Breast cancer continues to be the most frequently diagnosed malignancy among women, putting their life in jeopardy. Cancer immunotherapy is a novel approach with the ability to boost the host immune ...system to recognize and eradicate cancer cells with high selectivity. As a promising treatment, immunotherapy can not only eliminate the primary tumors, but also be proven to be effective in impeding metastasis and recurrence. However, the clinical application of cancer immunotherapy has faced some limitations including generating weak immune responses due to inadequate delivery of immunostimulants to the immune cells as well as uncontrolled modulation of immune system, which can give rise to autoimmunity and nonspecific inflammation. Growing evidence has suggested that nanotechnology may meet the needs of current cancer immunotherapy. Advanced biomaterials such as nanoparticles afford a unique opportunity to maximize the efficiency of immunotherapy and significantly diminish their toxic side-effects. Here we discuss recent advancements that have been made in nanoparticle-involving breast cancer immunotherapy, varying from direct activation of immune systems through the delivery of tumor antigens and adjuvants to immune cells to altering immunosuppression of tumor environment and combination with other conventional therapies.
Colorectal cancer (CRC) is one of the most common forms of solid tumors in the world with high rates of mortality and morbidity. Most cases of CRCs are initiated by inactivating mutations in a tumor ...suppressor gene, adenomatous polyposis coli (APC), leading to constitutive activation of the Wnt signaling pathway. This review summarizes the roles of somatic and germline mutations of the APC gene in hereditary as well as sporadic forms of CRC. We also discuss the diagnostic and prognostic value of the APC gene in the pathogenesis of CRC for a better understanding of CRC disease.
•Mutations in a tumor suppressor gene, Adenomatous Polyposis Coli (APC), are critical in colorectal cancer development.•This review summarizes the roles of somatic and germline mutations of the APC gene in CRC initiation and progression.•Therapeutic, diagnostic, and prognostic value of the APC gene mutations will be discussed in the pathogenesis of CRC.
There is growing evidence showing that single administration of immunotherapeutic agents has limited efficacy in a number of cancer patients mainly due to tumor heterogeneity and immunosuppressive ...tumor microenvironment. In this study, a novel nanoparticle-based strategy was applied to achieve efficient tumor-targeted therapy by combining chemotherapeutic agents, i.e., doxorubicin (Dox) and melittin (Mel), with an immune checkpoint inhibitor (PD-L1 DsiRNA). The proposed nanoparticle was prepared by the formation of a complex between Mel and PD-L1 DsiRNA (Dicer-substrate short-interfering RNA), followed by the loading of Dox. The surface of the resultant particles (DoxMel/PD-L1 DsiRNA) was then modified with hyaluronic acid (HA) to increase their stability and distribution. In addition, HA can also act as a tumor-targeting agent through binding to its receptor CD44 on the surface of cancer cells. We demonstrated that the surface engineering of DoxMel/PD-L1 DsiRNA with HA significantly enhances its specificity towards breast cancer cells. Moreover, we observed a noticeable reduction in PD-L1 expression together with a synergistic effect of Dox and Mel on killing cancer cells and inducing immunogenic cell death, leading to significantly diminished tumor growth in 4T1-breast tumor bearing Balb/c mice, improved survival rate and extensive infiltration of immune cells including cytotoxic T cells into the tumor microenvironment. Safety analysis revealed that there is no significant toxicity associated with the developed nanoparticle. All in all, the proposed targeted combination treatment strategy can be considered as a useful method to reduce cancer-associated mortality.
•A novel nanoparticle-based chemo-immunotherapy (DoxMel/PD-L1 DsiRNA@HA) for breast cancer was developed.•DoxMel/PD-L1 DsiRNA@HA significantly suppressed both primary and distant breast tumors in tumor-bearing Balb/c mice.•Induction of ICD along with suppression of PD-L1 expression by DoxMel/PD-L1 DsiRNA@HA led to a robust systemic immunity against cancer cells.•DoxMel/PD-L1 DsiRNA@HA has high potential for future clinical translation due to its high safety profile and strong anti-tumor efficacy.
Melanoma is a malignant tumor that accounts for the deadliest form of skin cancers. Despite the significant efforts made recently for development of immunotherapeutic strategies including using ...immune checkpoint inhibitors and cancer vaccines, the clinical outcomes are unsatisfying. Different factors affect efficient cancer immunotherapy such as side-effects, immunosuppressive tumor microenvironment, and tumor heterogeneity. In the past decades, various nanotechnology-based approaches have been developed to enhance the efficacy of cancer immunotherapy, in addition to diminishing the toxicity associated with it. Several studies have shown that proper application of nanomaterials can revolutionize the outcome of immunotherapy in diverse melanoma models. This review summarizes the recent advancement in the integration of nanotechnology and cancer immunotherapy in melanoma treatment. The importance of nanomaterials and their therapeutic advantages for patients with melanoma are also discussed.
Simultaneous delivery of tumor antigens and adjuvants to antigen presenting cells via nanoparticles activates T cells to attack cancer cells. This causes cancer cell death and release of tumor antigens into the tumor microenvironment, further stimulating the immune system. Display omitted
•Nanoparticles can diminish toxicity associated with free immunotherapeutic drug administration.•Delivery of nanoparticle-based vaccine can elicit a strong immune response against cancer cells.•Nanoparticle-based combination therapies can produce more effective therapeutic results.
The myocardium/heart is the most mitochondria-rich tissue in the human body with mitochondria comprising approximately 30% of total cardiomyocyte volume. As the resident "powerhouse" of cells, ...mitochondria help to fuel the high energy demands of a continuously beating myocardium. It is no surprise that mitochondrial dysfunction underscores the pathogenesis of many cardiovascular ailments, including those of viral origin such as virus-induced myocarditis. Enteroviruses have been especially linked to injuries of the myocardium and its sequelae dilated cardiomyopathy for which no effective therapies currently exist. Intriguingly, recent mechanistic insights have demonstrated viral infections to directly damage mitochondria, impair the mitochondrial quality control processes of the cell, such as disrupting mitochondrial antiviral innate immune signaling, and promoting mitochondrial-dependent pathological inflammation of the infected myocardium. In this review, we briefly highlight recent insights on the virus-mitochondria crosstalk and discuss the therapeutic implications of targeting mitochondria to preserve heart function and ultimately combat viral myocarditis.
The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the ...etiological agent for COVID-19, has infected over 50 million individuals’ worldwide with more than ∼1 million fatalities. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks urge for better understanding of viral subversion of autophagy. Using MHV-A59 as a model betacoronavirus, time-course infections revealed significant loss in the protein level of ULK1, a canonical autophagy-regulating kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target ULK1, we conducted in-vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from a C-terminal substrate recognition region. Over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagy.
•ULK1 is a novel target of betacoronavirus.•SARS-COV-2 papain-like protease (PLpro) cleaves ULK1 after G499.•PLpro disrupts ULK1 complex and cellular autophagy.•ULK1 is required early but dispensable during late MHV-A59 infection.
Short interfering RNAs (siRNAs) have provided novel insights into the field of cancer treatment in light of their ability to specifically target and silence cancer-associated genes. In recent years, ...numerous studies focus on determining genes that actively participate in tumor formation, invasion, and metastasis in order to establish new targets for cancer treatment. In spite of great advances in designing various siRNAs with diverse targets, efficient delivery of siRNAs to cancer cells is still the main challenge in siRNA-mediated cancer treatment. Recent advancements in the field of nanotechnology and nanomedicine hold great promise to meet this challenge. This review focuses on recent findings in cancer-associated genes and the application of siRNAs to successfully silence them in prostate cancer, as well as recent progress for effectual delivery of siRNAs to cancer cells.
Crocin is the major component of saffron, which is used in phytomedicine for the treatment of several diseases including diabetes, fatty liver, depression, menstruation disorders, and, of special ...interest in this review, inflammatory diseases. Promising selective anti‐inflammatory properties of this pharmacological active component have been observed in several studies. Saffron has been shown to exert anti‐inflammatory properties against several inflammatory diseases and can be used as a novel therapeutic agent for the treatment of inflammatory diseases either alone or in combination with other standard anti‐inflammatory agents. This review summarizes the protective role of saffron and its pharmacologically active constituents in the pathogenesis of inflammatory diseases including digestive diseases, dermatitis, asthma, atherosclerosis, and neurodegenerative diseases for a better understanding and hence a better management of these diseases.
Saffron has been shown to exert anti‐inflammatory properties against several inflammatory diseases and can be used as a novel therapeutic agent for the treatment of inflammatory diseases either alone or in combination with other standard anti‐inflammatory agents. This review summarizes the protective role of saffron and its pharmacologically active constituents in the pathogenesis of inflammatory diseases including digestive diseases, dermatitis, asthma, atherosclerosis, and neurodegenerative diseases for a better understanding and hence a better management of these diseases.
Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway ...in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory‐associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases.
In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases.
Immunotherapy has emerged as an efficient therapeutic approach for cancer management. However, stimulation of host immune system against cancer cells often fails to achieve promising clinical ...outcomes mainly owing to the immunosuppressive characteristics of the tumor microenvironment (TME). Combination therapeutics that can trigger sustained immunogenic cell death (ICD) have provided new opportunities for cancer treatment.
In this study, we designed and applied an ICD inducer regimen, including a genetically engineered oncolytic virus (miRNA-modified coxsackieviruses B3, miR-CVB3), a pore-forming lytic peptide (melittin, found in bee venom), and a synthetic toll-like receptor 9 ligand (CpG oligodeoxynucleotides), for breast cancer and melanoma treatment. We compared the anti-tumor efficacy of miR-CVB3 and CpG-melittin (CpGMel) alone and in combination (miR-CVB3 + CpGMel) and investigated possible mechanisms involved.
We demonstrated that miR-CVB3 + CpGMel had no major impact on viral growth, while enhancing the cellular uptake of CpGMel in vitro. We further showed that combination therapy led to significant increases in tumor cell death and release of damage-associated molecular patterns compared with individual treatment. In vivo studies in 4T1 tumor-bearing Balb/c mice revealed that both primary and distant tumors were significantly suppressed, and the survival rate was significantly prolonged after administration of miR-CVB3 + CpGMel compared with single treatment. This anti-tumor effect was accompanied by increased ICD and immune cell infiltration into the TME. Safety analysis showed no significant pathological abnormalities in Balb/c mice. Furthermore, the developed therapeutic regimen also demonstrated a great anti-tumor activity in B16F10 melanoma tumor-bearing C57BL/6 J mice.
Overall, our findings indicate that although single treatment using miR-CVB3 or CpGMel can efficiently delay tumor growth, combining oncolytic virus-based therapy can generate even stronger anti-tumor immunity, leading to a greater reduction in tumor size.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
