Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors.

Although p38 MAPK activation is essential for myogenesis, the upstream signaling mechanism that activates p38 during myogenesis remains undefined. We recently reported that p38 activation, myogenesis, and regeneration in cardiotoxin-injured soleus muscle are impaired in TNF-α receptor double-knockout (p55^−/−p75^−/−) mice. To fully evaluate the role of TNF-α in myogenic activation of p38, we tried to determine whether p38 activation in differentiating myoblasts requires autocrine TNF-α, and whether forced activation of p38 rescues impaired myogenesis and regeneration in the p55^−/−p75^−/− soleus. We observed an increase of TNF-α release from C2C12 or mouse primary myoblasts placed in low-serum differentiation medium. A TNF-α-neutralizing antibody added to differentiation medium blocked p38 activation and suppressed differentiation markers myocyte enhancer factor (MEF)-2C, myogenin, p21, and myosin heavy chain in C2C12 myoblasts. Conversely, recombinant TNF-α added to differentiation medium stimulated myogenesis at 0.05 ng/ml while inhibited it at 0.5 and 5 ng/ml. In addition, differentiation medium-induced p38 activation and myogenesis were compromised in primary myoblasts prepared from p55^−/−p75^−/− mice. Increased TNF-α release was also seen in cardiotoxin-injured soleus over the course of regeneration. Forced activation of p38 via the constitutive activator of p38, MKK6bE, rescued impaired myogenesis and regeneration in the cardiotoxin-injured p55^−/−p75^−/− soleus. These results indicate that TNF-α regulates myogenesis and muscle regeneration as a key activator of p38.

Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute a network of interactions compromising a variety of effectors such as pro-oxidants, ROS, mitochondrial enzymes, and nucleic transcription factors. Some of the compartmentalized HO-1 have been demonstrated as functioning in the progression of cancer. Emerging data show the multiple roles of HO-1 in tumorigenesis from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy. However, the role of HO-1 in tumorigenesis has not been systematically addressed. This review describes the crosstalk between HO-1 and oxidative stress, and following redox regulation in the tumorigenesis. HO-1-regulated signaling pathways are also summarized. This review aims to integrate basic information and current progress of HO-1 in cancer research in order to enhance the understandings and facilitate following studies.

Recent data suggest a physiological role for the proinflammatory cytokine TNF-α in skeletal muscle regeneration. However, the underlying mechanism is not understood. In the present study, we analyzed TNF-α-activated signaling pathways involved in myogenesis in soleus muscle injured by cardiotoxin (CTX) in TNF-α receptor double-knockout mice (p55^−/−p75^−/−). We found that activation of p38MAPK, which is critical for myogenesis, was blocked in CTX-injured p55^−/−p75^−/− soleus on day 3 postinjury when myogenic differentiation was being initiated, while activation of ERK1/2 and JNK MAPK, as well as transcription factor NF-κB, was not reduced. Consequently, the phosphorylation of transcription factor myocyte enhancer factor-2C, which is catalyzed by p38 and crucial for the expression of muscle-specific genes, was blunted. Meanwhile, expression of p38-dependent differentiation marker myogenin and p21 were suppressed. In addition, expression of cyclin D1 was fivefold that in wild-type (WT) soleus. These results suggest that myogenic differentiation is blocked or delayed in the absence of TNF-α signaling. Histological studies revealed abnormalities in regenerating p55^−/−p75^−/− soleus. On day 5 postinjury, new myofiber formation was clearly observed in WT soleus but not in p55^−/−p75^−/− soleus. To the contrary, p55^−/−p75^−/− soleus displayed renewed inflammation and dystrophic calcification. On day 12 postinjury, the muscle architecture of WT soleus was largely restored. Yet, in p55^−/−p75^−/− soleus, multifocal areas of inflammation, myofiber death, and myofibers with smaller cross-sectional area were observed. Functional studies demonstrated an attenuated recovery of contractile force in injured p55^−/−p75^−/− soleus. These data suggest that TNF-α signaling plays a critical regulatory role in muscle regeneration.

In mammals, triacylglycerol (TAG) accumulation in nonadipose tissue, termed lipotoxicity, develops with obesity and can provoke insulin resistance, overt diabetes, and ovarian dysfunction. Leptin, an adipose tissue hormone, may mediate these effects. Feed-satiated broiler breeder hens manifest lipotoxicity-like symptoms. Changes in body and organ weights, hepatic and plasma TAG, nonesterified fatty acids (NEFA), ovarian morphology, and egg production in response to acute voluntary increases of feed intake were measured in 2 studies with Cobb 500 broiler breeder hens provided with either 145 or ≥290g of feed/d per hen for 10 d. In both studies, no hen fed 145 g of feed/d exhibited ovarian abnormalities, whereas ∼50% of feed-satiated hens did. Egg production in feed-satiated hens was reduced from 73.3 to 55.8% (P = 0.001). Morphology indicated that apoptosis-induced atresia occurred in the hierarchical follicles. Fractional weight of yolk increased from 29.3 to 30.6% (P = 0.016) and no longer correlated to egg weight. Body, liver, and abdominal adipose weights were significantly greater (P < 0.05) in feed-satiated hens, as were plasma concentrations of glucose, NEFA, TAG, insulin, and leptin (P < 0.05). Feed-satiated hens with abnormal ovaries had significantly more liver and abdominal fat, greater plasma leptin and TAG concentrations, and more saturated fatty acids in plasma NEFA than did feed-satiated hens with normal ovaries. Differences in severity of lipotoxic metabolic and hormonal responses among feed-satiated hens were closely linked to the incidence of ovarian abnormalities and granulosa cell susceptibility to apoptosis and necrosis.