy following abdominoplasty after breast reconstruction with deep inferior epigastric perforator flaps.

Autologous breast reconstructions using deep inferior epigastric perforator (DIEP) flaps create a large incision, presenting an opportunity for surgical site complications. In this pilot study, we aimed to examine outcomes in DIEP donor site incisions managed with standard dressings (control; n = 5) or closed incision negative pressure therapy (ciNPT; n = 5). We observed no significant differences between group age, body mass index, and past medical history. Both treatment groups had a similar duration of hospital stay, the number of blood transfusions, and pain scores on postoperative day 2 (P > .05). There was a trend of higher drainage (P = .251) and shorter time to incision healing (P = .067) in the ciNPT group than the control though the difference was not statistically significant. We did observe a significant improvement in scar pigmentation, vascularity, and pliability at 3, 6, and 12 months post-surgery in the ciNPT group compared with control (P < .05). No surgical site complications were reported in the ciNPT group within the follow-up period. In the control group, one patient developed wound edge fat necrosis requiring reoperation. In conclusion, we report that ciNPT is a useful incision management system for DIEP flap donor site incisions and it facilitated improved scar quality over standard dressings in this small pilot study. Further clinical studies are required to assess the full advantages provided by ciNPT.

Propofol specifically suppresses IL-1ß secretion but increases bacterial survival in Staphylococcus aureus-infected RAW264.7 cells.

Anesthetics have immunomodulatory effects, but the use of different assay systems has contributed to inconsistent results in the literature. IL-1ß and reactive oxygen species (ROS) secreted by phagocytes are important factors that protect against Staphylococcus aureus infection. In this study, the effects of four intravenous anesthetics (propofol, thiamylal sodium, midazolam, and ketamine) on IL-1ß secretion, ROS, and bacterial survival in S. aureus-infected RAW264.7 cells were evaluated. S. aureus-infected RAW264.7 cells with or without intravenous anesthetic treatment were established as the experimental model. Cell supernatants were subjected to ELISAs to measure secreted IL-1ß. Cell pellets were subjected to qPCR and western blot analyses to analyze IL-1ß mRNA and protein levels. Luminol chemiluminescence assays were used to detect ROS, and bacterial survival was determined by counting the colony forming units at the beginning and end of the infection. Compared with the levels after treatment with the other intravenous anesthetics, secreted IL-1ß levels were lowest in the supernatant of S. aureus-infected RAW264.7 cell cultures after propofol treatment, but propofol did not decrease IL-1ß mRNA or protein expression. However, thiamylal sodium and midazolam decreased IL-1ß mRNA and protein expression in a dose-dependent manner. Additionally, propofol substantially decreased S. aureus-stimulated ROS and phagocytosis. Bacterial survival was strongly increased by propofol treatment. Of the four intravenous anesthetics, propofol was the most potent inhibitor of IL-1ß secretion and ROS level in S. aureus-infected RAW264.7 cells; moreover, propofol resulted in an increase in bacterial survival by inhibiting ROS and phagocytosis.

Lidocaine attenuates TMZ resistance and inhibits cell migration by modulating the MET pathway in glioblastoma cells.

Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Currently, the predominant clinical treatment is the combination of surgical resection with concurrent radiotherapy and chemotherapy, using temozolomide (TMZ) as the primary chemotherapy drug. Lidocaine, a widely used amide­based local anesthetic, has been found to have a significant anticancer effect. It has been reported that aberrant hepatocyte growth factor (HGF)/mesenchymal­epithelial transition factor (MET) signaling plays a role in the progression of brain tumors. However, it remains unclear whether lidocaine can regulate the MET pathway in GBM. In the present study, the clinical importance of the HGF/MET pathway was analyzed using bioinformatics. By establishing TMZ­resistant cell lines, the impact of combined treatment with lidocaine and TMZ was investigated. Additionally, the effects of lidocaine on cellular function were also examined and confirmed using knockdown techniques. The current findings revealed that the HGF/MET pathway played a key role in brain cancer, and its activation in GBM was associated with increased malignancy and poorer patient outcomes. Elevated HGF levels and activation of its receptor were found to be associated with TMZ resistance in GBM cells. Lidocaine effectively suppressed the HGF/MET pathway, thereby restoring TMZ sensitivity in TMZ­resistant cells. Furthermore, lidocaine also inhibited cell migration. Overall, these results indicated that inhibiting the HGF/MET pathway using lidocaine can enhance the sensitivity of GBM cells to TMZ and reduce cell migration, providing a potential basis for developing novel therapeutic strategies for GBM.

Modulation of secretory factors by lipofundin contributes to its anti­neuroinflammatory effects.

As the global population ages, the prevalence of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease and stroke continues to increase. Therefore, it is necessary to develop preventive and therapeutic methods against neuroinflammatory diseases. Lipofundin is a lipid emulsion commonly used in clinical anesthetic solvents and nutritional supplements. Lipid emulsions have been shown to possess anti-inflammatory properties. However, the potential beneficial effect of lipofundin against neuroinflammation requires elucidation. In the present study, two cell models were used to investigate the efficacy of lipofundin against neuroinflammation. In the first model, BV2 mouse microglial cells were treated with lipopolysaccharide (LPS) to induce nitric oxide (NO) production as a model of neuroinflammation. In the second model, HMC3 human microglial were activated by LPS, and changes in the secretion of factors associated with inflammation were analyzed using Luminex xMAP® technology. Griess assay results revealed that lipofundin significantly prevented and treated LPS-induced NO production. An anti-neuroinflammatory effect was also observed in HMC3 cells, where lipofundin exhibited excellent preventive and therapeutic properties by reducing the LPS-induced expression and secretion of interleukin-1ß. Notably, lipofundin also promoted the secretion of certain growth factors, suggesting a potential neuroprotective effect. These results demonstrate that, in addition to its role as a solvent for drugs and nutritional support, lipofundin may also have beneficial effects in alleviating the progression of neuroinflammation. These findings may serve as an important reference for future translational medicine applications.

ClinOleic Impairs ROS Production and Phagocytosis in M1 Macrophages Without Affecting M1 Differentiation.

Lipid emulsions are the primary source of calories and fatty acids that are used to provide essential energy and nutrients to patients suffering from severe intestinal failure and critical illness. However, their use has been linked to adverse effects on patient outcomes, notably affecting immune defenses and inflammatory responses. ClinOleic is a lipid emulsion containing a mixture of olive oil and soybean oil (80:20). The effect of ClinOleic on the differentiation of M1 macrophages remains unclear. In this study, we isolated human monocytes and added ClinOleic to differentiation culture media to investigate whether it affects monocyte polarization into M1 macrophages and macrophage functions, such as reactive oxygen species (ROS) production and phagocytosis. ROS production was stimulated by live S. aureus and detected with L-012, a chemiluminescence emission agent. Phagocytic capacity was assayed using pHrodo™ Green S. aureus Bioparticles® Conjugate. We found that M1 cell morphology, surface markers (CD80 and CD86), and M1-associated cytokines (TNF-α and IL-6) did not significantly change upon incubation with ClinOleic during M1 polarization. However, S. aureus-triggered ROS production was significantly lower in M1 macrophages differentiated with ClinOleic than in those not treated with ClinOleic. The inhibitory effect of ClinOleic on macrophage function also appeared in the phagocytosis assay. Taken together, these findings reveal that ClinOleic has a limited impact on the M1 differentiation phenotype but obviously reduces ROS production and phagocytosis.

Aldo-keto reductase family 1 member A1 (AKR1A1) exerts a protective function in alcohol-associated liver disease by reducing 4-HNE accumulation and p53 activation.

BACKGROUND: The development of alcohol-associated liver disease (ALD) is influenced by the amount and duration of alcohol consumption. The resulting liver damage can range from reversible stages, such as steatosis, steatohepatitis and alcoholic fibrosis, to the advanced and irreversible stage of cirrhosis. Aldo-keto reductase family 1 member A1 (AKR1A1) is a member of the aldo-keto reductase family that catalyzes the reduction of aldehyde groups to their corresponding alcohols in an NADPH-dependent manner. AKR1A1 was found to be downregulated in patients diagnosed with ALD. This study aims to interpret the protective effects of AKR1A1 on the development of ALD. METHODS: A 5% alcohol-fed (AF) Akr1a1 knockout (Akr1a1-/-) mouse model and an AML12 hepatocyte model were used. The effects of AKR1A1 on liver function, inflammation, oxidative stress, lipid accumulation, and fibrosis were assessed by ELISA, western blotting, RT‒PCR, and a variety of histological staining methods in AF-induced wild-type (WT) and Akr1a1-/- mice compared to control liquid diet-fed (PF) WT and Akr1a1-/- mice. RESULTS: The results demonstrated that AF-WT mice expressed higher levels of AKR1A1 than WT mice fed a control diet, and they did not show any noticeable liver steatosis. However, AF-Akr1a1-/- mice displayed a lower survival rate and more severe liver injury than AF-WT mice, as demonstrated by increased proinflammatory cytokines, oxidative stress, lipid accumulation, fibrosis, and reduced antioxidant enzymes in their livers. Additionally, elevated levels of 4-HNE and p53 phosphorylation were observed in AF-Akr1a1-/- mice, suggesting that the loss of AKR1A1 led to increased 4-HNE accumulation and subsequent activation of p53, which contributed to the progression of ALD. Furthermore, in AML12 hepatocytes, Akr1a1 knockdown aggravated oxidative stress and steatosis induced by palmitic acid/oleic acid (P/O) inflammation induced by lipopolysaccharide (LPS), and fibrosis induced by TGF-ß1. CONCLUSIONS: This loss-of-function study suggests that AKR1A1 plays a liver-protective role during chronic alcohol consumption by reducing the accumulation of 4-HNE and inhibiting 4-HNE-mediated p53 activation.

AQP1 Deficiency Drives Phthalate-Induced Epithelial Barrier Disruption through Intestinal Inflammation.

Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

SLC7A11 as a therapeutic target to attenuate phthalates-driven testosterone level decline in mice.

INTRODUCTION: Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. OBJECTIVES: Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. METHODS: We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis. RESULTS: In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. CONCLUSION: Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".

Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis.

As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.

Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-α, or interferons.

Due to the development of drug resistance, the outcome for the majority of patients with acute myeloid leukemia (acute myelogenous leukemia; AML) remains poor. To prevent drug resistance and increase the therapeutic efficacy of treating AML, the development of new combinatory drug therapies is necessary. Sonic hedgehog (Shh) is expressed in AML biopsies and is essential for the drug resistance of cancer stem cells of AML. AML patients are frequently infected by bacteria and exposed to lipopolysaccharide (LPS). LPS itself, its derivatives, and its downstream effectors, such as tumor necrosis factor-α (TNF-α) and interferons (IFNs), have been shown to provoke anti-tumor effects. The application of a Shh inhibitor against AML cells in the presence of LPS/TNF-α/IFNs has not been investigated. We found that the Shh inhibitor cyclopamine in combination with LPS treatment synergistically induced massive cell apoptosis in THP-1 and U937 cells. The cytotoxic effects of this combined drug treatment were confirmed in 5 additional AML cell lines, in primary AML cells, and in an AML mouse model. Replacing cyclopamine with another Shh inhibitor, Sant-1, had the same effect. LPS could be substituted by TNF-α or IFNs to induce AML cell death in combination with cyclopamine. Our results suggest a potential strategy for the development of new therapies employing Shh antagonists in the presence of LPS/TNF-α/IFNs for the treatment of AML patients.

Heme-oxygenase-1 as a target for phthalate-induced cardiomyocytes ferroptosis.

Phthalates as a large group of environmental pollutants are used primarily as plasticizers and solvents, which have become a growing problem worldwide. Epidemiological results show that severity of heart disease is related to degree of environmental contamination. As the most usually used phthalate, di(2-ethylhexyl) phthalate (DEHP) has toxic effects on organism health and is also a major cause of heart damage. Ingestion of food, liquid, or dust contaminated with DEHP are major routes of exposure. The purpose of the present research was to determine the mechanism of cardiotoxicity in mice after exposure to DEHP. Here, male mice were treated by gavage with three different doses of (50, 200 and 500 mg/kg b.w.) DEHP for 28 days. Our research showed that DEHP brought about histopathological changes involving cardiomyocyte lysis and rupture, and ultrastructural damage such as dissolution and loss of mitochondrial cristae. Furthermore, DEHP induced oxidative stress and a significant decline in the antioxidant function, which activates nuclear factor E2-related factor 2 (Nrf2)/heme-oxygense-1 (HO-1) signaling pathways. Interestingly, DEHP resulted in lipid peroxidation and increased ferrous ion content, suggesting that ferroptosis occurred in mouse hearts. Therefore, our findings demonstrated that DEHP could induce cardiac ferroptosis via upregulation of HO-1. The present study provides novel evidence of HO-1 as a target for DEHP-induced cardiotoxicity.

Oncolytic viruses-modulated immunogenic cell death, apoptosis and autophagy linking to virotherapy and cancer immune response.

Recent reports have revealed that oncolytic viruses (OVs) play a significant role in cancer therapy. The infection of OVs such as oncolytic vaccinia virus (OVV), vesicular stomatitis virus (VSV), parvovirus, mammalian reovirus (MRV), human adenovirus, Newcastle disease virus (NDV), herpes simplex virus (HSV), avian reovirus (ARV), Orf virus (ORFV), inactivated Sendai virus (ISV), enterovirus, and coxsackievirus offer unique opportunities in immunotherapy through diverse and dynamic pathways. This mini-review focuses on the mechanisms of OVs-mediated virotherapy and their effects on immunogenic cell death (ICD), apoptosis, autophagy and regulation of the immune system.