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1.
Oncol Lett ; 21(6): 458, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1225869

ABSTRACT

Cryoablation is an emerging type of treatment for cancer. The sensitization of tumors using cryosensitizing agents prior to treatment enhances ablation efficiency and may improve clinical outcomes. Water efflux, which is regulated by aquaporin channels, contributes to cancer cell damage achieved through cryoablation. An increase in aquaporin (AQP) 3 is cryoprotective, whereas its inhibition augments cryodamage. The present study aimed to investigate aquaporin (AQP1, AQP3 and AQP5) gene expression and cellular localization in response to cryoinjury. Cultured breast cancer cells (MDA-MB-231 and MCF-7) were exposed to freezing to induce cryoinjury. RNA and protein extracts were then analyzed using reverse transcription-quantitative PCR and western blotting, respectively. Localization of aquaporins was studied using immunocytochemistry. Additionally, cells were transfected with small interfering RNA to silence aquaporin gene expression and cell viability was assessed using the Sulforhodamine B assay. Cryoinjury did not influence gene expression of AQPs, except for a 4-fold increase of AQP1 expression in MDA-MD-231 cells. There were no clear differences in AQP protein expression for either cell lines upon exposure to frozen and non-frozen temperatures, with the exception of fainter AQP5 bands for non-frozen MCF-7 cells. The exposure of cancer cells to freezing temperatures altered the localization of AQP1 and AQP3 proteins in both MCF-7 and MDA-MD-231 cells. The silencing of AQP1, AQP3 and AQP5 exacerbated MDA-MD-231 cell damage associated with freezing compared with control siRNA. This was also observed with AQP3 and AQP5 silencing in MCF-7 cells. Inhibition of aquaporins may potentially enhance cryoinjury. This cryosensitizing process may be used as an adjunct to breast cancer cryotherapy, especially in the border area targeted by cryoablation where freezing temperatures are not cold enough to induce cellular damage.

2.
Pharmacol Ther ; 224: 107825, 2021 08.
Article in English | MEDLINE | ID: covidwho-1117458

ABSTRACT

Coronaviruses (CoVs) are a group of single stranded RNA viruses, of which some of them such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are associated with deadly worldwide human diseases. Coronavirus disease-2019 (COVID-19), a condition caused by SARS-CoV-2, results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with high mortality in the elderly and in people with underlying comorbidities. Results from several studies suggest that CoVs localize in mitochondria and interact with mitochondrial protein translocation machinery to target their encoded products to mitochondria. Coronaviruses encode a number of proteins; this process is essential for viral replication through inhibiting degradation of viral proteins and host misfolded proteins including those in mitochondria. These viruses seem to maintain their replication by altering mitochondrial dynamics and targeting mitochondrial-associated antiviral signaling (MAVS), allowing them to evade host innate immunity. Coronaviruses infections such as COVID-19 are more severe in aging patients. Since endogenous melatonin levels are often dramatically reduced in the aged and because it is a potent anti-inflammatory agent, melatonin has been proposed to be useful in CoVs infections by altering proteasomal and mitochondrial activities. Melatonin inhibits mitochondrial fission due to its antioxidant and inhibitory effects on cytosolic calcium overload. The collective data suggests that melatonin may mediate mitochondrial adaptations through regulating both mitochondrial dynamics and biogenesis. We propose that melatonin may inhibit SARS-CoV-2-induced cell damage by regulating mitochondrial physiology.


Subject(s)
COVID-19/drug therapy , Melatonin/pharmacology , Mitochondria/pathology , Aged , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , COVID-19/complications , COVID-19/virology , Coronavirus Infections/complications , Coronavirus Infections/virology , Female , Humans , Melatonin/administration & dosage , Mitochondria/drug effects , Mitochondria/virology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/virology , Virus Replication
3.
Pharmaceutics ; 13(2)2021 Feb 07.
Article in English | MEDLINE | ID: covidwho-1069855

ABSTRACT

The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of respiratory diseases. Due to the lack of efficient treatments for acute respiratory distress syndrome caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the action of MSCs has also been studied. This review describes mode of action and use of MSCs and MSC-derived products in the treatment of lung diseases including the respective advantages and limitations of the products. Further, issues related to standardized production are addressed. Administration by inhalation of MSCs, compared to intravenous injection, could decrease cell damage by shear stress, eliminate the barrier to reach target cells in the alveoli, prevent thrombus formation in the pulmonary vasculature and retention in filter for extracorporeal membrane oxygenation. There is more feasible to deliver extracellular vesicles than MSCs with inhalers, offering the advantage of non-invasive and repeated administration by the patient. Major obstacles for comparison of results are heterogeneity of the products, differences in the treatment protocols and small study cohorts.

4.
Cells ; 10(1)2021 01 11.
Article in English | MEDLINE | ID: covidwho-1067688

ABSTRACT

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.


Subject(s)
Regenerative Medicine , Tripartite Motif Proteins/metabolism , Animals , Glucose/metabolism , Humans , Phylogeny , Regeneration , Tripartite Motif Proteins/chemistry
5.
Biochem Pharmacol ; 183: 114302, 2021 01.
Article in English | MEDLINE | ID: covidwho-893616

ABSTRACT

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 µM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form ß of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1ß and TNF-α in serum. In conclusion, oral administration of crystal form ß of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.


Subject(s)
Antioxidants/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Flavanones/therapeutic use , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Antioxidants/pharmacokinetics , COVID-19/metabolism , Chlorocebus aethiops , Dose-Response Relationship, Drug , Female , Flavanones/pharmacokinetics , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Random Allocation , Rats , Rats, Sprague-Dawley , Treatment Outcome , Vero Cells
6.
Crit Care Res Pract ; 2020: 4743904, 2020.
Article in English | MEDLINE | ID: covidwho-814264

ABSTRACT

OBJECTIVE: In physiological conditions, arterial blood lactate concentration is equal to or lower than central venous blood lactate concentration. A reversal in this rate (i.e., higher lactate concentration in central venous blood), which could reflect a derangement in the mitochondrial metabolism of lung cells induced by inflammation, has been previously reported in patients with ARDS but has been never explored in COVID-19 patients. The aim of this study was to explore if the COVID-19-induced lung cell damage was mirrored by an arterial lactatemia higher than the central venous one; then if the administration of anti-inflammatory therapy (i.e., canakinumab 300 mg subcutaneous) could normalize such abnormal lactate a-cv difference. METHODS: A prospective cohort study was conducted, started on March 25, 2020, for a duration of 10 days, enrolling 21 patients affected by severe COVID-19 pneumonia undergoing mechanical ventilation consecutively admitted to the ICU of the Rimini Hospital, Italy. Arterial and central venous blood samples were contemporarily collected to calculate the difference between arterial and central venous lactate (Delta a-cv lactate) concentrations within 24 h from tracheal intubation (T 0) and 24 hours after canakinumab administration (T 1). RESULTS: At T 0, 19 of 21 (90.5%) patients showed a pathologic Delta a-cv lactate (median 0.15 mmol/L; IQR 0.07-0.25). In the 13 patients undergoing canakinumab administration, at T 1, Delta a-cv lactate decreased in 92.3% of cases, the decrease being statistically significant (T 0: median 0.24, IQR 0.09-0.31 mmol/L; T 1: median -0.01, IQR -0.08-0.04 mmol/L; p=0.002). CONCLUSION: A reversed Delta a-cv lactate might be interpreted as one of the effects of COVID-19-related cytokine storm, which could reflect a derangement in the mitochondrial metabolism of lung cells induced by severe inflammation or other uncoupling mediators. In addition, Delta a-cv lactate decrease might also reflect the anti-inflammatory activity of canakinumab. Our preliminary findings need to be confirmed by larger outcome studies.

7.
Toxicol Rep ; 7: 768-771, 2020.
Article in English | MEDLINE | ID: covidwho-603581

ABSTRACT

During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. Coronavirus infections can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection, thus early NAC as intervention should be evaluated in a clinical trial setting.

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