Current Medicinal Chemistry - Volume 28, Issue 25, 2021

The Interferon-induced protein with tetratricopeptide repeats (IFIT) family is an important component of the antiviral immune response. There are currently four known IFIT family members in humans, namely IFIT1, IFIT2, IFIT3 and IFIT5. Recent discoveries have brought attention to the significant roles of IFITs in cancer. This review summarises current knowledge on the biological roles of different IFIT proteins in various types of malignant neoplasm, and highlights the potential use of these molecules as cancer biomarkers and prognostic factors.

The complement component 1, q subcomponent binding protein (C1QBP/gC1q-R/p32/HABP1/TAP/YBAP1), is a ubiquitous, multifunctional protein. C1QBP localizes mainly to mitochondria due to its N-terminal mitochondrial localization signal, but it can also be found in different subcellular compartments including the cell surface, nucleus, cytoplasm, and extracellular space. C1QBP has been reported to interact with a variety of proteins that have apparently unrelated functions. C1QBP has also been observed to interact with hyaluronic acid and RNA. These findings suggest that C1QBP has both mitochondrial and extramitochondrial functions. The C1QBP binding sites of many partner proteins are located within basic and intrinsically disordered regions of these molecules, consistent with the hypothesis that C1QBP functions as a molecular chaperone. C1QBP expression is elevated in various types of human cancers, including breast cancer. Moreover, it has been implicated in the development, progression, and metastasis of cancer cells based on loss-of-function and gain-of-function studies using cancer cell lines and xenograft models. Hence C1QBP could be a molecular target in breast cancer therapy. Studies using antibodies, tumor homing peptides such as LyP-1, and small molecules that target C1QBP warrant further investigation as C1QBP is a potential therapeutic target.

The successive stages of breast cancer growth and dissemination depend on cell-autonomous factors and the communication between tumor cells and their surrounding cellular and extracellular matrix microenvironment. The cell surface heparan sulfate proteoglycan Syndecan-1 is dysregulated both in tumor cells and cells of the breast tumor stroma, indicating a potential role in the pathogenesis of this most frequent malignancy in women. Indeed, Syndecan-1 interacts with numerous ligands and receptors relevant to tumor progression, affecting processes as diverse as cancer stem cell function, cell proliferation, apoptosis, cell adhesion, migration and invasion, tumor angiogenesis, and leukocyte function in the tumor stroma. The present review summarizes the current understanding of breast carcinogenesis in correlation with their Syndecan-1 expression, involved mechanisms, and proposed therapeutic strategies against Syndecan-1-related malignancy.

HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer, where they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs embedded within the HOX cluster and the role of these molecules in breast cancer, have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

Background: Transcriptome analyses have revealed the presence of numerous long non-coding RNAs (lncRNAs) in mammalian cells. Many lncRNAs are expressed in development-, differentiation-, and disease-specific manners, suggesting their importance as cell regulators. Some nuclear lncRNAs are bound to specific genomic loci, either near or distant from their own transcription sites, and regulate gene expression in cis or trans. These lncRNAs recruit epigenetic factors, including the DNA methyl transferase and histone modification complex, and mediate both the 3D genome structure and nuclear domains. LncRNAs are now considered as an emerging member of epigenetic regulators. LncRNAs are dysregulated in various types of cancer and act as either oncogenic or tumor- suppressing factors. They are involved in virtually all of the cancer hallmarks and are potential diagnostic markers and therapeutic targets. Objective: In this review, we describe several representative lncRNAs and provide a current overview of the mechanisms by which lncRNAs participate in epigenetic regulation and contribute to cancer development.

Breast cancer is one of the most lethal cancers in women worldwide, and the development of efficient treatments faces several challenges. Breast cancer is characterized by histological and functional heterogeneity in aspects such as tumorigenesis, metastasis, and drug resistance. RNA therapy has emerged as a highly attractive class of drugs for the treatment and prevention of breast cancer. It might play remarkable regulatory roles in the treatment of targeted cells by either increasing or silencing expressions of specific proteins, and such features of RNA-based drugs cause high selectivity and low risk of off-target effect in breast cancer. RNA therapy exerts anti-proliferative and pro-apoptotic effects upon cell culture systems, animal models, and in clinical trials in most studies. In this mini-review, we outline the classifications, mechanisms, advantages, and challenges of RNA therapy and highlight its application in breast cancer treatment. Additionally, we summarize the clinical trials of RNA-targeting therapies and the development of anti-tumor RNA drugs and provide future directions for RNA therapeutics in breast cancer.

Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, including radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibitors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

Despite diagnostic and therapeutic advances in breast cancer, it remains the most frequently diagnosed malignancy in females, with the highest cancer-related mortality rate in women globally. With an improved understanding of the complex interactions between breast cancer and the immune system, immunotherapy has shown great potential in clinical management, potentially adding to current treatment modalities. These immunotherapeutic approaches include adoptive cell transfer therapy, cancer vaccination, monoclonal antibody therapy, and oncolytic virus therapy. Depending on the immune cells and cytokines present, the tumour microenvironment (TME) can be immunosuppressive or favourable for mounting an immune response. Effector lymphocytes play an essential role during an anticancer immune response, but their activities can be suppressed by the hostile TME. Many studies have made good progress in the modulation of the immune response to allow the identification and elimination of tumour cells. However, the efficacy of these immunotherapies is patient-specific and highly dependent on the immunological profile of the tumour and its TME. This review will give an overview of breast cancer, the immune system as well as their complex relationship. Strategies and approaches that can harness the potential of immunotherapy that engages lymphocytes in the treatment of breast cancer, along with their current challenges, will also be discussed.

High-intensity focused ultrasound (HIFU) is a non-invasive method of ablating malignant tumors. This paper will review the current clinical application of HIFU specially in the treatment of breast cancer. In addition to clinical studies, this review will also look into some basic studies that could address the technical issues related to this modality. In general, HIFU is considered to be safe being non-invasive and non-ionizing. The complication occurrence rate is low and repeated treatment is possible, making it an attractive option for some patients. However, for more than two decades since it was first used to treat breast cancer, clinical studies on HIFU still remain at the investigative stage and are only available in several centers. Reasons contributing to such few studies on HIFU include lack of specialized medical team and bioengineering technical staff, and breast cancer-dedicated imaging-HIFU platform to attain positive outcomes. Despite these circumstances, we believe that HIFU will eventually become the treatment of choice for most breast cancer patients in the near future.

Objective and Aims: This study aims to conduct a systematic review and meta-analysis for prospective studies to investigate the improvement effects of natto on bone mineral density (BMD) in perimenopausal women. Methods: PubMed, EMBASE and Cochrane database searched upto February 2019. This study was carried out according to the PRISMA guidelines10 for systematic reviews. The protocol of the review was registered in the PROSPERO registry (CRD42019133183). Results: The review identified 3 unique prospective studies comprising 1658 non-overlapping participants. Meta-analysis showed that natto could significantly improve lumbar bone mineral density (BMD) (P=0.002, WMD=0.26; 95% CI:0.09-0.43) in cohort studies. However, the randomized controlled study showed no statistical difference between the two (P=0.31, WMD=0.05; 95% CI:- 0.05-0.15). In addition, natto significantly improved the BMD of the femoral neck in a cohort study and randomized control study (P=0.03, WMD=0.42). 95% CI:0.05-0.79, I2= 72%); (P < 0.0001, WMD=0.16; 95% CI:0.08-0.24), respectively. However, all studies demonstrated that natto has no improvement effects on a hip joint (BMD). In that, the cohort study showed no statistical significance between the natto intake group and the control group (P=0.21, WMD=0.10). 95% CI:-0.06-0.25, I2= 18%) and the randomized controlled study also showed no statistical significance between the natto intake group and the control group (P=0.09, WMD=-0.06). 95% CI:-0.13- 0.01). Conclusion: Through our current systematic review and meta-analyize of these prosepctive studies of natto's anti-osteoporostic effecs on BMD, we found that the dietary intake of natto demonstrated a improving effects on the BMD of the femoral neck, but has no effects on the hip joint. Such interesting results may be related to the differences between anatomical structure between various tissues. Besides that, the results of the RCT study and cohort study on the lumbar spine were not the same, which may be related to the fact that participants in the RCT study were Caucasian and participants in the cohort study were Asian. Therefore, more large-sample and high-quality RCT studies are needed to further clarify the improvement effect of natto on osteoporosis.

Tuberculosis, caused by Mycobacterium tuberculosis, is one of the oldest diseases in the world and is one of the top ten causes of death in the world, ranking first mortality in infectious diseases, far beyond the frightening disease AIDS. Besides that, spinal tuberculosis is the most common form of extrapulmonary tuberculosis, accounting for approximately 1 to 3% of all tuberculosis cases, and accounting for 50% of musculoskeletal infections. However, the drug-resistant situation of spinal tuberculosis is still challenging world wide. This situation directly leads that spinal tuberculosis has a high disability rate and is difficult to treat, which causes a heavy burden to patients, families and society. Therefore, it has been one of the focuses of tuberculosis researchers and spine doctors. Considering that, in this review, we aim to overview the current studies that focused on the novel understanding of current spinal tuberculosis medicine usage and extensive explorations for treating this severe disease.

Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Partial or radical nephrectomy is the major surgical management for localized RCC, however, almost 30% of patients will develop recurrence and metastasis after surgery. Metastatic RCC (mRCC) is a disease with a very poor prognosis, and the 5-year survival of the mRCC is commonly less than 10%. Unfortunately, mRCC is highly resistant to chemo and radiotherapy. Therefore, mRCC treatment has become a big challenge for researchers as well as clinicians. RCC is characterized as clear genetic background, especially with von Hippel-Lindau (VHL) gene loss or mutation in more than 70% of the cases. Several molecular factors and signaling pathways have been discovered to possess impact on the progression of RCC, including VHL-HIF-VEGF angiogenesis signaling, PI3K/AKT/mTOR signaling, epithelial-to-mesenchymal transition-related pathways, and Wnt/β-catenin pathway, which play crucial roles in the growth, invasiveness, metastasis and angiogenesis of RCC. Based on the recent studies of these signaling pathways, some medicines as well as immune check-point inhibitors have been developed, which have shown potential therapeutic effects for mRCC. Therefore, our current review aims to summarize the recent progress of the treatment for mRCC, with a special focus on the strategies to improve the responsiveness of medicines in patients with mRCC.

Osteoporosis is very common in middle-aged and elderly people, and its main feature is a disease characterized by bone mass reduction and bone microstructure changes, accompanied by a corresponding increase in the risk of fracture. This is a disease affected by many factors and is more common in postmenopausal women. Currently, the treatment of osteoporosis is mainly to prevent bone resorption and reduce the risk of fracture; a variety of drugs have been used in the treatment of osteoporosis and achieved good results. In recent years, with the in-depth study of intestinal microorganisms, a strong impact of intestinal microflora on bone metabolism in terms of immunity has been reported. It can be observed in mouse-based models, which indicates that intestinal flora may be a potential new target for changing bone mineral density (BMD). Therefore, the intestinal flora is a complex system that affects and regulates the absorption of calcium and vitamin D. It affects the permeability of the intestine through its own secretion of related influencing factors and its own activities, and further affects the secretion of human hormones and immune response. Besides that, T helper cells, lymphocytes, TNF, IL-17, and the RANKL system play a key role. The impact of probiotics and prebiotics on humans is controversial due to the scarcity of research data. However, many studies have shown that the role of probiotics in different animals varies with gender, age and hormone secretion. Changes in the intestinal flora are closely related to osteopenia and/or osteoporosis. Changing its composition and activity may be a reliable strategy for altering bone quality, although further clinical studies are needed to determine the correct human method.