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Colorectal cancer (CRC) ranks among the leading causes of cancer-related deaths worldwide. Enhancing CRC diagnosis and prognosis requires the development of improved biomarkers and therapeutic targets. Emerging evidence suggests that the unfolded protein response (UPR) plays a pivotal role in CRC progression, presenting new opportunities for diagnosis, treatment, and prevention. This study hypothesizes that genetic variants in endoplasmic reticulum (ER) stress response genes influence CRC susceptibility. We examined the frequencies of SNPs in PERK (rs13045) and GRP78/BiP (rs430397) within a South Iranian cohort. We mapped the cellular and molecular features of PERK and GRP78 genes in colorectal cancer, observing their differential expressions in tumor and metastatic tissues. We constructed co-expression and protein-protein interaction networks and performed gene set enrichment analysis, highlighting autophagy as a significant pathway through KEGG. Furthermore, the study included 64 CRC patients and 60 control subjects. DNA extraction and genotyping were conducted using high-resolution melting (HRM) analysis. Significant differences in PERK and GRP78 expressions were observed between CRC tissues and controls. Variations in PERK and GRP78 genotypes were significantly correlated with CRC risk. Utilizing a Multi-Target Directed Ligands approach, a dual PERK/GRP78 inhibitor was designed and subjected to molecular modeling studies. Docking experiments indicated high-affinity binding between the proposed inhibitor and both genes, PERK and GRP78, suggesting a novel therapy for CRC. These findings highlight the importance of understanding genetic backgrounds in different populations to assess CRC risk. Polymorphisms in UPR signaling pathway elements may serve as potential markers for predicting CRC susceptibility, paving the way for personalized therapeutic strategies.
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BACKGROUND: Despite extensive research on the use of low-power lasers for TMD treatment, the extent of their effectiveness remains uncertain. OBJECTIVE: This study aimed to investigate the therapeutic or placebo effect of LLLT for TMD, and to compare it with standard treatment methods. A unique aspect of this study was the inclusion of a control group that received only standard treatment, allowing for an assessment of the placebo effect of LLLT. METHODS: A total of 42 patients with TMD were referred to Kerman Dental School Pain Clinic and were randomly assigned to three groups: group A received LLLT, group B was a placebo group and group C was a control group that received only standard treatment. The laser groups received gallium-aluminium-arsenide laser treatment twice a week for 10 sessions. Patients' jaw movement rate indicators and VAS index were evaluated at the start of treatment, and indicators were re-recorded every week for 5 weeks. SPSS 21 was used for statistical analysis, including ANOVA and Tukey's post hoc tests for inter-group comparisons. The repeated measurement test was used to analyse the data. RESULTS: All groups showed significant improvement in VAS indicators (p = .0001), lateral jaw movements (p = .0001), forward jaw movement (p = .007) but not for maximum mouth opening. No significant difference was observed between the groups at the end of the study (p = .000). CONCLUSION: Our study provides insights into LLLT's effectiveness for TMD, suggesting it cannot replace standard treatment alone. These findings contribute to the literature and emphasise the importance of including a control group in future studies to assess the placebo effect of LLLT.
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Terapia por Luz de Baja Intensidad , Trastornos de la Articulación Temporomandibular , Humanos , Efecto Placebo , Trastornos de la Articulación Temporomandibular/radioterapiaRESUMEN
The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism, in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding, and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen, which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathologic conditions, the cross-talk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlights potential therapeutic implications for numerous cancers.
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Neoplasias , Fosfatidilinositol 3-Quinasas , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Respuesta de Proteína Desplegada , Estrés del Retículo Endoplásmico , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.
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Neoplasias , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Genes p53 , Neoplasias/genética , Neoplasias/patología , Carcinogénesis/genética , Transformación Celular Neoplásica/metabolismo , Microambiente Tumoral/genéticaRESUMEN
The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.
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Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a ß-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Vacunas contra la COVID-19 , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Statement of the Problem: Oral lichen planus (OLP) and other oral lichenoid lesions (OLL) are reported to have the potential of malignant transformation and dysplastic changes, turning into oral squamous cell carcinoma (SCC). While the world health organization (WHO) has classified OLP as a precancerous lesion of the oral cavity, there is still much debate among researchers about its risks and malignancy potential. Purpose: The present study aimed to determine malignant transformation in OLP and OLL and understand related risk factors. Materials and Method: This retrospective study was performed on 356 patients of the Oral Medicine Department of Dental School of Kerman Medical University from 1998 to 2020. All patients' records were gathered. In addition, patients were followed up routinely. Second biopsy was taken as needed. The samples, previously taken from the patients, were re-evaluated according to WHO histopathologic criteria for diagnosing OLP, OLL, dysplasia, and SCC by an experienced pathologist and compared with first reports. Results: Dysplastic changes were observed in 6.2% of the patients. In more than half of the patients, dysplastic changes were present right from the start and 2.20% of the patients had experienced dysplastic changes averagely within 2.05 years of the onset of lesions. Multiple logistic regression showed that the risk of dysplasia increases with aging (p= 0.013), smoking (p= 0.0001), and thyroid disorders (p= 0.008). Conclusion: Given the rather high prevalence of oral lichen planus and lichenoid lesions, further research appears to be needed to determine the etiology of these lesions, malignant transformations, and the factors affecting this probability. Considering the findings, it is imperative to meticulously record the information of all patients with oral lichen planus and lichenoid lesions in the initial examinations as well as close follow-ups and employ diagnostic tools such as toluidine blue staining or even repeat biopsy when necessary.
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Introduction: The purpose of this study was to determine the therapeutic effect of low-level laser therapy (LLLT) on acute pain and the range of mouth opening after condylar closed reduction surgery. The use of low-level lasers, especially to reduce inflammation and pain, has received more attention in recent years. The results of many studies performed in this field are contradictory, and the effectiveness of low-level lasers in the treatment of patients is still uncertain. Methods: This study was performed as a randomized, double-blinded clinical trial on 40 patients with condylar closed reduction surgery. Patients were randomly assigned to two groups of 20 patients, including the placebo and intervention groups. In the intervention group, the patients received LLLT (100 mw, 2 J/cm2, 20 S/point, 14 extraoral points, 7 days). The range of jaw movements after opening the intermaxillary-fixation was measured. Patients' pain was assessed using the visual analog scale (VAS). Data were analyzed using SPSS software version 21, the chi-square test, and repeated measures ANOVA. Results: There was no significant difference between the study groups in terms of the range of jaw motions. The mean VAS score was 56.85 (SD=3.817) in the intervention group and 60.95 (SD=4.861) in the placebo group, showing a statistically significant difference between the two groups at the end of the study (P=0.007) Conclusion: The results of this study indicated the effectiveness of low-level lasers in reducing acute pain in patients undergoing closed condylar surgery. Iranian Registry of Clinical Trials (IRCT20200520047519N1).
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The mechanistic/mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, which plays a pivotal role in regulating numerous cellular functions including cell growth, proliferation, survival, and metabolism by integrating a variety of extracellular and intracellular signals in the tumor microenvironment (TME). Dysregulation of the mTOR pathway is frequently reported in many types of human tumors, and targeting the PI3K/Akt/mTOR signaling pathway has been considered an attractive potential therapeutic target in cancer. The PI3K/Akt/mTOR signaling transduction pathway is important not only in the development and progression of cancers but also for its critical regulatory role in the tumor microenvironment. Immunologically, mTOR is emerging as a key regulator of immune responses. The mTOR signaling pathway plays an essential regulatory role in the differentiation and function of both innate and adaptive immune cells. Considering the central role of mTOR in metabolic and translational reprogramming, it can affect tumor-associated immune cells to undergo phenotypic and functional reprogramming in TME. The mTOR-mediated inflammatory response can also promote the recruitment of immune cells to TME, resulting in exerting the anti-tumor functions or promoting cancer cell growth, progression, and metastasis. Thus, deregulated mTOR signaling in cancer can modulate the TME, thereby affecting the tumor immune microenvironment. Here, we review the current knowledge regarding the crucial role of the PI3K/Akt/mTOR pathway in controlling and shaping the immune responses in TME.