Bosnian Journal of Basic Medical Sciences (BJBMS)
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Osteoarthritis of the knee - biochemical aspect of applied therapies: a review
Get PDFThe most prevalent form of arthritis is osteoarthritis (OA) of the knee, which is characterized by a degeneration of articular cartilage resulting in the development of osteophytes, or bone spurs. Main goals of OA treatment are to reduce pain, slow the disease progression, and improve joint function and the quality of life. The purpose of this study was to verify all the therapies recommended by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) from the biochemical point of view. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of eicosanoids, whereas paracetamol prevents the production of prostaglandin (PG) by interacting with peroxidase (POX) site of the prostaglandin H2 synthase complex. Tramadol is an opioid that has a dual mechanism of action: it binds to the μ-opioid receptor and it inhibits serotonin and adrenaline. Corticosteroids, which are also prescribed for OA pain, inhibit the activity of phospholipase A2 and block the synthesis of arachidonate-derived eicosanoids. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) are drugs that are well tolerated by patients and help to restore proteoglycan matrix of the cartilage. These drugs include compounds that naturally build articular cartilage. The articular cartilage, as well as the bone located around the cartilage, are destroyed as osteoarthritis progresses. Thus, bisphosphonates, commonly used in the treatment of osteoporosis, were evaluated as potential therapy. However, there is no official recommendation for their use in therapy. The aim of the study was to analyze the biochemical mechanisms of principal drugs used for the treatment of knee OA. Therefore, a narrative review summarizing the current knowledge regarding the applied therapies was prepared
Emerging roles of sortilin in affecting the metabolism of glucose and lipid profiles
Get PDFDyslipidemia has recently been identified as an important factor in modulating the progression of several health conditions, grouped as cardio-metabolic syndrome and including obesity,insulin resistance, and atherosclerosis. Among multiple factors which regulate the development of cardio-metabolic syndrome, sortilin has been found in multiple cell types, such as adipocyte, hepatocyte, and macrophage, suggesting that sortilin is correlated to the development and the severity of cardio-metabolic syndrome. Consistently, several genome-wide association (GWAS) and basic experimental research studies are being conducted to find novel gene loci involved in regulating the pathological progression of cardio-metabolic syndrome. According to these data, both SORT1 gene and sortilin protein have an important function in regulating the circulating lipid and glucose metabolism resulting in modulation of disease progression. In this comprehensive review, we summarize the recent research results in regards to sortilin function in modulating the circulating lipid and glucose metabolism. Moreover, we also discuss and analyze the emerging evidence elucidating the potential mechanisms by which sortilin affects synthesis and secretion of lipid and glucose
Comparison of confirmed and probable COVID-19 patients in the intensive care unit during the normalization period
Get PDFThe decrease in social distance together with the normalization period as of June 1, 2020 in our country caused an increase in the number of COVID 19 patients. Our aim was to compare the demographic features, clinical courses and outcomes of confirmed and probable coronavirus disease 2019 (COVID-19) patients admitted to our intensive care unit (ICU) during the normalization period. Critically ill 128 COVID-19 patients between June 1 - December 2, 2020 were analyzed retrospectively. The mean age was 69.7±15.5y (61.7% male). Sixty-one patients (47.7%) were confirmed. Dyspnea (75.0%) was the most common symptom and hypertension (71.1%) was the most common comorbidity. The mean Acute Physiology and Chronic Health Evaluation System (APACHE II) score; Glasgow Coma Score (GCS); Sequential Organ Failure Assessment (SOFA) scores on ICU admission were 17.4 ± 8.2, 12.3 ± 3.9 and 5.9 ± 3.4, respectively. 101 patients (78.1%) received low flow oxygen, 48 had high flow oxygen therapy (37.5%) and 59 (46.1%) had invasive mechanical ventilation. 53 patients (41.4%) had vasopressor therapy and 30 (23.4%) patients had renal replacement therapy (RRT) due to acute kidney injury (AKI). Confirmed patients were more tachypneic (p=0.005) and more hypoxemic than probable patients (p<0.001). Acute respiratory distress syndrome (ARDS) and AKI were more common in confirmed patients than probable (both p<0.001). Confirmed patients had higher values of hemoglobin, C- reactive protein, fibrinogen, D-dimer than probables (respectively, p=0.028, 0.006, 0.000, 0.019). The overall mortality was higher in confirmed patients (p=0.209, 52.6% vs 47.4%). Complications are more common among confirmed COVID-19 patients admitted to ICU. The mortality rate of confirmed COVID-19 patients admitted to the ICU was found to be higher than probable patients. Mortality of confirmed cases were higher than prediction of APACHE-II scoring system
ROS responsive polyethylenimine-based fluorinated polymers for enhanced transfection efficiency and lower cytotoxicity
Get PDFCationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF12.5%, TKPF25% and TKPF50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Such gene vectors exhibited the following features: (1) fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions; (2) The fluorophilic effect mediated efficient cellular uptake and endosomal escape; (3) ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. Notably, TKPFs also exhibited great serum resistance in gene delivery and TKPF50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrates that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application
The effect of sarcopenia on erlotinib therapy in patients with metastatic lung adenocarcinoma
Get PDFErlotinib, a tyrosine kinase inhibitor, has been shown to improve the survival of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Sarcopenia is a status with increasing importance in lung cancer, and it may predict a poor prognosis. We aimed to evaluate the impact of sarcopenia on erlotinib therapy and prognosis in patients with EGFR-mutated (exon 19 or 21 L858R) metastatic lung adenocarcinoma. Sarcopenia was defined as skeletal muscle index ≤39 cm2/m2 for women and ≤55 cm2/m2 for men. The patient characteristics, inflammation parameters, clinical and survival outcomes of the erlotinib therapy were examined according to sarcopenia status. We also analyzed the erlotinib treatment-related toxicity. Seventy-two patients were included in our retrospective study, and the mean age of the patients was 63.7 years. A total of 39 (54.2%) patients were diagnosed with sarcopenia. Patients with sarcopenia had a poor prognosis and had a shorter median progression-free survival (PFS) than patients without sarcopenia (10.5 months vs. 21.8 months, p=0.002). Sarcopenia (HR 2.08) and C-reactive protein > 6.5 mg/L (HR 2.57) were determined as independent poor prognostic factors for PFS of erlotinib therapy. Treatment-related toxicity occurred in 34.7% of patients treated with erlotinib, and sarcopenia did not significantly affect treatment-related toxicity. We also found that sarcopenia significantly affected the response to erlotinib. The expected survival outcomes may be low when erlotinib therapy is used in patients with sarcopenia and metastatic lung adenocarcinoma. This study showed that survival and clinical outcomes could be better predicted by detecting sarcopenia in patients with lung cancer using erlotinib
IC50: an unsuitable measure for large-sized prostate cancer spheroids in drug sensitivity evaluation
Get PDFPreclinical models of tumors have the potential to become valuable tools for commercial drug research and development, and 3D culture systems are gaining traction in this area, particularly in prostate cancer (PCa) research. However, nearly all 3D drug design and screening assessments are based on 2D experiments, suggesting limitations of 3D drug testing. To simulate the natural response of human cells to the drug, we detected the half-maximal inhibitory concentration (IC50) changes of 2D/3D LNCaP cells in the drug docetaxel, as well as the sensitivity of different morphologies of 2D/3D LNCaP to docetaxel treatment. In contrast to 2D LNCaP cells, the evaluation of LNCaP spheroids’ susceptibility to treatment was more complicated; the fitness of IC50 curves of 2D and 3D tumor cell preclinical models differs significantly. IC50 curves were unsuitable for large-sized LNCaP spheroids. More evaluation indexes (such as max inhibition) and experiments (such as spheroids formation) should be explored and performed to evaluate the susceptibility systematically
Inhibition of IRAK 1/4 alleviates colitis by inhibiting TLR4/ NF-κB pathway and protecting the intestinal barrier
Get PDFInterleukin-1 receptor-associated kinase 1/4 (IRAK1/4) is the main kinase of the Toll-like receptor (TLR)-mediated pathway, considered a new target for treating inflammatory diseases. Studies showed a significant correlation between TLRs and inflammatory responses in ulcerative colitis (UC). Therefore, in this study, after inducing experimental colitis in mice with 3% dextran sulfate sodium (DSS), different concentrations of IRAK1/4 inhibitors were administered intraperitoneally. Then, the disease activity index was assessed, including the degree of pathological damage, by HE staining. Subsequently, while western blotting detected the TLR4/NF-κB pathway and intestinal barrier protein expression (Zonula-1, Occludin, Claudin-1, JAM-A), real-time polymerase chain reaction (RT-PCR) detected the mRNA expression levels of IRAK1/4 and mucin1/2. Furthermore, the expression levels of Zonula-1 and occludin were detected by immunofluorescence, including the plasma FITC-dextran 4000 concentration, to evaluate intestinal barrier permeability. However, ELISA measured the expression of inflammatory factors to reflect intestinal inflammation in mice. Investigations showed that the IRAK 1/4 inhibitor significantly reduced clinical symptoms and pathological DSS-induced colitis damage in mice and then inhibited the cytoplasmic and nuclear translocation of NF-κB p65, including the phosphorylation of IκBα and reduction in downstream inflammatory factor production. Therefore, we established that the IRAK1/4 inhibitor effectively improves colitis induced by DSS, partly by inhibiting the TLR4/NF-κB pathway, reducing inflammation, and maintaining the integrity of the colonic barrier
Perineural spread in head and neck malignancies: imaging findings - an updated literature review
Get PDFPerineural spread (PNS) represents the tumor’s ability to disseminate along nerves. The aim of this article is to review the relevant literature about the PNS in head and neck tumors (HN). The important information for imaging analysis is summarized in a diagnostic flow-chart. The pathogenesis, clinical signs, prognostic importance, and technical considerations for computer tomography and magnetic resonance imaging are briefly discussed. The anatomical pathways of the cranial nerves (CNs) and the main check-points are synthesized. Most commonly affected nerves are the trigeminal and facial, although any of the CNs may be involved. The described imaging features represent important clues for an optimal differential diagnosis. PNS worsens the prognosis and significantly changes the treatment, thus radiologists should be aware of this entity and be able to find it on imaging in the appropriate clinical context
Resveratrol ameliorates neuronal apoptosis and cognitive impairment by activating the SIRT1/RhoA pathway in rats after anesthesia with sevoflurane
Get PDFStudies have shown that long-term exposure to sevoflurane (SEV) may cause postoperative cognitive dysfunction. This study aimed to investigate the effects of resveratrol (RES) treatment on the changes in the cognitive function of rats after prolonged anesthesia with SEV. Seventy-six adult male rats were used in this study. The SEV model was established under continuous anesthesia for 6 h. Rats were randomly classified into four groups as follows: control, SEV+vehicle, SEV+pre-RES (RES was administered 24 h before establishing the SEV model), and SEV+post-RES (RES was administered 1 h after establishing the SEV model) groups. Neurobehavioral outcomes and the potential mechanism underlying RES-mediated neuroprotection through the SIRT1/RhoA signaling pathway were evaluated. The water maze test showed that long-term exposure to SEV may lead to loss of learning and memory ability in rats (p<0.05). Compared with the SEV+vehicle group, the RES treatment groups showed significantly improved neurobehavioral scores (p<0.05). Additionally, the SEV+pre-RES group had a better outcome than the SEV+vehicle group on days 1 or 2 (p<0.05), unlike the SEV+post-RES group (p>0.05). Western blotting showed that SIRT1, RhoA, and cleaved Caspase-3 (CC3) expression significantly increased in the SEV+vehicle group (p<0.05), while Bcl2 expression decreased (p < 0.05). RES treatment further upregulated SIRT1 and Bcl2 expression and downregulated the expression of RhoA and CC3 (p<0.05). In conclusion, RES treatment improved cognitive dysfunction by reducing neuronal apoptosis in adult rats exposed to SEV. RES partly exerted a neuroprotective effect through the activation of the SIRT1/RhoA signaling pathway
LncRNA ADAMTS9-AS1 knockdown suppresses cell proliferation and migration in glioma through downregulating Wnt/β-catenin signaling pathway
Get PDFThe long non‐coding RNA antisense 1 ADAMTS9-AS1 has been reported to serve as an oncogene or tumor suppressor in several tumors, including colorectal cancer and hepatocellular carcinoma. Nevertheless, the clinical significance and biological behaviors of ADAMTS9-AS1 in glioma still remain unclear. Therefore, the goal of this study was to evaluate the functional roles and potential mechanisms of ADAMTS9-AS1 in glioma cells. Using quantitative real-time PCR analysis, we found that ADAMTS9-AS1 was upregulated in glioma tissues and cells in comparison to corresponding controls. ADAMTS9-AS1 expression level was correlated to tumor size (p=0.005) and WHO grade (p=0.002). Kaplan-Meier analysis and Cox multivariate analysis showed that ADAMTS9-AS1 could serve as an independent prognostic factor affecting the overall survival of glioma patients. Functionally, depletion of ADAMTS9-AS1 significantly suppressed the proliferation, migration and invasion in glioma cell lines (U251 and U87), as shown via CCK-8 assay, Edu corporation assay, wound healing assay and transwell assay. Furthermore, we demonstrated that knockdown of ADAMTS9-AS1 suppressed Wnt1, β-catenin, c-myc and PCNA, while upregulating E-cadherin expression. In conclusion, our data revealed that ADAMTS9-AS1 confers oncogenic function in the progression of glioma, thus targeting ADAMTS9-AS1 might be a promising therapeutic strategy for this disease