Advances in Treatments for Epidermolysis Bullosa (EB): Emphasis on Stem Cell-Based Therapy.

Epidermolysis bullosa (EB) is a rare genetic dermatosis characterized by skin fragility and blister formation. With a wide phenotypic spectrum and potential extracutaneous manifestations, EB poses significant morbidity and mortality risks. Currently classified into four main subtypes based on the level of skin cleavage, EB is caused by genetic mutations affecting proteins crucial for maintaining skin integrity. The management of EB primarily focuses on preventing complications and treating symptoms through wound care, pain management, and other supportive measures. However, recent advancements in the fields of stem cell therapy, tissue engineering, and gene therapy have shown promise as potential treatments for EB. Stem cells capable of differentiating into skin cells, have demonstrated positive outcomes in preclinical and early clinical trials by promoting wound healing and reducing inflammation. Gene therapy, on the other hand, aims to correct the underlying genetic defects responsible for EB by introducing functional copies of mutated genes or modifying existing genes to restore protein function. Particularly for severe subtypes like Recessive Dystrophic Epidermolysis Bullosa (RDEB), gene therapy holds significant potential. This review aims to evaluate the role of new therapeutic approaches in the treatment of EB. The review includes findings from studies conducted on humans. While early studies and clinical trials have shown promising results, further research and trials are necessary to establish the safety and efficacy of these innovative approaches for EB treatment.

Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.

Effect of resveratrol and curcumin and the potential synergism on hypertension: A mini-review of human and animal model studies.

Resveratrol (RES) and curcumin (CUR) are two of the most extensively studied bioactive compounds in cardiovascular research from the past until today. These compounds have effectively lowered blood pressure by downregulating the renin-angiotensin system, exerting antioxidant effects, and exhibiting antiproliferative activities on blood vessels. This study aims to summarize the results of human and animal studies investigating the effects of CUR, RES, and their combination on hypertension and the molecular mechanisms involved. The published trials' results are controversial regarding blood pressure reduction with different doses of RES and CUR, highlighting the need to address this issue.

Role of microRNA-494 in tumor progression.

Various progresses in tumor therapy during the recent decades have significantly reduced the cancer related deaths globally. However, there is still a high rate of mortality in these patients. The early stage tumors have no aggressive and clear clinical symptoms in the majority of cancer types, which causes a high rate of therapeutic failure in advanced tumor stages. Therefore, identification of the molecular tumor biology can be promising to introduce the early diagnostic markers. MicroRNAs (miRNAs) are the key regulators of cellular processes that can also be involved in tumor progression as tumor-suppressor or oncogene. Due to the high stability of miRNAs in body fluids, they can be used as the non-invasive diagnostic tumor markers. In the present review, we discussed the role of miR-494 in tumor progression. It has been shown that miR-494 has mainly a tumor suppressor function by regulation of transcriptional and structural factors and signaling pathways such as transforming growth factor-ß (TGF-ß), WNT, and Janus kinase (JAK)-signal transducer and activator of transcription (STAT). The phosphatase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) axis has been also reported as the main target of miR-494 as an oncogene. These findings suggest that miR-494 is a non-invasive diagnostic marker for the early diagnosis and therapeutic management of cancer patients.

MicroRNAs as the critical regulators of tumor angiogenesis in liver cancer.

Liver cancer is one of the most common malignancies in human digestive system. Despite the recent therapeutic methods, there is a high rate of mortality among liver cancer patients. Late diagnosis in the advanced tumor stages can be one of the main reasons for the poor prognosis in these patients. Therefore, investigating the molecular mechanisms of liver cancer can be helpful for the early stage tumor detection and treatment. Vascular expansion in liver tumors can be one of the important reasons for poor prognosis and aggressiveness. Therefore, anti-angiogenic drugs are widely used in liver cancer patients. MicroRNAs (miRNAs) have key roles in the regulation of angiogenesis in liver tumors. Due to the high stability of miRNAs in body fluids, these factors are widely used as the non-invasive diagnostic and prognostic markers in cancer patients. Regarding, the importance of angiogenesis during liver tumor growth and invasion, in the present review, we discussed the role of miRNAs in regulation of angiogenesis in these tumors. It has been reported that miRNAs mainly exert an anti-angiogenic function by regulation of tumor microenvironment, transcription factors, and signaling pathways in liver tumors. This review can be an effective step to suggest the miRNAs for the non-invasive early detection of malignant and invasive liver tumors.

PRC2 mediated KLF2 down regulation: a therapeutic and diagnostic axis during tumor progression.

Surgery and chemo-radiotherapy are used as the common first-line treatment options in many cancers. However, tumor relapse is observed in many cancer patients following such first-line treatments. Therefore, targeted therapy according to the molecular cancer biology can be very important in reducing tumor recurrence. In this regard, a wide range of monoclonal antibodies against the growth factors and their receptors can offer more targeted treatment in cancer patients. However, due to the importance of growth factors in the normal biology of body cells, side effects can also be observed following the application of growth factor inhibitors. Therefore, more specific factors should be introduced as therapeutic targets with less side effects. Krüppel-like factors 2 (KLF2) belongs to the KLF family of transcription factors that are involved in the regulation of many cellular processes. KLF2 deregulations have been also reported during the progression of many tumors. In the present review we discussed the molecular mechanisms of KLF2 during tumor growth and invasion. It has been shown that the KLF2 as a tumor suppressor is mainly inhibited by the non-coding RNAs (ncRNAs) through the polycomb repressive complex 2 (PRC2) recruitment. This review is an effective step towards introducing the KLF2 as a suitable diagnostic and therapeutic target in cancer patients.

The crosstalk between non-coding RNA polymorphisms and resistance to lung cancer therapies.

Lung cancer (LC) is one of the most common cancer-related mortality in the world. Even with intensive multimodality therapies, lung cancer has a poor prognosis and a high morbidity rate. This review focused on the role of non-coding RNA polymorphisms such as lncRNAs and miRNAs in the resistance to LC therapies, which could open promising avenue for better therapeutic response. Of note, there is currently no valid biomarker to predict lung cancer sensitivity in patients during treatment. Since genetic variations cause many challenges in treating patients, genotyping of known polymorphisms must be thoroughly explored to find desirable treatment platforms. With this knowledge, individualized treatments could become more possible in management of LC.

MicroRNAs as the critical regulators of Forkhead box protein family during gynecological and breast tumor progression and metastasis.

Gynecological and breast tumors are one of the main causes of cancer-related mortalities among women. Despite recent advances in diagnostic and therapeutic methods, tumor relapse is observed in a high percentage of these patients due to the treatment failure. Late diagnosis in advanced tumor stages is one of the main reasons for the treatment failure and recurrence in these tumors. Therefore, it is necessary to assess the molecular mechanisms involved in progression of these tumors to introduce the efficient early diagnostic markers. Fokhead Box (FOX) is a family of transcription factors with a key role in regulation of a wide variety of cellular mechanisms. Deregulation of FOX proteins has been observed in different cancers. MicroRNAs (miRNAs) as a group of non-coding RNAs have important roles in post-transcriptional regulation of the genes involved in cellular mechanisms. They are also the non-invasive diagnostic markers due to their high stability in body fluids. Considering the importance of FOX proteins in the progression of breast and gynecological tumors, we investigated the role of miRNAs in regulation of the FOX proteins in these tumors. MicroRNAs were mainly involved in progression of these tumors through FOXM, FOXP, and FOXO. The present review paves the way to suggest a non-invasive diagnostic panel marker based on the miRNAs/FOX axis in breast and gynecological cancers.

MicroRNA-495: a therapeutic and diagnostic tumor marker.

Therapeutic and diagnostic progresses have significantly reduced the mortality rate among cancer patients during the last decade. However, there is still a high rate of mortality among cancer patients. One of the important reasons involved in the high mortality rate is the late diagnosis in advanced tumor stages that causes the failure of therapeutic strategies in these patients. Therefore, investigating the molecular mechanisms involved in tumor progression has an important role in introducing the efficient early detection markers. MicroRNAs (miRNAs) as stable factors in body fluids are always considered as non-invasive diagnostic and prognostic markers. In the present review, we investigated the role of miR-495 in tumor progression. It has been reported that miR-495 has mainly a tumor suppressor function through the regulation of transcription factors and tyrosine kinases as well as cellular processes such as multidrug resistance, chromatin remodeling, and signaling pathways. This review can be an effective step towards introducing the miR-495 as a non-invasive diagnostic/prognostic marker as well as a suitable target in tumor therapy.

MicroRNAs as the pivotal regulators of cisplatin resistance in head and neck cancers.

Although, there is a high rate of good prognosis in early stage head and neck tumors, about half of these tumors are detected in advanced stages with poor prognosis. A combination of chemotherapy, radiotherapy, and surgery is the treatment option in head and neck cancer (HNC) patients. Although, cisplatin (CDDP) as the first-line drug has a significant role in the treatment of HNC patients, CDDP resistance can be observed in a large number of these patients. Therefore, identification of the molecular mechanisms involved in CDDP resistance can help to reduce the side effects and also provides a better therapeutic management. MicroRNAs (miRNAs) as the post-transcriptional regulators play an important role in drug resistance. Therefore, in the present review we investigated the role of miRNAs in CDDP response of head and neck tumors. It has been reported that the miRNAs exerted their roles in CDDP response by regulation of signaling pathways such as WNT, NOTCH, PI3K/AKT, TGF-ß, and NF-kB as well as apoptosis, autophagy, and EMT process. The present review paves the way to suggest a non-invasive miRNA based panel marker for the prediction of CDDP response among HNC patients. Therefore, such diagnostic miRNA based panel marker reduces the CDDP side effects and improves the clinical outcomes of these patients following an efficient therapeutic management.

Long non-coding RNAs as the critical regulators of PI3K/AKT, TGF-ß, and MAPK signaling pathways during breast tumor progression.

Breast cancer (BC) as one of the most common causes of human deaths among women, is always considered one of the global health challenges. Despite various advances in diagnostic and therapeutic methods, a significant percentage of BC patients have a poor prognosis due to the lack of therapeutic response. Therefore, investigating the molecular mechanisms involved in BC progression can improve the therapeutic and diagnostic strategies in these patients. Cytokine and growth factor-dependent signaling pathways play a key role during BC progression. In addition to cytokines and growth factors, long non-coding RNAs (lncRNAs) have also important roles in regulation of such signaling pathways. Therefore, in the present review we discussed the role of lncRNAs in regulation of PI3K/AKT, MAPK, and TGF-ß signaling pathways in breast tumor cells. It has been shown that lncRNAs mainly have an oncogenic role through the promotion of these signaling pathways in BC. This review can be an effective step in introducing the lncRNAs inhibition as a probable therapeutic strategy to reduce tumor growth by suppression of PI3K/AKT, MAPK, and TGF-ß signaling pathways in BC patients. In addition, considering the oncogenic role and increased levels of lncRNAs expressions in majority of the breast tumors, lncRNAs can be also considered as the reliable diagnostic markers in BC patients.

PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies that are considered as a global health challenge. Despite many progresses in therapeutic methods, there is still a high rate of mortality rate among CRC patients that is associated with poor prognosis and distant metastasis. Therefore, investigating the molecular mechanisms involved in CRC metastasis can improve the prognosis. Epithelial-mesenchymal transition (EMT) process is considered as one of the main molecular mechanisms involved in CRC metastasis, which can be regulated by various signaling pathways. PI3K/AKT signaling pathway has a key role in CRC cell proliferation and migration. In the present review, we discussed the role of PI3K/AKT pathway CRC metastasis through the regulation of the EMT process. It has been shown that PI3K/AKT pathway can induce the EMT process by down regulation of epithelial markers, while up regulation of mesenchymal markers and EMT-specific transcription factors that promote CRC metastasis. This review can be an effective step toward introducing the PI3K/AKT/EMT axis to predict prognosis as well as a therapeutic target among CRC patients. Video Abstract.

Role of the long non-coding RNAs in regulation of Gemcitabine response in tumor cells.

Chemotherapy is widely used as one of the first line therapeutic methods in cancer patients. However, chemotherapeutic resistance is one of the most common problems in cancer patients, which leads to the therapeutic failure and tumor relapse. Considering the side effects of chemotherapy drugs in normal tissues, it is required to investigate the molecular mechanisms involved in drug resistance to improve the therapeutic strategies in cancer patients. Long non-coding RNAs (lncRNAs) have pivotal roles in regulation of cellular processes associated with drug resistance. LncRNAs deregulations have been frequently reported in a wide range of chemo-resistant tumors. Gemcitabine (GEM) as a nucleoside analog has a wide therapeutic application in different cancers. However, GEM resistance is considered as a therapeutic challenge. Considering the role of lncRNAs in the occurrence of GEM resistance, in the present review we discussed the molecular mechanisms of lncRNAs in regulation of GEM response among cancer patients. It has been reported that lncRNAs have mainly an oncogenic role as the inducers of GEM resistance through direct or indirect regulation of transcription factors, autophagy, polycomb complex, and signaling pathways such as PI3K/AKT, MAPK, WNT, JAK/STAT, and TGF-ß. This review paves the way to present the lncRNAs as non-invasive markers to predict GEM response in cancer patients. Therefore, lncRNAs can be introduced as the efficient markers to reduce the possible chemotherapeutic side effects in GEM resistant cancer patients and define a suitable therapeutic strategy among these patients.

Forkhead box proteins as the critical regulators of cisplatin response in tumor cells.

Cisplatin (CDDP) is one of the most common chemotherapy drugs used in a wide range of cancer patients; however, there is a high rate of CDDP resistance among cancer patients. Considering the side effects of cisplatin in normal tissues, it is necessary to predict the CDDP response in cancer patients. Therefore, identifying the molecular mechanisms involved in CDDP resistance can help to introduce the prognostic markers. Several molecular mechanisms such as apoptosis inhibition, drug efflux, drug detoxification, and increased DNA repair are involved in CDDP resistance. Regarding the key role of transcription factors in regulation of many cellular processes related to drug resistance, in the present review, we discussed the role of Forkhead box (FOX) protein family in CDDP response. It has been reported that FOX proteins mainly promote CDDP resistance through the regulation of DNA repair, autophagy, epithelial-mesenchymal transition (EMT), and signaling pathways. Therefore, FOX proteins can be introduced as the prognostic markers to predict CDDP response in cancer patients. In addition, considering that oncogenic role of FOX proteins, the CDDP treatment along with FOX inhibition can be used as a therapeutic strategy in cancer patients.

MicroRNAs as the pivotal regulators of cisplatin resistance in osteosarcoma.

Osteosarcoma (OS) is an aggressive bone tumor that originates from mesenchymal cells. It is considered as the eighth most frequent childhood cancer that mainly affects the tibia and femur among the teenagers and young adults. OS can be usually diagnosed by a combination of MRI and surgical biopsy. The intra-arterial cisplatin (CDDP) and Adriamycin is one of the methods of choices for the OS treatment. CDDP induces tumor cell death by disturbing the DNA replication. Although, CDDP has a critical role in improving the clinical complication in OS patients, a high ratio of CDDP resistance is observed among these patients. Prolonged CDDP administrations have also serious side effects in normal tissues and organs. Therefore, the molecular mechanisms of CDDP resistance should be clarified to define the novel therapeutic modalities in OS. Multidrug resistance (MDR) can be caused by various cellular and molecular processes such as drug efflux, detoxification, and signaling pathways. MicroRNAs (miRNAs) are the key regulators of CDDP response by the post transcriptional regulation of target genes involved in MDR. In the present review we have discussed all of the miRNAs associated with CDDP response in OS cells. It was observed that the majority of reported miRNAs increased CDDP sensitivity in OS cells through the regulation of signaling pathways, apoptosis, transporters, and autophagy. This review highlights the miRNAs as reliable non-invasive markers for the prediction of CDDP response in OS patients.

Role of microRNAs in regulation of doxorubicin and paclitaxel responses in lung tumor cells.

Lung cancer as the leading cause of cancer related mortality is always one of the main global health challenges. Despite the recent progresses in therapeutic methods, the mortality rate is still significantly high among lung cancer patients. A wide range of therapeutic methods including chemotherapy, radiotherapy, and surgery are used to treat lung cancer. Doxorubicin (DOX) and Paclitaxel (TXL) are widely used as the first-line chemotherapeutic drugs in lung cancer. However, there is a significant high percentage of DOX/TXL resistance in lung cancer patients, which leads to tumor recurrence and metastasis. Considering, the side effects of these drugs in normal tissues, it is required to clarify the molecular mechanisms of DOX/TXL resistance to introduce the efficient prognostic and therapeutic markers in lung cancer. MicroRNAs (miRNAs) have key roles in regulation of different pathophysiological processes including cell division, apoptosis, migration, and drug resistance. MiRNA deregulations are widely associated with chemo resistance in various cancers. Therefore, considering the importance of miRNAs in chemotherapy response, in the present review, we discussed the role of miRNAs in regulation of DOX/TXL response in lung cancer patients. It has been reported that miRNAs mainly induced DOX/TXL sensitivity in lung tumor cells by the regulation of signaling pathways, autophagy, transcription factors, and apoptosis. This review can be an effective step in introducing miRNAs as the non-invasive prognostic markers to predict DOX/TXL response in lung cancer patients.

Role of forkhead box proteins in regulation of doxorubicin and paclitaxel responses in tumor cells: A comprehensive review.

Chemotherapy is one of the common first-line therapeutic methods in cancer patients. Despite the significant effects in improving the quality of life and survival of patients, chemo resistance is observed in a significant part of cancer patients, which leads to tumor recurrence and metastasis. Doxorubicin (DOX) and paclitaxel (PTX) are used as the first-line drugs in a wide range of tumors; however, DOX/PTX resistance limits their use in cancer patients. Considering the DOX/PTX side effects in normal tissues, identification of DOX/PTX resistant cancer patients is required to choose the most efficient therapeutic strategy for these patients. Investigating the molecular mechanisms involved in DOX/PTX response can help to improve the prognosis in cancer patients. Several cellular processes such as drug efflux, autophagy, and DNA repair are associated with chemo resistance that can be regulated by transcription factors as the main effectors in signaling pathways. Forkhead box (FOX) family of transcription factor has a key role in regulating cellular processes such as cell differentiation, migration, apoptosis, and proliferation. FOX deregulations have been associated with resistance to chemotherapy in different cancers. Therefore, we discussed the role of FOX protein family in DOX/PTX response. It has been reported that FOX proteins are mainly involved in DOX/PTX response by regulation of drug efflux, autophagy, structural proteins, and signaling pathways such as PI3K/AKT, NF-kb, and JNK. This review is an effective step in introducing the FOX protein family as the reliable prognostic markers and therapeutic targets in cancer patients.

Applications of poly(lactic acid) in bone tissue engineering: A review article.

BACKGROUND: Bone tissue engineering is a promising approach to large-scale bone regeneration. This involves the use of an artificial extracellular matrix or scaffold and osteoblasts to promote osteogenesis and ossification at defect sites. Scaffolds are constructed using biomaterials that typically have properties similar to those of natural bone. METHOD: In this study, which is a review of the literature, various evidences have been discussed in the field of Poly Lactic acid (PLA) polymer application and modifications made on it in order to induce osteogenesis and repair bone lesions. RESULTS: PLA is a synthetic aliphatic polymer that has been extensively used for scaffold construction in bone tissue engineering owing to its good processability, biocompatibility, and flexibility in design. However, PLA has some drawbacks, including low osteoconductivity, low cellular adhesion, and the possibility of inflammatory reactions owing to acidic discharge in a living environment. To overcome these issues, a combination of PLA and other biomaterials has been introduced. CONCLUSIONS: This short review discusses PLA's characteristics of PLA, its applications in bone regeneration, and its combination with other biomaterials.

Molecular biology of microRNA-342 during tumor progression and invasion.

Cancer is considered as one of the main causes of human deaths and health challenges in the world. Various factors are involved in the high death rate of cancer patients, including late diagnosis and drug resistance that result in treatment failure and tumor recurrence. Invasive diagnostic methods are one of the main reasons of late tumor detection in cancer patients. Therefore, it is necessary to investigate the molecular tumor biology to introduce efficient non-invasive markers. MicroRNAs (miRNAs) are involved in regulation of the cellular mechanisms such as cell proliferation, apoptosis, and migration. MiRNAs deregulations have been also frequently shown in different tumor types. Here, we discussed the molecular mechanisms of miR-342 during tumor growth. MiR-342 mainly functions as a tumor suppressor by the regulation of transcription factors and signaling pathways such as WNT, PI3K/AKT, NF-kB, and MAPK. Therefore, miR-342 mimics can be used as a reliable therapeutic strategy to inhibit the tumor cells growth. The present review can also pave the way to introduce the miR-342 as a non-invasive diagnostic/prognostic marker in cancer patients.

Dual targeting of TGF-ß and PD-L1 inhibits tumor growth in TGF-ß/PD-L1-driven colorectal carcinoma.

Immunosuppressive factors within the tumor microenvironment (TME), such as Transforming growth factor beta (TGF-ß), constitute a crucial hindrance to immunotherapeutic approaches in colorectal cancer (CRC). Furthermore, immune checkpoint factors (e.g., programmed death-ligand 1 [PD-L1]) inhibit T-cell proliferation and activation. To cope with the inhibitory effect of immune checkpoints, the therapeutic value of dual targeting PD-L1 and TGF-ß pathways via M7824 plus 5-FU in CRC has been evaluated. Integrative-systems biology approaches and RNAseq were used to assess the differential level of genes associated with 88 metastatic-CRC patients. The level of PD-L1 and TGF-ß was evaluated in a validation cohort. The anti-proliferative, migratory, and apoptotic effects of PD-L1/TGF-ß inhibitor, M7824, were assessed by MTT, wound-healing assay, and flow cytometry. Anti-tumor activity was assessed in a xenograft model, followed by biochemical studies and histological staining, and gene/protein expression analyses by RT-PCR and ELISA/IHC. The result of differentially expressed genes (DEGs) analysis showed 1268 upregulated and 1074 downregulated genes in CRC patients. Among the highest scoring genes and dysregulated pathways associated with CRC, PD-L1, and TGF-ß were identified and further validated in 92 CRC patients. Targeting of PD-L1-TGF-ß inhibited cell growth and migration, associated with modulation of CyclinD1 and MMP9. Furthermore, M7824 inhibited tumor growth via targeting TGF-ß and PD-L1 pathways, resulting in modulation of inflammatory response and fibrosis via TNF-α/IL6/CD4-8 and COL1A1/1A2, respectively. In conclusion, our data illustrated that co-targeting PD-L1 and TGF-ß pathways increased the effect of Fluorouracil (5-FU) and reduced the tumor growth in PD-L1/TGF-ß expressing tumors, providing a new therapeutic option in the treatment of CRC.