Immunosenescence and Inflammaging in COVID-19.

Despite knowledge gaps in understanding the full spectrum of the hyperinflammatory phase caused by SARS-CoV-2, according to the World Health Organization (WHO), COVID-19 is still the leading cause of death worldwide. Susceptible people to severe COVID-19 are those with underlying medical conditions or those with dysregulated and senescence-associated immune responses. As the immune system undergoes aging in the elderly, such drastic changes predispose them to various diseases and affect their responsiveness to infections, as seen in COVID-19. At-risk groups experience poor prognosis in terms of disease recovery. Changes in the quantity and quality of immune cell function have been described in numerous literature sites. Impaired immune cell function along with age-related metabolic changes can lead to features such as hyperinflammatory response, immunosenescence, and inflammaging in COVID-19. Inflammaging is related to the increased activity of the most inflammatory factors and is the main cause of age-related diseases and tissue failure in the elderly. Since hyperinflammation is a common feature of most severe cases of COVID-19, this pathway, which is not fully understood, leads to immunosenescence and inflammaging in some individuals, especially in the elderly and those with comorbidities. In this review, we shed some light on the age-related abnormalities of innate and adaptive immune cells and how hyperinflammatory immune responses contribute to the inflammaging process, leading to clinical deterioration. Further, we provide insights into immunomodulation-based therapeutic approaches, which are potentially important considerations in vaccine design for elderly populations.

Concomitant effects of paclitaxel and celecoxib on genes involved in apoptosis of triple-negative metastatic breast cancer cells.

Although triple-negative breast cancer accounts for less than one-fifth of breast cancers, it has a higher rate of metastasis and mortality. This study investigated the effects of combination treatment with paclitaxel and celecoxib on the expression of genes involved in the apoptosis of triple-negative metastatic breast cancer cells. MDA-MB-231 cells were cultured and then treated with certain concentrations of celecoxib (CLX), paclitaxel (PTX), and combination of them for 24 and 48 h. Cell viability was assessed by the MTT method. The real-time PCR method was utilized to assess the expression level of the genes involved in apoptosis. Western blotting was used for evaluating protein expression. IC50 values for CLX and PTX were 73.95 µM and 3.15 µM, respectively. The results demonstrated that PTX, CLX, and PTX + CLX significantly (p < 0.05) reduced cell viability. The comparison of combination treatment with PTX showed a significant increase in caspase 3 gene expression at both time points, in Bax gene expression after 48 h, and a remarkable decrease in Bcl-2 gene expression at both times. Western blotting results were in line with genes' expression. These findings indicate that a combination of PTX and CLX results in a significantly more reduction in cell viability of breast cancer cells. In addition, it seems CLX may be an effective agent in regulating the expression level of caspase 3, Bax, and Bcl-2 when combined with PTX.

Selumetinib: a selective MEK1 inhibitor for solid tumor treatment.

Cancer incidence is rapidly growing. Solid tumors are responsible for a majority of cancers. Recently, molecular-targeted agents have played a significant role in cancer treatment. Ras-Raf-MEK-ERK signaling pathway, is a substantial element in the survival, propagation, and drug resistance of human cancers. MEK is a specific part of the so-called cascade, and ERK proteins are its sole target. Furthermore, their downstream position in the Ras-ERK cascade, is noteworthy to direct their function in patients with upstream mutated genes. MEK1 mutations are responsible for initiating several solid tumors. Selumetinib (AZD6244) is a second-generation, selective, potent, and non-ATP competitive allosteric MEK1 inhibitor. The efficacy of selumetinib in various solid tumors such as colorectal cancer, lung cancer, neurofibroma, and melanoma is investigated. The present paper provides an overview of the MAPK cascade, the role of selumetinib as a MEK1/2 inhibitor, and the related findings of clinical trials for solid tumor treatment.

Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects.

In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials.

SARS-CoV-2 and Guillain-Barré Syndrome: Lessons from Viral Infections.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. COVID-19 has a broad clinical spectrum from asymptomatic patients to multiorgan dysfunction and septic shock. Most of the common symptoms of COVID-19 are classified as respiratory disorders, but some reports show neurological involvements. During the COVID-19 pandemic, a case series of neurological complications, such as Guillain-Barré syndrome (GBS), were reported. GBS is a neuroimmune disorder with acute inflammatory radicular polyneuropathy in different parts of the peripheral nerve. Some studies have reported GBS as an inflammatory neuropathy related to various viral infections, such as cytomegalovirus (CMV), Epstein-Barr Virus (EBV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), influenza, and Zika virus. There are some immunomodulation approaches for the management of GBS. Studies have evaluated the effects of the various therapeutic approaches, including intravenous immunoglobulin (IVIG), plasma exchange (PE), complement inhibitors, and corticosteroids to regulate overactivation of immune responses during GBS in experimental and clinical studies. In this regard, the possible association between GBS and SARS-CoV-2 infection during the outbreak of the current pandemic and also the mentioned therapeutic approaches were reviewed.

Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective.

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1ß levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.

Blockade of CD73 using siRNA loaded chitosan lactate nanoparticles functionalized with TAT-hyaluronate enhances doxorubicin mediated cytotoxicity in cancer cells both in vitro and in vivo.

Chemotherapy drugs are still one of the first treatment options used in many cancers; however, problems such as cytotoxic side effects on normal cells after systemic administration and resistance to treatment have reduced the use of chemotherapeutics day by day. Targeted delivery of these drugs to the tumor site and sensitization of cancer cells to death induced by chemotherapy drugs are ways that can overcome the limitations of the use of these drugs. In this study, we designed and generated a novel nanocarrier composed of chitosan lactate nanoparticles (NPs) functionalized by HIV-1 derived TAT peptide (Transactivating transcriptional activator) and hyaluronate (HA) to deliver CD73 siRNA and doxorubicin to 4T1 and CT26 cancer cells, both in vivo and in vitro, as a novel combinatorial treatment strategy. The CD73 molecule plays a key role in many cancer cell behaviors such as proliferation, angiogenesis, metastasis, imunosuppression, and resistance to chemotherapy. Therefore, we decided to reduce the side effects of DOX by simultaneously transmitting CD73 siRNA and DOX by CL-TAT-HA NPs, increase the susceptibility of cancer cells to DOX-induced cell death, and stimulate anti-tumor immune responses, for the first time. These results indicated that simultaneous transfer of CD73 siRNA and DOX to cancer cells (4 T1 and CT26) increased cell death and inhibited the prolifration and spread of cancer cells. Also, the preferential aggregation of NPs in the tumor microenvironment reduced tumor growh, promoted the survival of tumor-bearing mice, and induced anti-tumor immune responses. These findings indicate that CL-TAT-HA NPs are a good candidate for targeted siRNA/drug delivery to cancer cells and the simultaneous transfer of CD73 siRNA and DOX to cancer cells using this nanocarrier can be used to treat cancer.

Immunopharmacological perspective on zinc in SARS-CoV-2 infection.

The novel SARS-CoV-2 which was first reported in China is the cause of infection known as COVID-19. In comparison with other coronaviruses such as SARS-CoV and MERS, the mortality rate of SARS-CoV-2 is lower but the transmissibility is higher. Immune dysregulation is the most common feature of the immunopathogenesis of COVID-19 that leads to hyperinflammation. Micronutrients such as zinc are essential for normal immune function. According to the assessment of WHO, approximately one-third of the world's society suffer from zinc deficiency. Low plasma levels of zinc are associated with abnormal immune system functions such as impaired chemotaxis of polymorphonuclear cells (PMNs) and phagocytosis, dysregulated intracellular killing, overexpression of the inflammatory cytokines, lymphopenia, decreased antibody production, and sensitivity to microbes especially viral respiratory infections. Zinc exerts numerous direct and indirect effects against a wide variety of viral species particularly RNA viruses. The use of zinc and a combination of zinc-pyrithione at low concentrations impede SARS-CoV replication in vitro. Accordingly, zinc can inhibit the elongation step of RNA transcription. Furthermore, zinc might improve antiviral immunity by up-regulation of IFNα through JAK/STAT1 signaling pathway in leukocytes. On the other hand, zinc supplementation might ameliorate tissue damage caused by mechanical ventilation in critical COVID-19 patients. Finally, zinc might be used in combination with antiviral medications for the management of COVID-19 patients. In the current review article, we review and discuss the immunobiological roles and antiviral properties as well as the therapeutic application of zinc in SARS-CoV-2 and related coronaviruses infections.

Anticancer potential of metformin: focusing on gastrointestinal cancers.

Gastrointestinal cancers are one of the most common types of cancer that have high annual mortality; therefore, identification and introduction of safe drugs in the control and prevention of these cancers are of particular importance. Metformin, a lipophilic biguanide, is the most commonly prescribed agent for type 2 diabetes management. In addition to its great effects on lowering the blood glucose concentrations, the anti-cancer properties of this drug have been reported in many types of cancers such as gastrointestinal cancers. Hence the effects of this agent as a safe drug on the reduction of gastrointestinal cancer risk and suppression of these types of cancers have been studied in different clinical trials. Furthermore, the proposed mechanisms of metformin in preventing the growth of these cancers have been investigated in several studies. In this review, we discuss recent advances in elucidating the molecular mechanisms that are relevant for metformin use in gastrointestinal cancer treatment.

The role of regulatory T cells in the pathogenesis and treatment of prostate cancer.

Despite developments in the treatment of various cancers, prostate cancer is one of the deadliest diseases known to men. Systemic therapies such as androgen deprivation, chemotherapy, and radiation therapy have not been very successful in treating this disease. Numerous studies have shown that there is a direct relationship between cancer progression and inhibition of anti-tumor immune responses that can lead to progression of various malignancies, including prostate cancer. Interestingly, CD4+CD25+FoxP3+ regulatory T cells significantly accumulate and increase in draining lymph nodes and PBMCs of patients with prostate cancer and other solid tumors. In vivo and in vitro studies have shown that Tregs can suppress anti-tumor responses, which is directly related to the increased risk of cancer recurrence. Tregs are essential for preserving self-tolerance and inhibiting extra immune responses harmful to the host. Since the tumor-related antigens are mainly self-antigens, Tregs could play a major role in tumor progression. Accordingly, it has discovered that prostate cancer patients with higher Tregs have poor prognosis and low survival rates. However, anti-tumor responses can be reinforced by suppression of Tregs with using monoclonal antibodies against CD25 and CTLA-4. Therefore, depleting Tregs or suppressing their functions could be one of the effective ways for prostate cancer immunotherapy. The purpose of this review is to investigate the role of Treg cells in the progression of prostate cancer and to evaluate effective strategies for the treatment of prostate cancer by regulating Treg cells.

Anti-Mucin1 Aptamer-Conjugated Chitosan Nanoparticles for Targeted Co-Delivery of Docetaxel and IGF-1R siRNA to SKBR3 Metastatic Breast Cancer Cells

Background: Targeted co-delivery of siRNA and a chemotherapeutic drug is an attractive approach to cancer drug design and treatment. This study was carried out to design an anti-Mucin1 aptamer (Apt)-conjugated chitosan nanoparticle (NP) for targeted co-delivery of insulin-like growth factor receptor 1 (IGF-1R) Silencer siRNA and docetaxel (DTX) to SKBR3 cells. Methods: Characterization of nano-drugs, cellular uptake of NPs, cell viability, and gene expression studies were evaluated based on metastatic breast cancer cells. Results: The results of this study showed that NPs had spherical and smooth morphology with 110-118 nm in size and had positive zeta potential (12-14 mV). siRNA and DTX were considerably loaded into NPs. The appropriate conjugation of the Apt to the NPs was affirmed by gel electrophoresis. The Apt-conjugated NPs were observed to enhance the cellular uptake of NPs into the SKBR3 cells. Although the combination treatment significantly decreased the cell viability of SKBR3 cells, the augmentative effect was observed when Apt was conjugated to NPs. Furthermore, Apt-conjugated NPs dramatically reduced the genetic expression of IGF-1R, signal transducers and activators of transcription 3 (STAT3), matrix metalloproteinases (MMP9), and vascular growth factor (VEGF). Conclusion: The targeted NPs may augment the targeting of pathways involved in tumorigenesis and metastasis of breast cancer. Therefore, more animal model experiments are needed to further clarify the efficacy and safety of this functionalized nanodrug.

Targeted Co-Delivery of Docetaxel and cMET siRNA for Treatment of Mucin1 Overexpressing Breast Cancer Cells.

Purpose: Targeted treatment of breast cancer through combination of chemotherapeutic agents and siRNA had been drawing much attention in recent researches. This study was carried out to evaluate mucin1 aptamer-conjugated chitosan nanoparticles containing docetaxel and cMET siRNA on SKBR3 cells. Methods: Nano-drugs were characterized by transmission electron microscope, Zetasizer and loading efficiency calculation. siRNA entrapment onto nanoparticles, stability of siRNA-loaded nanoparticles and conjugation of mucin1 aptamer to nanoparticles were evaluated via separate electrophoresis. Cellular uptake of the targeted nanoparticles was evaluated through GFP-plasmid expression in mucin1+ SKBR3 vs. mucin1- CHO cells. Protein expression, cell viability and gene expression were assessed by Western Blotting, MTT assay, and Quantitative Real Time-PCR, respectively. Results: Characterization of nano-drugs represented the ideal size (110.5± 3.9 nm), zeta potential (11.6± 0.8 mV), and loading efficiency of 90.7% and 88.3% for siRNA and docetaxel, respectively. Different gel electrophoresis affirmed the conjugation of aptamers to nanoparticles and entrapment of siRNA onto nanoparticles. Increased cellular uptake of aptamer-conjugated nanoparticles was confirmed by GFP expression. cMET gene silencing was confirmed by Western Blotting. The significant (p ≤0.0001) impact of combination targeted therapy vs. control on cell viability was shown. Results of Quantitative Real Time-PCR represented a remarkably decreased (p ≤0.0001) expression of the studied genes involving in tumorigenicity, metastasis, invasion, and angiogenesis (STAT3, IL8, MMP2, MMP9, and VEGF) by targeted combination treatment vs. control. Conclusion: The mucin1 aptamer-conjugated chitosan nanoparticles, containing docetaxel and cMET siRNA, is suggested for treatment of mucin1+ metastatic breast cancer cells. However, further studies should be conducted on animal models.

Testosterone replacement attenuates haloperidol-induced catalepsy in male rats.

PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disease. Recent studies have indicated a higher prevalence of PD in male gender. Furthermore testosterone deficiency is more common among male parkinsonians in compare to healthy men. This study was aimed to investigate the effect of testosterone on catalepsy, in male rats. METHODS: The study carried out on male Wistar rats. To induce catalepsy, haloperidol (1 mg/kg, i.p) as D2 antagonist was administered before testing animals via Bar test. Animals were gonadectomized to investigate testosterone elimination effect on catalepsy, and also the androgen receptor blocker, flutamide, and the aromatase inhibitor, letrozole, were administered in certain groups of animals. The bar test method was used to evaluate haloperidol-induced catalepsy. RESULTS: Haloperidol 1 mg/kg, i.p, was able to induce catalepsy. Gonadectomy worsened the catalepsy and subchronic testosterone replacement could restore this effect to the level of normal animals. While low dose of flutamide administration represented an improvement in cataleptic symptoms, higher doses worsened catalepsy. Letrozole(4mg/kg,sc) administered animals represented nearly the same cataleptic symptoms as the control group. CONCLUSION: Testosterone deficiency increases catalepsy and testosterone replacement can significantly be effective in catalepsy remission. It seems that the anticataleptic effect of testosterone is exerted through affecting on androgenic receptors.

Selenium effect on oxidative stress factors in septic rats.

PURPOSE: Severe oxidative stress is an important event that occurs in patients with sepsis. The body has extensive and multiple defense mechanisms against the reactive oxygen species (ROS) produced during inflammation and sepsis. One of these mechanisms includes a group of enzymes that utilize selenium as their cofactor. The purpose of this study is investigating of Selenium effect on oxidative stress factors in animal model of sepsis. METHODS: Sepsis was induced by caecal ligation and puncture (CLP) method. 30 Male Wistar rats were divided into following groups: sham group; CLP group; 100 µg/kg Selenium- treated CLP group. 12 hours after inducing sepsis animals were killed and lungs were removed. One of the lungs was frozen in liquid nitrogen and kept at -70°C for enzymatic activity analysis and the other was kept in formalin 10% until tissue section preparation performed for histopathological studies. RESULTS: The Myeloperoxidase (MPO) activity was decreased in Selenium- treated CLP group. Inflammation score of lung tissue was lowered in Selenium- treated CLP group, but it wasn't statically significant. Level of glutathione peroxidase (GPx) was higher in CLP and Selenium- treated CLP groups. CONCLUSION: It seems that Selenium has protective effect on lung inflammation during acute lung injury. Also it may improve some stress oxidative profile during CLP model of sepsis.

Neonatal NMDA receptor blockade alters anxiety- and depression-related behaviors in a sex-dependent manner in mice.

There is increasing evidence that N-methyl-D-aspartate (NMDA) receptor blockade in the neonatal period has a long-lasting influence on brain and behavior development and has been linked to an increased risk for neuropsychiatric disorders in later life. We sought to determine whether postnatal NMDA receptor blockade can affect normal development of body weight, corticosterone levels, anxiety- and depression-related behaviors in male and female mice in adulthood. For this purpose, male and female NMRI mice were treated with either saline or phencyclidine (PCP; 5 and 10 mg/kg, s.c.) on postnatal days (PND) 7, 9, and 11, and then subjected to different behavioral tests, including open field, elevated plus-maze, elevated zero-maze, light-dark box, tail suspension test and forced swimming test in adulthood. The results indicated that neonatal PCP treatment reduced body weight during neonatal and adulthood periods, and did not alter baseline corticosterone levels in both male and female mice. Moreover, this study obtained some experimental evidence showing the PCP at dose of 10 mg/kg increases stress-induced corticosterone levels, anxiety- and depression-related behaviors in males, while decreasing levels of anxiety without any significant effect on depression in female mice in adulthood. These data support the argument that neonatal NMDA receptor blockade can lead to behavioral abnormalities and psychiatric diseases in adulthood. Collectively, our findings suggest that neonatal exposure to PCP may have profound effects on the development of anxiety- and depression-related behaviors in a sex- and dose-dependent manner in mice.

Impacts of early intervention with fluoxetine following early neonatal immune activation on depression-like behaviors and body weight in mice.

Several reports have suggested that early neonatal immune activation adversely influences the hypothalamic-pituitary-adrenal (HPA) axis development in humans and animal models. In addition, there have been several studies indicating that early intervention with fluoxetine (FLX) can alter HPA axis development and function, and prevent occurrence of behavioral abnormalities induced by common early-life insults. The present study aims to investigate the effects of early intervention with FLX following early neonatal immune activation on depression-like behaviors and body weight in mice. Neonatal mice in their postnatal days (PNDs) 3 and 5 received either lipopolysaccharide (LPS; 50 µg/kg, s.c.) or saline treatment, then male and female mice of both neonatal intervention groups received oral administration of FLX (5 and 10 mg/kg/day) or water via regular drinking bottles during the periadolescent period (PNDs 35-65). The results showed that neonatal LPS exposure elevated depression-like behaviors accompanied by increasing corticosterone levels in adulthood and decreasing body weight during neonatal and adolescent periods. Furthermore, the periadolescent FLX treatment inhibited the depression-like behaviors induced by neonatal infection in both sexes. This study obtained some experimental evidence indicating the potential adverse impacts of the FLX on normal behavioral development in male control animals. In conclusion, our findings suggest that an early pharmacological intervention with FLX may prevent emergence of depression-like behaviors induced by neonatal immune challenge without any detrimental effect on health in a sex- and dose-dependent manner in mice.