The fear of SARS-CoV-2 infection is due to its high mortality related to seasonal flu. To date, few medicines have been developed to significantly reduce the mortality of the severe COVID-19 patients, especially those requiring tracheal intubation. The severity and mortality of SARS-CoV-2 infection not only depend on the viral virulence, but are primarily determined by the cytokine storm and the destructive inflammation driven by the host immune reaction. Thus, to target the host immune response might be a better strategy to combat this pandemic. Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication. These render it a potentially excellent candidate for treatment of the severe COVID-19 cases. Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality. If successful, it would make the SARS-CoV-2 pandemic less fearful and help to return life back to normalcy. 

https://doi.org/10.1016/j.lfs.2022.120368

Mechanisms and clinical evidence to support melatonin's use in severe COVID-19 patients to lower mortality

Microplastics (MPs) generally refer to the plastic fragments or particles smaller than 5 mm in diameter, which are closely concerned due to their widespread presence in the environment. Recent studies have shown that MPs have a serious threat on the reproductive health of organisms. Pigs are often selected as the model animals because of their high similarity to human tissues and organs. However, there are no reports on the effects and mechanisms of MPs exposure on swine germ cells. In the present study, we established swine testis (ST) cell models exposed to 250, 500, and 1000 μg/ml polystyrene microplastics (PS‐MPs, 1–10 μm), respectively. The findings revealed that PS‐MPs reduced cell viability dose‐dependently. Acridine orange/ethidium bromide staining and flow cytometry results indicated the occurrence of apoptosis and necrosis in ST cells under PS‐MPs exposure, and the expression changes of relevant marker genes (B‐cell lymphoma‐2, Bcl‐2 Associated X, Caspase‐3, Caspase‐9, Receptor‐interacting protein kinase 1, Receptor‐interacting protein kinase 3, Mixed lineage kinase domain‐like, and Caspase‐8) were clarified via quantitative real‐time PCR and western blot. Further mechanistic studies found that PS‐MPs treatment induced excessive intracellular reactive oxygen species (ROS) production, which promoted the phosphorylation of mitogen‐activated protein kinase (MAPK) pathway‐related genes (P38, c‐Jun N‐terminal kinase, extracellular regulated protein kinases) and activated the downstream gene hypoxia‐inducible factor (HIF1α). In conclusion, our study suggests that PS‐MPs treatment causes apoptosis and necroptosis in ST cells via ROS/MAPK/HIF1α signaling pathway.

Polystyrene microplastics induce apoptosis and necroptosis in swine testis cells via ROS/MAPK/HIF1α pathway

Dexmedetomidine (DEX) suppresses inflammatory responses and protects against organ injury. The aim of the present study was to investigate the effect of DEX on airway hyperresponsiveness (AHR) and allergic airway inflammation, as well as its underlying mechanism of action in a murine model of ovalbumin (OVA)-induced asthma. A total of 30 female BALB/c mice were divided into 6 groups (n=5 mice/group): Control, OVA, OVA + DEX (20, 30 or 50 µg/kg) and OVA + TAK-242 [a toll-like receptor 4 (TLR4) inhibitor]. The mice were intraperitoneally injected with 20, 30 or 50 µg/kg DEX 1 h before OVA challenge. AHR to inhaled methacholine (Mch) was measured, and the mice were sacrificed 24 h after the last challenge. AHR following Mch inhalation was measured using the FlexiVent apparatus. Hematoxylin and eosin, periodic acid-Schiff and Wright-Giemsa staining was performed to evaluate inflammatory cell infiltration in the lung tissue. The levels of IL-4, IL-5 and IL-13 in the bronchoalveolar lavage fluid were analyzed using ELISA, and their mRNA expression levels in the lung tissue were examined using reverse transcription-quantitative PCR. The protein expression of TLR4, NF-κB and phosphorylated (p)NF-κB in the lung tissue was also detected using immunohistochemistry. In the murine OVA-induced asthma model, DEX decreased AHR following Mch inhalation and reduced the infiltration of inflammatory cells. IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluid were significantly lower following DEX treatment. Furthermore, DEX treatment inhibited the expression of TLR4, NF-κB and p-NF-κB in the lung tissue and exhibited a similar effect to TAK-242 treatment. In conclusion, DEX may attenuate AHR and allergic airway inflammation by inhibiting the TLR4/NF-κB pathway. These results suggested that DEX may represent a potential anti-inflammatory agent for the treatment and management of patients with asthma.

https://www.spandidos-publications.com/10.3892/mmr.2022.12590/download

Dexmedetomidine alleviates airway hyperresponsiveness and allergic airway inflammation through the TLR4/NF-κB signaling pathway in mice

The testis is an important male reproductive organ, which ensures reproductive function via the secretion of testosterone and the generation of spermatozoa. Testis development begins in the embryonic period, continues after birth, and generally reaches functional maturation at puberty. The stress-activated kinase, p38 mitogen-activated protein kinase (MAPK), regulates multiple cell processes including proliferation, differentiation, apoptosis, and cellular stress responses. p38 MAPK signalling plays a crucial role in testis development by regulating spermatogenesis, the fate determination of pre-Sertoli, and primordial germ cells during embryogenesis, the proliferation of testicular cells in the postnatal period, and the functions of mature Sertoli and Leydig cells. In addition, p38 MAPK signalling is involved in decreased male fertility when exposed to various harmful stimuli. This review will describe in detail the biological functions of p38 MAPK signalling in testis development and male reproduction, together with its pathological role in male infertility.

https://downloads.hindawi.com/journals/omcl/2022/6891897.pdf

Role of p38 MAPK Signalling in Testis Development and Male Fertility

Abstract Background Ionizing radiations (IR) have widespread useful applications in our daily life; however, they have unfavorable effects on reproductive health. Maintaining testicular health following IR exposure is an important requirement for reproductive potential. The current study explored the role of melatonin (MLT) in mitigating IR-induced injury in young adult rat testis. Methods Rats were given daily MLT (25 mg/kg) for 3 and 14 days after receiving 4 Gy γ-radiation. Results Serum MLT levels and other antioxidants, including glutathione content, and the activity of glutathione peroxidase and glutathione reductase in the testis of the irradiated rats were remarkably maintained by MLT administration in irradiated rats. Hence, the hydrogen peroxide level declined with remarkably reduced formation of oxidative stress markers, 4-hydroxynonenal, and 8-Hydroxy-2′-deoxyguanosine in the testis of irradiated animals after MLT administration. The redox status improvement caused a remarkable regression of proapoptotic protein (p53, Cyto-c, and caspase-3) in the testis and improved inflammatory cytokines (CRP and IL-6), and anti-inflammatory cytokine (interleukin IL-10) in serum. This is associated with restoration of disturbed sex hormonal balance, androgen receptor upregulation, and testicular cell proliferation activity in irradiated rats, explaining the improvement of sperm parameters (count, motility, viability, and deformation). Consequently, spermatogenic cell depletion and decreased seminiferous tubule diameter and perimeter were attenuated by MLT treatment post irradiation. Moreover, the testis of irradiated-MLT-treated rats showed well-organized histological architecture and normal sperm morphology. Conclusions These results show that radiation-induced testicular injury is mitigated following IR exposure through synergistic interdependence between the antioxidant, anti-inflammatory, anti-apoptotic, and anti-DNA damage actions of MLT. 

/pdf/utility-of-melatonin-in-mitigating-ionizing-radiation-1hnkmuk9.pdf

Utility of melatonin in mitigating ionizing radiation-induced testis injury through synergistic interdependence of its biological properties

The ameliorative effect of melatonin on LPS-induced Sertoli cells inflammatory and tight junctions damage via suppression of the TLR4/MyD88/NF-κB signaling pathway in newborn calf

Cadmium induces testosterone synthesis disorder by testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to reduced sexual behavior in piglets.

Yulong Li

Papers

The ameliorative effect of melatonin on LPS-induced Sertoli cells inflammatory and tight junctions damage via suppression of the TLR4/MyD88/NF-κB signaling pathway in newborn calf

Cadmium induces testosterone synthesis disorder by testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to reduced sexual behavior in piglets.

Progesterone regulates inflammation and receptivity of cells via the NF-κB and LIF/STAT3 pathways.

Alleviative effect of melatonin on the decrease of uterine receptivity caused by blood ammonia through ROS/NF-κB pathway in dairy cow.