Current Drug Targets - Volume 21, Issue 4, 2020

Spinal tuberculosis is a common manifestation of extrapulmonary tuberculosis and osteoarticular tuberculosis. Common clinical manifestations include constitutional symptoms, back pain, spinal tenderness, paraplegia, and spinal deformities. They are the common causes of paralysis and could increase the mortality in patients. Most cases of spinal tuberculosis remaining undiagnosed, and early clinical symptoms and imaging manifestations lack specificity, which explained the reason why it is difficult to identify from atypical spinal metastases, brucellosis and other diseases. The rate of missed diagnosis and misdiagnosis for spinal tuberculosis is high. If spinal tuberculosis diagnostic targets could be early detected, the therapeutic targets can be effectively treated, which can not only control the progress of the disease and shorten the course of treatment, but also reduce the economic pressure and avoid spinal deformity. Therefore, early diagnosis should be our focus. Comprehensive use of a variety of diagnostic targets can improve the early diagnosis rate of spinal tuberculosis. Here, we review the progress of laboratory, imaging and gene detection in the diagnosis of spinal tuberculosis in recent years.

Although studies have established the role of integrins in bone homeostasis, especially in osteoclastogenesis, and these molecules are novel and promising therapeutic drug targets for bone loss diseases, such as: osteolysis, the cellular mechanism still elusive. Bone homeostasis takes place through the interaction of bone cells (osteoblasts and osteoclast) via the activation of intercellular adhesion molecule-1 (ICAM-1), which is a critical submolecule of integrin. In the present study, we reviewed several novel studies on integrins and their submolecule, ICAM-1, in bone homeostasis. In order to demonstrated that ICAM-1 might exert dual effects on osteoclastogenesis by directly affecting the adhesive ability of mature osteoclasts and indirectly participating in RANKL/RANK induced osteoclastic precursors differentiation. Although these results still need to be verified in the future, the extending study about the role of ICAM-1 in osteoclastogenesis will cerntainly provide a promising therapeutic target for the treatment of bone loss diseases.

Inflammation is the most common pathology in many orthopedic diseases, such as: rheumatoid arthritis (RA), osteoarthritis (OA) and other reasons caused osteolysis. The leading factor of inflammation was considered as the differentiation of monocyte and the polarization of macrophage. However, cytokines and different cell models could regulate this progress in some aspects. Therefore, in the current review, we summarize several cytokines and cell models, which could lead to inflammatory orthopedic diseases via regulating monocytes and macrophages. In order to extensively explore the potential therapeutic and medicine targets for inflammation-induced bone diseases.

Millions of people, especially for the aging people, are suffered by bone-loss diseases, such as rheumatoid arthritis (RA) and osteoporosis. Therefore, better understanding the involved mechanisms of bone metabolism is required for further treat on such diseases. Particularly, during the pathological process of bone losing, RANKL as a member of the tumor necrosis factor (TNF) superfamily, could induce osteoclast precursor cells differentiate into mature osteoclast, which grant its essential role in osteolysis. In recent years, with the increased attention paid to the natural compounds discovering studies, the therapeutic application of natural plant-derivatives have been widely recognized. Therefore, our present study aim to summarize the current novel research progressions on RANKL and its downstream signaling pathways in bone cellular differentiation, and provide a further insight for RANKL as the important drug targets in bone loss diseases. Besides that, in our current study, we also aim to briefly introduce the current application of several natural compounds for treating RANKL-mediated osteoclastic activation by modulating the RANKL signaling pathway and their therapeutic effects on the prevention of osteoporosis, osteoarthritis (OA) and RA.

Osteoclasts are originated from monocytic precursors of the hematopoietic lineage. Regulation of gene expression by transcription factors is one of the major mechanisms for controlling cellular functions. This is particularly important in the process of osteoclast production. As a main regulatory transcriptional factor, nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) plays a significant role in osteoclast differentiation. Although current studies focus on the regulatory effects of treatment in the process of osteoclastogenesis, many of these drugs possess cytotoxicity which is harmful to bone formation. Naturally occurring compounds with less or no side effects are most required in present clinical and fundamental study. In this paper, we summarize several plant-derived compounds in inhibiting osteoclastogenesis.

The existence of the multi-drug resistant (MDR) pathogenic fungus, Candida auris came to light in 2009. This particular organism is capable of causing nosocomial infections in immunecompromised persons. This pathogen is associated with consistent candidemia with high mortality rate and presents a serious global health threat. Whole genome sequence (WGS) investigation detected powerful phylogeographic Candida auris genotypes which are specialized to particular geological areas indicating dissemination of particular genotype among provinces. Furthermore, this organism frequently exhibits multidrug-resistance and displays an unusual sensitivity profile. Identification techniques that are commercialized to test Candida auris often show inconsistent results and this misidentification leads to treatment failure which complicates the management of candidiasis. Till date, Candida auris has been progressively recorded from several countries and therefore its preventive control measures are paramount to interrupt its transmission. In this review, we discussed prevalence, biology, drug-resistance phenomena, virulence factors and management of Candida auris infections.

Background: Neutrophilic asthma is generally associated with the absence of eosinophils and activation of non- predominant type 2 immunological pathways. It involves bronchial inflammation followed by different degrees of airway remodeling. Neutrophilic inflammation activates specific cellular and molecular pathways due to inhalation of environmental trigger factors such as exhaust fumes, cigarette smoke, occupation-related agents, and infections. Objective: This review discusses the involvement of neutrophils in asthma and potentially related target therapies. Results: Corticosteroid resistance is the hallmark of neutrophilic asthma which increases disease severity and leads to difficult-to-control asthma. Patients with neutrophil-dominant asthma are characterized by low levels of (or absence of) Th2 cytokines. Due to the shortage of effective treatments for neutrophilic asthma newer biologics are being developed that target type 2 asthma symptoms and phenotypes. Understanding different biomarkers, inflammatory pathways and treatment strategies involved in neutrophilic asthma will help to decrease adverse effects related to corticosteroid insensitivity. Better insight of targets involved in neutrophilic inflammation can lead to improved therapies. Conclusion: Further evaluation and clinical trials of emerging biologics involved in neutrophilic asthma needs to be performed before bringing them into clinical practice.

Neuroendocrine neoplasms (NENs) are rare tumors that mainly occur in the gastroenteropancreatic (GEP) tract and lungs. According to the current World Health Organization classification for GEP-NENs and lung NENs, treatment strategies differ for well-differentiated and poorly differentiated subtypes. For well-differentiated GEP-NENs, somatostatin analogues (SSA), peptide receptor radionuclide therapy, and molecular-targeted agents are approved as the standards of care based on phase III clinical trial data. Promising data regarding the use of everolimus and the novel SSA pasireotide for lung NENs are emerging, though additional studies are required to confirm these effects. For poorly differentiated tumors from the GEP tract and lung, a platinum-based cytotoxic regimen is widely used. Genomic analysis has recently revealed a diverse pattern of primary organ-dependent mutations, and the use of traditional treatment strategies versus organ-specific strategies is currently under discussion. In addition, clinical trials for several molecular-targeted agents and immune checkpoint inhibitors for the treatment of NENs are currently underway. Accumulating genomic information is expected to contribute to the development of novel therapies for other organ-derived NENs or poorly differentiated neuroendocrine carcinomas (NECs). Here, we provide an updated overview of the current knowledge regarding genomic profiles and representative agents for NENs and highlight the prospects for future investigations.

Various strategies for the use of zein for controlled drug release have been investigated and reported in the literature, especially engineering strategies for using zein conjugates to enhance oral bioavailability and targeted delivery, which has attracted interest in recent research. Although still limited, the ability to fabricate self-assembling nanoparticles loaded with molecules of interest offering functional groups for potential conjugation could yield zein-based conjugates with promise as materials for drug delivery. In the current review, recent studies on zein-based conjugates with outstanding features are discussed based on the various types of conjugation. The key physicochemical characterization methods for the chemical conjugation and identification of zein are also summarized. Further opportunities to develop zein-based materials through conjugation will provide promising alternative formulations for a number of drug candidates.

Radiotherapy is considered a second life in Renal Cell Carcinoma (RCC) patients, mainly due to the introduction of immune checkpoint inhibitors, such as anti-Programmed-death (PD)-1, alone or in combination with anti-Cytotoxic T-Lymphocyte Antigen (CTLA)-4. Several trials are investigating the efficacy/safety of immune checkpoint inhibitors in sequential or combined strategies with radiotherapy. Chimeric Antigen Receptor (CAR)-T cells therapy as a promising approach in cancer patients has opened the way to novel possibilities of integrating therapies. The identification of biomarkers of tumor response to these combinations represents a challenge in RCC, together with the research for the best partner for immunotherapy in metastatic patients. In this review we illustrated preclinical/clinical data on the integration of radiotherapy with immunocheckpoint inhibitors or CART cells in RCC.