Novel strategies in HPV­16­related cervical cancer treatment: An in vitro study of combined siRNA-E5 with oxaliplatin and ifosfamide chemotherapy.

BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

Comparison of human monkeypox, chickenpox and smallpox: a comprehensive review of pathology and dermatological manifestations.

Variola virus, the causing agent of smallpox, was eradicated in 1980s and today no new cases are reported. The first human infectious illness to be eliminated globally is variola. On the contrary to Variola, monkeypox, which is a zoonotic and variola-like disease, has nowadays turned to be a major health problem worldwide. VZV is a neurotropic virus and the cause of varicella (chickenpox) and herpes zoster (shingles), which is also a highly infectious disease, especially prevalent in children. These three skin diseases-monkeypox, smallpox, and chickenpox-are frequently mistaken with one another due to similar manifestations including fever, rash, myalgia, chills and headache, but they can all be distinguished by their distinctive symptoms. Although these rash-causing disorders might present different skin lesions; diagnostic tests can be extremely useful in their differentiation. We searched for these concepts on a search engine like Google Scholar, scanning the results for alternative words and phrases, and examined relevant abstracts or articles for alternative words. The clinical diagnosis of monkeypox infection is commonly made based on the occurrence pattern of its skin rash. It is possible in varicella to concurrently identify lesions in their various stages including macular, papular, vesicular, pustular, and crusts; however, monkeypox lesions are all in the same stage and evolve with the same rate. In this review, we have tried to provide a holistic and comprehensive comparison between these three skin infections with a focus on the newly epidemic monkeypox, bringing about the most recent knowledge about its features and its diagnosis.

siRNA-E6 sensitizes HPV-16-related cervical cancer through Oxaliplatin: an in vitro study on anti-cancer combination therapy.

BACKGROUND: Persistent infection with high-risk Human papillomaviruses (HPV), such as hr-HPV-16 and hr-HPV-18, lead to cervical cancer, the fourth most common cancer in the world. In the present study, we investigated the alteration of E6 oncogene expression by E6-specific short interfering RNA (siRNA) combined with Oxaliplatin. METHODS: The cervical cancer cell line, CaSki, was transfected with E6-siRNA, then treated with Oxaliplatin. The cellular genes, such as p53, MMP9, Nanog, and caspases expression, were assessed by quantitative real-time PCR. The cell death rate, cell cycle, and cell viability were assessed by Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, colony formation assay and scratch test determined the stemness ability and cell metastasis, respectively. RESULTS: Combination therapy increased the re-expression of genes involved in the p53-dependent apoptosis pathway (increase in apoptosis to 44.2%), and reduced stemness and metastasis ability compared to either siRNA or Oxaliplatin monotherapy. Together, our results demonstrate that E6-siRNA and Oxaliplatin combination increased the cervical cancer cells' sensitivity to Oxaliplatin and decreased the survival rate, proliferation, and metastasis, and consequently escalated apoptosis rate, induced cell cycle arrest in the sub-G1 stage, and reduced the chemotherapy drug dosage. CONCLUSION: Inhibition of E6 oncogene expression and subsequent E6-siRNA with Oxaliplatin combination therapy could be a novel strategy for cervical cancer treatment.

Hepatic Disorders and COVID-19: From Pathophysiology to Treatment Strategy.

Following the SARS-CoV-2 outbreak and the subsequent development of the COVID-19 pandemic, organs such as the lungs, kidneys, liver, heart, and brain have been identified as priority organs. Liver diseases are considered a risk factor for high mortality from the COVID-19 pandemic. Besides, liver damage has been demonstrated in a substantial proportion of patients with COVID-19, especially those with severe clinical symptoms. Furthermore, antiviral medications, immunosuppressive drugs after liver transplantation, pre-existing hepatic diseases, and chronic liver diseases such as cirrhosis have also been implicated in SARS-CoV-2-induced liver injury. As a result, some precautions have been taken to prevent, monitor the virus, and avoid immunocompromised and susceptible individuals, such as liver and kidney transplant recipients, from being infected with SARS-CoV-2, thereby avoiding an increase in mortality. The purpose of this review was to examine the impairment caused by SARS-CoV-2 infection and the impact of drugs used during the pandemic on the mortality range and therefore the possibility of preventive measures in patients with liver disease.

Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade.

Since December 2019, a novel coronavirus that represents a serious threat to human lives has emerged. There is still no definite treatment for severe cases of the disease caused by this virus, named coronavirus disease 2019 (COVID-19). One of the most considered treatment strategies targets the exaggerated immune regulator, and interleukin (IL)-6 is a crucial pro-inflammatory mediator. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases show an elevated level of IL-6 related to disease severity. IL-6 activity can be inhibited by the following: IL-6 itself, IL-6 signaling pathways such as Janus kinase and signal transducer and activator of transcription (JAK-STAT), gp130, IL-6R, and downstream activated ILs, such as IL-17 and IL-6 cytokine. Currently, according to these studies and their results, IL-6 blockade with anti-IL-6 or its receptor antibodies such as tocilizumab in COVID-19 is beneficial in severe cases and may reduce the mortality rate. JAK-STAT inhibitors block the cytokine storm by inhibiting several crucial pro-inflammatory mediators such as TNF-α and IL-6 and have shown various results in clinical trials. IL-6 induces IL-17 secretion, and IL-17 is involved in the pathogenesis of inflammatory processes. Clinical trials of anti-IL-17 drugs are currently recruiting, and anti-gp130 antibody is preclinical. However, this agent has shown positive effects in inflammatory bowel disease clinical trials and could be tested for SARS-CoV-2. This study aimed to review the role of IL-6 in the cytokine storm and studies regarding IL-6 and blockade of its inflammatory pathways in COVID-19 to determine if any of these agents are beneficial for COVID-19 patients.

Cluster of differentiation frequency on antigen presenting-cells: The next step to cervical cancer prognosis?

Viruses may transform infected cells into benign or malignant tumors, promoting cell growth and survival via various intracellular pathways. Some oncogenic DNA viruses, such as human papillomaviruses, can lead to squamous intraepithelial lesions and cervical cancer. Furthermore, the early HPV virus'soncoproteins have been attributed to cancer initiation and development and tumor-enhancing action. In addition to viral oncoproteins, antigen-presenting cells (APC) and the number of clusters of differentiation (CD) markers expressed on their surface play an essential role in disease progression or tumorigenesis inhibition. This article discussed the function of CD markers in the interaction between APCs and cancer cells, immune cells' function in the infection process, and finally infected cells' malignancy. We investigated targeting these markers as a novel insight to create a new therapeutic or diagnosis strategy to prevent cervical cancer progression.

A review of COVID-19 vaccines and major considerations for diabetic patients.

The necessity and impact of SARS-CoV2 on the world's health have led to developing and producing practical and useful vaccines for this deadly respiratory virus. Since April 2020, a vaccine for the virus has been developed. Given that comorbidities such as diabetes, hypertension, and cardiovascular disease are more prone to viruses and the risk of infection, vaccines should be designed to protect against high-risk respiratory illnesses. Including SARS, MERS, influenza, and the SARS-CoV-2 provide a safe immune response. Here, we review the information and studies that have been done to help develop strategies and perspectives for producing a safe and ideal vaccine to prevent COVID-19 in normal people, especially at high-risk groups such as diabetes patients.

Spectrum and Burden of Influenza Infection: An Approach to Identify Predictors of Morbidity and Mortality Rate from the Patients of the Northwest of Iran.

Background: The objective of this research is to analyze influenza-induced complications, symptoms, and the interaction of morbidity and mortality rates in hospitalized influenza cases based on age-sex dispersion, influenza virus subtype, prescribed medications, and underlying conditions. Materials and Methods: We performed this retrospective study using a dataset of 10,517 hospitalized individuals, including 3,101 laboratory-confirmed influenza cases from patients of all ages who had attended hospitals in the Northwest of Iran due to respiratory complications. Results: The most prevalent strain which circulated annually was influenza A/H3N2. In contrast to previous studies, our findings suggested that influenza A/H1N1 has the highest mortality rate and the most severe complications.Regardless of virus type/subtype, the most susceptible age group for influenza was 0-9 years old in both males and females. Meanwhile the high-risk age group among males was 50-59 years old and among females were over 80 age group (mortality rate ≈ 20%). Chronic obstructive pulmonary disease (COPD) (32%) and cardiovascular disease (CVD) (30%) were the most prevalent active underlying diseases among the patients who died, with the latter being more prevalent in males over the age of 70. Patients with a history of chemotherapy had the highest mortality rate. Patients who were prescribed a combination of antibiotics and antivirals had better outcomes with lowest mortality rate. Conclusion: Our findings demonstrated that annual influenza seasons are often marked by changes in influenza types and subtypes, with variations in the severity. Development of a standardized set of arrays that best correspond with infections, can be useful in guiding diagnostic and therapeutic decisions.