Current Pharmaceutical Design - Volume 28, Issue 4, 2022

Diabetes is a chronic non-communicable disease caused by several different routes, which has attracted increasing attention. In order to speed up the development of new selective drugs, machine learning (ML) technology has been applied in the process of diabetes drug development and opens up a new blueprint for drug design. This review provides a comprehensive portrayal of the application of ML in antidiabetic drug use.

Neuromyelitis optica spectrum disorder (NMOSD) is an acute or subacute demyelinating disease that affects mainly the optic nerve and spinal cord. A major proportion of NMOSD cases have a relationship with autoimmunity to aquaporin 4 (AQP4) found on the central nervous system. NMOSD can occur repeatedly, causing symptoms such as decreased vision and weakness of limbs. The main goal of the current therapy is to relieve acute symptoms and prevent recurrence of the disease. Without timely and appropriate treatment, the recurrence and disability rates are high. In the present work, we review recent advances in the diagnosis and treatment of patients with NMOSD, as well as the pathogenesis and mechanisms of AQP4-IgG-seropositive NMOSD.

The current clinical first-line treatment of neuropathic pain still considers only the nervous system as the target, and its therapeutic effect is limited. An increasing number of studies support the opinion that neuropathic pain is a result of the combined action of the sensory nervous system and the related immune system. Under physiological conditions, both the nervous system and the immune system can maintain homeostasis by adjusting the mitochondrial function when sensing noxious stimulation. However, in the case of neuropathic pain, mitochondrial regulatory dysfunction occurs, which may result from the decreased expression of SIRT1. In this study, we review the role of SIRT1 in neuropathic pain from the viewpoint of neuroimmunity.

Objective: The aim of the study was to verify the ability of the deep learning model to identify five subtypes and normal images in non-contrast enhancement CT of intracranial hemorrhage. Methods: A total of 351 patients (39 patients in the normal group, 312 patients in the intracranial hemorrhage group) who underwent intracranial hemorrhage noncontrast enhanced CT were selected, obtaining 2768 images in total (514 images for the normal group, 398 images for the epidural hemorrhage group, 501 images for the subdural hemorrhage group, 497 images for the intraventricular hemorrhage group, 415 images for the cerebral parenchymal hemorrhage group, and 443 images for the subarachnoid hemorrhage group). Based on the diagnostic reports of two radiologists with more than 10 years of experience, the ResNet-18 and DenseNet-121 deep learning models were selected. Transfer learning was used. 80% of the data was used for training models, 10% was used for validating model performance against overfitting, and the last 10% was used for the final evaluation of the model. Assessment indicators included accuracy, sensitivity, specificity, and AUC values. Results: The overall accuracy of ResNet-18 and DenseNet-121 models was obtained as 89.64% and 82.5%, respectively. The sensitivity and specificity of identifying five subtypes and normal images were above 0.80. The sensitivity of the DenseNet-121 model to recognize intraventricular hemorrhage and cerebral parenchymal hemorrhage was lower than 0.80, 0.73, and 0.76, respectively. The AUC values of the two deep learning models were found to be above 0.9. Conclusion: The deep learning model can accurately identify the five subtypes of intracranial hemorrhage and normal images, and it can be used as a new tool for clinical diagnosis in the future.

Venous thromboembolism (VTE), clinically presented as deep-vein thrombosis (DVT) or pulmonary embolism (PE), constitutes a major global healthcare concern with severe complications, long-term morbidity, and mortality. Although several clinical, genetic, and acquired risk factors for VTE have been identified, the molecular pathophysiology and mechanisms of disease progression remain poorly understood. Anticoagulation has been the cornerstone of therapy for decades, but data is sparse regarding primary and secondary VTE prevention, as well as optimal therapy duration. In this review, we discuss the role of factor Xa in the coagulation cascade and the different choices of anticoagulation therapy based on patients’ predisposing risk factors and risk of event recurrence. Further, we compare newer agents to traditional anticoagulation treatment based on the most recent studies and guidelines.

Objectives: Thrombomodulin (TM) is closely related to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). However, current evidence on circulating TM levels in SLE patients is contradictory. We conducted this meta-analysis to more accurately assess circulating TM levels in patients with SLE and lupus nephritis (LN) and to analyze related influencing factors. Methods: Systematic search of relevant documents was conducted in PubMed, Embase, and The Cochrane Library databases (up to 28 February 2021). Studies on the comparison of circulating TM between SLE patients and controls were screened and evaluated for inclusion. Random-effects model analysis was applied to calculate the combined standardized mean difference (SMD) with a 95% confidence interval (CI). Heterogeneity was estimated by Q statistics and I2. Results: A total of 353 articles were identified, 14 provided adequate information for this study finally. The results illustrated that SLE patients had higher TM levels than healthy controls (SMD=0.38, 95% CI: 0.02 to 0.74, p=0.04). Circulating TM levels were increased in patients with active SLE compared to inactive SLE patients (SMD=1.12, 95% CI: 0.03 to 2.20, p=0.04). In addition, circulating TM levels of SLE patients with LN were higher than those without LN (SMD=4.55, 95% CI: 1.97 to 7.12, p=0.001). Conclusion: The circulating TM levels in SLE patients are enhanced. In addition, circulating TM levels may be practical in reflecting the disease activity and nephritis involvement of SLE patients.

Background: Pancreatic ductal adenocarcinoma (PDAC), which ranks forth on the cancer-related death statistics still is both a diagnostic and a therapeutic challenge. Adenocarcinoma of the exocrine human pancreas originates in most instances from malignant transformation of ductal epithelial cells, alternatively by Acinar-Ductal Metaplasia (ADM). RA-96 antibody targets to a mucin M1, according to the more recent nomenclature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usability of multimodal nanoparticle carrying covalently coupled RA-96 Fab fragments for pancreatic tumor imaging. Methods: In order to make and evaluate a novel, better targeting, theranostic nanoparticle, iron nanoparticles and the optical dye indocyanin green (ICG) were encapsulated into the cationic sphingomyelin (SM) consisting liposomes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor homing ability. ICG and iron nanoparticle-encapsulated liposomes were studied in vitro with cells and (i) their visibility in magnetic resonance imaging (MRI), (ii) optical, (iii) Magnetic particle spectroscopy (MPS) and (iv) photoacoustic settings was tested in vitro and also in in vivo models. The targeting ability and MRI and photoacoustic visibility of the RA-96-nanoparticles were first tested in vitro cell models where cell binding and internalization were studied. In in vivo experiments liposomal nanoparticles were injected into the tail vain using an orthotopic pancreatic tumor xenograft model and subcutaneous pancreatic cancer cell xenografts bearing mice to determine in vivo targeting abilities of RA-96-conjugated liposomes Results: Multimodal liposomes could be detected by MRI, MPS and by photoacoustic imaging in addition to optical imaging showing a wide range of imaging utility. The fluorescent imaging of ICG in pancreatic tumor cells Panc89 and Capan-2 revealed an increased association of ICG-encapsulated liposomes carrying RA-96 Fab fragments in vitro compared to the control liposomes without covalently linked RA-96. Fluorescent molecular tomography (FMT) studies showed increased accumulation of the RA96-targeted nanoparticles in the tumor area compared to non-targeted controls in vivo. Similar accumulation in the tumor sites could be seen with liposomal ferric particles in MRI. Fluorescent tumor signal was confirmed by using an intraoperative fluorescent imaging system, which showed fluorescent labeling of pancreatic tumors. Conclusion: These results suggest that RA-96-targeted liposomes encapsulating ICG and iron nanoparticles can be used to image pancreatic tumors with a variety of optical and magnetic imaging techniques. Additionally, they might be a suitable drug delivery tool to improve treatment of PDAC patients.

Background: Oxandrolone is a synthetic testosterone analog that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus. Aim: This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats. Methods: Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR. Results: Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest, which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P-value < 0.05). Conclusion: Metformin administration provided protection against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes

Introduction: Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior measures, and neurochemistry. Methods: The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, with the remaining rats underwent a four-week- long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. Results: Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased CB1 binding in several cortical and basal ganglia regions of the brain compared to rats with no abstinence period. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower CB1 binding mainly in the basal ganglia regions and the hindlimb region of the somatosensory cortex compared to rats with no abstinence period. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [3H] SR141716A binding in many of the cortical and basal ganglia regions examined than rats given LD MP. These results highlight the biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels, while abstinence from LD MP seemed to decrease CB1 levels. Conclusion: Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.