Gene & Protein in Disease

Effect of Dunaliella salina on myocardial ischemia-reperfusion injury through KEAP1/NRF2 pathway activation and JAK2/STAT3 pathway inhibition

Jingjing Song — 2023-04-26

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening vascular emergency, in which oxidative stress and excessive inflammation reactions play significant roles. Dunaliella salina is rich in natural beta (β)-carotene, which is considered an antioxidant and anti-cancer compound, preventing night blindness, delaying aging, and regulating immunity. Due to its unique nutritional and functional components, D. salina has the potential to be developed as a nutritional health food. At present, it is unknown whether D. salina can rescue MIRI. The present study aimed at investigating whether D. salina has protective effect on MIRI and at exploring its potential mechanism. We developed a Langendorff perfused heart model in mice. The mice were given D. salina by gavage at a dose of 500 mg/kg for 7 days consecutively. It was found that D. salina could improve left ventricle function and reduce the rate of malignant arrhythmia and infarct size (P < 0.01). Furthermore, D. salina administration increased superoxide dismutase and decreased malondialdehyde content in myocardial tissue (P < 0.01). Importantly, real-time polymerase chain reaction and Western blot results showed that D. salina caused nuclear factor (erythroid-derived 2)-like 2 (NRF2) activation and enhanced the expression of antioxidative genes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) (P < 0.05 and P < 0.01, respectively). At the same time, the phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3) was inhibited (P < 0.05 and P < 0.01, respectively), and proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-6 decreased with D. salina administration (P < 0.05). In conclusion, D. salina has a protective effect on MIRI, which may be mediated by promoting kelch-like ECH-associated protein 1 (KEAP1)/NRF2 pathway and inhibiting JAK2/STAT3 signaling pathway.

Multiple PDZ domain protein regulates sperm motility through CatSper channel

Dandan Wang — 2023-06-30

Multiple PDZ domain protein (MPDZ) is a component of the crumbs cell polarity complex and is ubiquitously expressed in mammalian tissues. In mouse sperm, MPDZ was identified as a regulator of the sperm acrosome reaction in the past two decades. Here, a relationship between MPDZ and sperm motility was discovered. During breeding, we found that MPDZ-null mice had smaller litter size. The Ca²⁺ signal in mouse sperm decreased. Computer-assisted semen analysis revealed that MPDZ-null males had reduced mouse sperm motility. In humans, MPDZ expression is positively associated with sperm motility. Considering the regulatory role of the CatSper channel in sperm motility and fertility, we identified the expression profile of CatSper subunits (CatSper1–4) and found a reduction at both the transcriptional and translational levels in MPDZ-null mouse spermatozoa. However, in vitro, only CatSper1/2 expression was upregulated in MPDZ-overexpressing GC2 cells. Meanwhile, we found an upregulated cell Ca²⁺ signal when MPDZ was overexpressed in GC2 cells. Mechanical analysis revealed that MPDZ bound to the signal transducer and activator of transcription 3 (Stat3) and promoted its phosphorylation at tyrosine 705 (Y705) to upregulate CatSper1/2 expression. Inhibition of Stat3 (Y705) phosphorylation or Stat3 expression attenuated the effect of MPDZ on CatSper1/2 expression. These results suggested that MPDZ was responsible for the transcriptional regulation of the CatSper channel, at least in part, to regulate Ca²⁺ signal and sperm motility. To the best of our knowledge, this is the first study to highlight the importance of MPDZ acting as a regulator of sperm motility.

Basic and clinical insights of Mu (μ)-opioid receptor in cancer

Ruidong Ding — 2023-03-29

Cancer is a public health problem that is extremely harmful to people’s health. Most cancer patients experience severe pain in the advanced stage, which will seriously affect their prognosis. At present, opioids, such as morphine, have been used as the drug of choice for treating moderate to severe cancer-related pain. Mu (μ)-opioid receptor (MOR) is expressed in many different cancer cells. In this article, we present the relationship between MOR and tumor pathophysiology; summarize the molecular mechanism and effect of MOR on tumor proliferation and progression, tumor angiogenesis, tumor immunity, and cancer therapy; and propose the future research direction of MOR for cancer treatment. MOR could be as a promising prognostic biomarker and immune checkpoint in cancer therapy.

Hematoma clearance by reactive microglia after intracerebral hemorrhage

Zhenhua Zhang — 2023-03-30

Intracerebral hemorrhage (ICH) is a subtype of stroke with high incidence rate and mortality. The pathogenesis of ICH involves primary brain injury and secondary brain injury. Unfortunately, no approved treatment options and therapies targeting them have shown satisfactory outcomes. Microglia are resident innate immune cells with phagocytic function in the central nervous system that rapidly respond to brain injury. Recent research has indicated that reactive microglia with enhanced phagocytosis reprogrammed by the interleukin 10 (IL-10) signaling pathway are critical for endogenous hematoma clearance. In this review, we first summarize the progress of microglial activation and function after ICH, focusing on specific microglial markers, pro- and anti-inflammatory molecules, as well as phenotypic and functional changes. The available evidence supports that microglia play a dual role after ICH. Second, we summarize the results of previous studies on hematoma clearance, focusing on reactive microglia in clearing hematoma through endogenous pathways reprogrammed by IL-10 or other molecules and necessitating the prospect of further research in this field. This review will help us better understand the role of reactive microglia in hematoma clearance and identify potential therapeutic targets to facilitate translational research in this direction.