According to numerous animal studies, adverse environmental stimuli, including physical, chemical, and biological factors, can cause low‐grade chronic inflammation and subsequent tumor development. Human epidemiological evidence has confirmed the close relationship between chronic inflammation and tumorigenesis. However, the mechanisms driving the development of persistent inflammation toward tumorigenesis remain unclear. In this study, we assess the potential role of reactive oxygen species (ROS) and associated mechanisms in modulating inflammation‐induced tumorigenesis. Recent reports have emphasized the cross‐talk between oxidative stress and inflammation in many pathological processes. Exposure to carcinogenic environmental hazards may lead to oxidative damage, which further stimulates the infiltration of various types of inflammatory cells. In turn, increased cytokine and chemokine release from inflammatory cells promotes ROS production in chronic lesions, even in the absence of hazardous stimuli. Moreover, ROS not only cause DNA damage but also participate in cell proliferation, differentiation, and apoptosis by modulating several transcription factors and signaling pathways. We summarize how changes in the redox state can trigger the development of chronic inflammatory lesions into tumors. Generally, cancer cells require an appropriate inflammatory microenvironment to support their growth, spread, and metastasis, and ROS may provide the necessary catalyst for inflammation‐driven cancer. In conclusion, ROS bridge the gap between chronic inflammation and tumor development; therefore, targeting ROS and inflammation represents a new avenue for the prevention and treatment of cancer.

Macrophage recruitment and pro-inflammatory differentiation are hallmarks of various diseases, including infection and sepsis. Although studies suggest that mitochondria may regulate macrophage immune responses, it remains unclear whether mitochondrial mass affects macrophage pro-inflammatory differentiation. Here, we found that lipopolysaccharide (LPS)-activated macrophages possess higher mitochondrial mass than resting cells. Therefore, this study aimed to explore the functional role and molecular mechanisms of increased mitochondrial mass in pro-inflammatory differentiated macrophages. Results show that an increase in the mitochondrial mass of macrophages positively correlates with inflammatory cytokine generation in response to LPS. RNA-seq analysis revealed that LPS promotes signal transducers and activators of transcription 2 (Stat2) and dynamin-related protein 1 (Drp1) expression, which are enriched in positive mitochondrial fission regulation. Meanwhile, knockdown or pharmacological inhibition of Drp1 blunts LPS-induced mitochondrial mass increase and pro-inflammatory differentiation. Moreover, Stat2 boosts Drp1 phosphorylation at serine 616, required for Drp1-mediated mitochondrial fission. LPS also causes Stat2-and Drp1-dependent biogenesis, which contributes to the generation of additional mitochondria. However, these mitochondria are profoundly remodeled, displaying fragmented morphology, loose cristae, reduced Δψm, and metabolic programming. Furthermore, these remodeled mitochondria shift their function from ATP synthesis to reactive oxygen species (ROS) production, which drives NFκB-dependent inflammatory cytokine transcription. Interestingly, an increase in mitochondrial mass with constitutively active phosphomimetic mutant of Drp1 (Drp1S616E) boosted pro-inflammatory response in macrophages without LPS stimulation. In vivo, we also demonstrated that Mdivi-1 administration inhibits LPS-induced macrophage pro-inflammatory differentiation. Importantly, we observed Stat2 phosphorylation and Drp1-dependent mitochondrial mass increase in macrophages isolated from LPS-challenged mice. In conclusion, we comprehensively demonstrate that a Stat2-Drp1 dependent mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. Therefore, targeting the Stat2-Drp1 axis may provide novel therapeutic approaches for treating infection and inflammatory diseases.

Background: Phosgene (carbonyl dichloride) gas is an indispensable chemical inter‐mediate used in numerous industrial processes. There is no clear consensus as to its time‐ and inhaled‐dose‐dependent etiopathologies and associated preventive or therapeutic treatment strategies.Methods: Cardiopulmonary function was examined in rats exposed by inhalation to the alveolar irritant phosgene or to the airway irritant chlorine during and following exposure. Terminal measurements focused on hematology, protein extravasation in bronchoalveolar lavage (BAL), and increased lung weight. Noninvasive diagnostic and prognostic endpoints in exhaled breath (carbon dioxide and nitric oxide) were used to detect the clinically occult stage of pulmonary edema.Results: The first event observed in rats following high but sublethal acute exposure to phosgene was the stimulation of alveolar nociceptive vagal receptors. This afferent stimulation resulted in dramatic changes in cardiopulmonary functions, ventilation: perfusion imbalances, and progressive pulmonary edema and phospholipoproteinosis. Hematology revealed hemoconcentration to be an early marker of pulmonary edema and fibrin as a discriminating endpoint that was positive for the airway irritant chlorine and negative for the alveolar irritant phosgene.Conclusions: The application of each gas produced typical ALI/ARDS (acute lung injury/acute respiratory distress syndrome) characteristics. Phosgene‐induced ALI showed evidence of persistent apnea periods, bradycardia, and shifts of vascular fluid from the peripheral to the pulmonary circulation. Carbon dioxide in expired gas was suggestive of increased ventilation dead space and appeared to be a harbinger of progressively developing lung edema. Treatment with the iNOS inhibitor aminoguanidine aerosol by inhalation reduced the severity of phosgene‐induced ALI when applied at low dose‐rates. Symptomatic treatment regimens were considered inferior to causal modes of treatment.

Obesity, diabetes and related metabolic disorders are among the top prevalent metabolism-related diseases with increasing threat to human health throughout the world. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins possessing anti-diabetic, antioxidant, hypolipidemic and anti-inflammatory activities. A nano-formulation of OA was recently developed to evaluate the efficiency of nano-OA in the treatment of insulin-resistance and metabolic disorders in high fat and fructose (HFF) diet-fed rats. This study further identified that nano-OA could reduce the increase of body weights, serum insulin, insulin sensitivity index, serum triglycerides, and cholesterol in HFF-fed rats. In consistence, nano-OA was able to attenuate HFF diet-induced lipid accumulation in the liver and improve the structural integrity of mitochondria and endoplasmic reticulum in liver and pancreas in animals fed with HFF diet. In addition, nan-OA can efficaciously mitigate the increase of levels of malondialdehyde (MDA) and nitric oxide (NO), and serum superoxide dismutase (SOD) and catalase (CAT) activities in blood samples. The beneficial effects of nano-OA was further evidenced to be superior to OA formulated in arabic gum and rosiglitazone treatment. Together, this study provides the evidence that nano-OA can effectively improve HFF diet-induced metabolic dysfunctions in rats by improving its bioavailability and pharmacodynamic properties and thus nano-OA may be a potentially efficient agent to treat obesity-related diabetes and metabolic disorders.