Therapeutic Technologies Research Articles

Complexes of ortho-Phthalic Acid in Spontaneous Animal Tumors.

The presence of diethyl-, dibutyl-, and 2-ethylhexyl phthalates in spontaneous animal tumors was determined for the first time. Small-cell breast cancer of the dog and Ehrlich ascites carcinoma with the cells are particularly rich of these compounds. It is assumed that the level of phthalates in these cells is due to the activity of expression of nuclear receptors for estrogens and progesterone, as well as the peculiarities of the metabolism of xenobiotics. The accumulation of these compounds in tumor cells can increase their malignancy. The data obtained can be used for development of new diagnostic and therapeutic technologies.

Comentarios adicionales al artículo de Eymard Torres-Rodriguez et al: Disminución del riesgo cardiovascular en pacientes obesos que participaron en un programa de medicina de estilo de vida

Dear Editor Chronic diseases have occupied a leading place in global morbidity and mortality statistics, given the increase in life expectancy and access to new therapeutic technologies and advanced drugs. Cardio-metabolic diseases such as diabetes, high blood pressure, dyslipidemia, and obesity, among others, are clear examples of both the impact and the advent of new therapeutic opportunities. In this study, the effect of a lifestyle program on the cardiovascular risk of enrolled patients was evaluated.

Adaptive under-actuated control for capacitive micro-machined ultrasonic transducer based on an accurate nonlinear modeling

A capacitive micromachined ultrasonic transducer (CMUT) due to many benefits is being considered as an imaging and therapeutic technology recently. The critical challenge is to stabilize the system beyond the pull-in voltage considering imposed perturbations. The CMUT system, on the other hand, has a low range of movement and it is intrinsically unstable, which can result in a pull-in phenomenon. Consequently, in order to use the CMUT systems in a variety of medical applications that require high tuning ratio, a closed-loop control technique has been designed for these systems aims at increasing the maximum capacitance and enhancing tunability as well. In this study, using the closed-loop control, the resistance of micro-plate against the pull-in phenomenon has been examined. Also, in the description of the system a more accurate nonlinear modeling has been considered in the presence of an under-actuated sliding model control strategy with finite convergence time. Besides, adaptive protocols with unknown upper bounds have been designed to compensate the effects of uncertainty, unmodeled dynamics and external disturbances. The performance of controller in terms of improving output pressure, stabilizing the CMUT and its robustness to imposed perturbations have been investigated. Finally, numerical simulations are presented to verify the usefulness and applicability of the proposed control strategy.

Blood-brain barrier crossing using magnetic stimulated nanoparticles

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly (ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.848) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the distribution coefficient from blood to brain under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47% in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91% compared to the group without SMF. The PBPK model and in vivo validation in this paper lay a solid foundation for future study on non-invasive targeted drug delivery to the brain.

Nucleic Acid-Based COVID-19 Therapy Targeting Cytokine Storms: Strategies to Quell the Storm.

Coronavirus disease 2019 (COVID-19) has shaken the world and triggered drastic changes in our lifestyle to control it. Despite the non-typical efforts, COVID-19 still thrives and plagues humanity worldwide. The unparalleled degree of infection has been met with an exceptional degree of research to counteract it. Many drugs and therapeutic technologies have been repurposed and discovered, but no groundbreaking antiviral agent has been introduced yet to eradicate COVID-19 and restore normalcy. As lethality is directly correlated with the severity of disease, hospitalized severe cases are of the greatest importance to reduce, especially the cytokine storm phenomenon. This severe inflammatory phenomenon characterized by elevated levels of inflammatory mediators can be targeted to relieve symptoms and save the infected patients. One of the promising therapeutic strategies to combat COVID-19 is nucleic acid-based therapeutic approaches, including microRNAs (miRNAs). This work is an up-to-date review aimed to comprehensively discuss the current nucleic acid-based therapeutics against COVID-19 and their mechanisms of action, taking into consideration the emerging SARS-CoV-2 variants of concern, as well as providing potential future directions. miRNAs can be used to run interference with the expression of viral proteins, while endogenous miRNAs can be targeted as well, offering a versatile platform to control SARS-CoV-2 infection. By targeting these miRNAs, the COVID-19-induced cytokine storm can be suppressed. Therefore, nucleic acid-based therapeutics (miRNAs included) have a latent ability to break the COVID-19 infection in general and quell the cytokine storm in particular.

Cancer of the oral mucosa (cancer of the tongue, floor of mouth, lower jaw, cheek)/lip: modern therapeutic technologies

Purpose. Evaluation of the effectiveness of three treatment options for cancer oral mucosa (cancer of the tongue and floor of mouth, cheek, lower jaw)/lip (OC/lip). Materials and methods. Treated 100 patients with OC/lip: combined treatment with surgery at the first stage and postoperative conformal external beam radiation therapy (EBRT) of 50 Gy — 40 patients; combined conformal EBRT and brachytherapy (BT HDR) — 40 patients; EBRT and photodynamic therapy (PDT) with intensive laser hyperthermia — 20 patients. The age of the patients ranged from 26 to 90 years; among them were 55 men and 45 women. Results. Five-year overall survival (OS) and relapse-free survival (RFS) in patients with tumors of various localization was 88% and 73.3% respectively with a good quality of life. Five-year OS was for combined method of treatment — 82,8%; combined EBRT and brachytherapy — 94,4% and EBRT in combination with PDT and laser hyperthermia — 83,3% (р=0,561). With tumors of stage I–II, the five-year OS was 94.4% and III–IV stage — decreased to 73.1% with a high level of statistical significance of the χ²=6.042, p=0.014. Conclusions. OC and lip cancer is most effectively cured in the I–II stage of the disease with the initial implementation of the surgical stage preceding EBRT. EBRT with photodynamic therapy and laser hyperthermia is effective for contraindications for patients to brachytherapy. The determination of PM (predictive markers) is a promising direction in optimizing the antitumor treatment of malignant neoplasms of OC/lip.

Support-Free PEDOT:PSS Fibers as Multifunctional Microelectrodes for In Vivo Neural Recording and Modulation.

In vivo microelectrodes are essential for neuroscience studies. However, development of microelectrodes with both flexibility and multifunctionality for recording chemical and electrical signals in the same extracellular microspace and modulating neural activity remains challenging. Here, we find that pure PEDOT:PSS fibers (i.e., support-free) exhibit high conductivity, fast heterogeneous electron transfer, and suitable charge storage and injection capabilities, and can thus directly act as microelectrodes not only for chemical and electrophysiological recording in the same extracellular microspace, but also for electromodulation of neural microcircuit activity. Moreover, the microelectrodes mechanically match with neural tissues, exhibiting less foreign body responses. Given the multifunctionality, flexibility, and biocompatibility, the support-free PEDOT:PSS-based microelectrodes offer a new avenue to microelectrode technology for neuroscience research, diagnostics and therapeutics.

Support‐Free PEDOT:PSS Fibers as Multifunctional Microelectrodes for In Vivo Neural Recording and Modulation

AbstractIn vivo microelectrodes are essential for neuroscience studies. However, development of microelectrodes with both flexibility and multifunctionality for recording chemical and electrical signals in the same extracellular microspace and modulating neural activity remains challenging. Here, we find that pure PEDOT:PSS fibers (i.e., support‐free) exhibit high conductivity, fast heterogeneous electron transfer, and suitable charge storage and injection capabilities, and can thus directly act as microelectrodes not only for chemical and electrophysiological recording in the same extracellular microspace, but also for electromodulation of neural microcircuit activity. Moreover, the microelectrodes mechanically match with neural tissues, exhibiting less foreign body responses. Given the multifunctionality, flexibility, and biocompatibility, the support‐free PEDOT:PSS‐based microelectrodes offer a new avenue to microelectrode technology for neuroscience research, diagnostics and therapeutics.

Management of chronic empyema thoracis in children, a single center retrospective observational study

Abstract: Background: Chronic empyema thoracis (CET) is common in developing and developed countries despite advancement in diagnostic and therapeutic technologies. Some of the cases of CET can be managed with antibiotics and tube drainage alone, some of them managed with less extensive surgical procedure like video-assisted thoracoscopic surgery (VATS) or open decortication alone, while some of the complicated cases need extensive decortication and debridement of necrotic lung tissue or lobectomy. Our aim is to present our experience of management of cases of chronic empyema thoracis in children. Methods and Material: This is a retrospective observational study of cases, managed at tertiary care center with chronic empyema thoracis. Records of cases of CET admitted, referred or transferred to department of pediatric surgery at our center over last three years were studied. Demographic data, clinical, radiological profile, surgical/ non-surgical intervention, hospital stay, aetiology, outcome was analysed. Follow up was up to the last recorded outpatient visit. This study is a retrospective observational study with small number of cases statistical tool are not used to draw any statistical interference. Results: Twenty-nine cases with median age 3 years, male to female ratio was 25:4 were admitted over three years. Pre-operative bronchopleural fistula was seen in four. Five cases were managed conservatively, twenty underwent decortication alone while four cases required decortication along with lobectomy. Tuberculosis was detected in three cases. A pyogenic organism was identified in ten cases only. Post-operative ventilation was required in three patients. There was no mortality. All thrived well at 12-18 months follow up. Conclusions: Management of chronic empyema should be case based. Cases of CET in children can managed with conservative (with appropriate drainage of cavity, proper antibiotics, and nutritional build-up of child), thoracotomy and decortications alone or some time removal of disease lung also required depending on clinical and radiological finding of cases.

Innovative developments and emerging technologies in RNA therapeutics

Innovative developments and emerging technologies in RNA therapeutics

Specific expression and functions of circular RNAs.

In recent years, circular RNAs (circRNAs), a new class of RNA molecules characterized by their covalently closed circular structure, have become a new research paradigm in RNA biology. Many circRNAs are conserved among eukaryotes, localize in specific subcellular compartments, and play different biological roles. Accumulating evidence shows that circRNAs regulate a diversity of cellular processes by acting as miRNA sponges, anchors for circRNA binding proteins (cRBPs), transcriptional regulators, molecular scaffolds, and sources for translation of small proteins/peptides. The emergence of the biological functions of circRNAs has brought a new perspective to our understanding of cellular physiology and disease pathogenesis. Recent studies have shown that the expression of circRNAs is tissue- and cell type-specific and specifically regulated through development or disease progression, where they exert specific biological functions. However, the mechanisms underlying these remain largely unknown. A deeper understanding of how the specific expression of circRNAs is regulated to exert specific biological functions will enable the use of circRNA as a biomarker in clinical practice and the development of new therapeutic approaches. This review aims to summarize recent developments in circRNA biogenesis, functions, and molecular mechanisms. We also provide some specific circRNAs as examples to show their tissue-specific distribution and evaluate the possibility of applying circRNA technologies in molecular research and therapeutics.

Focused Ultrasound for Pediatric Diseases.

Focused ultrasound (FUS) is a noninvasive therapeutic technology with multiple pediatric clinical applications. The ability of focused ultrasound to target tissues deep in the body without exposing children to the morbidities associated with conventional surgery, interventional procedures, or radiation offers significant advantages. In 2021, there are 10 clinical pediatric focused ultrasound studies evaluating various musculoskeletal, oncologic, neurologic, and vascular diseases of which 8 are actively recruiting and 2 are completed. Pediatric musculoskeletal applications of FUS include treatment of osteoid osteoma and bone metastases using thermal ablation and high-intensity FUS. Pediatric oncologic applications of FUS include treatment of soft tissue tumors including desmoid tumors, malignant sarcomas, and neuroblastoma with high-intensity FUS ablation alone, or in combination with targeted chemotherapy delivery. Pediatric neurologic applications include treatment of benign tumors such as hypothalamic hamartomas with thermal ablation and malignant diffuse intrinsic pontine glioma with low-intensity FUS for blood brain barrier opening and targeted drug delivery. Additionally, low-intensity FUS can be used to treat seizures. Pediatric vascular applications of FUS include treatment of arteriovenous malformations and twin-twin transfusion syndrome using ablation and vascular occlusion. FUS treatment appears safe and efficacious in pediatric populations across many subspecialties. Although there are 7 Food and Drug Administration-approved indications for adult applications of FUS, the first Food and Drug Administration approval for pediatric patients with osteoid osteoma was obtained in 2020. This review summarizes the preclinical and clinical research on focused ultrasound of potential benefit to pediatric populations.

Role of Mitophagy in Coronary Heart Disease: Targeting the Mitochondrial Dysfunction and Inflammatory Regulation.

Coronary heart disease (CHD) is one of the main causes of death worldwide. In the past few decades, several in-depth research on the pathological mechanisms and effective treatment methods for CHD have been conducted. At present, the intervention of a variety of therapeutic drugs and treatment technologies have greatly reduced the burden on global public health. However, severe arrhythmia and myocardial fibrosis accompanying CHD in the later stages need to be addressed urgently. Mitochondria are important structural components for energy production and the main sites for aerobic respiration in cells. Mitochondria are involved in arrhythmia, myocardial fibrosis, and acute CHD and play a crucial role in regulating myocardial ischemia/hypoxia. Mitochondrial dysfunction or mitophagy disorders (including receptor-dependent mitophagy and receptor-independent mitophagy) play an important role in the pathogenesis of CHD, especially mitophagy. Mitophagy acts as a “mediator” in the inflammatory damage of cardiomyocytes or vascular endothelial cells and can clear mitochondria or organelles damaged by inflammation under normal conditions. We reviewed experimental advances providing evidence that mitochondrial homeostasis or mitochondrial quality control are important in the pathological mechanism of CHD. Further, we reviewed and summarized relevant regulatory drugs that target mitochondrial function and quality control.

Clinical research–When it matters

Clinical research runs through the entire progress of the science and technology which has been currently and previously applied to the medical field. It has gradually developed into a standardized procedure and played an important role in understanding the etiology and characteristics of diseases. Clinical research assess the effectiveness and safety of new/improved diagnostic or therapeutic technologies, implants, instruments, or drug applications, to discover new data and improve potential deficiencies in previous medical knowledge.

Clinical translation of advanced colonic drug delivery technologies

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

DISBALANCE OF BIORADICAL PROCESSES AS THE MAIN CAUSE OF DISORGANIZATION OF CONNECTIVE TISSUE STRUCTURES IN EXPERIMENTAL PERIODONTITIS

Abstract: Relevance. The features of the dynamics of free radical processes, as well as the metabolism of collagen structures of the connective tissue matrix against the background of periodontitis will reveal deeper pathogenetic mechanisms and application points for the introduction of new therapeutic and diagnostic technologies into practice. The purpose of the study. Assessment and establishment of interrelations between the intensity of bio-radical processes and collagen metabolism in dynamics in experimental periodontitis. Materials and methods. The study used 45 white nonlinear rats, on which the model of periodontitis proposed by Shkolnaya K. D., Atrushkevich V.G. (Patent RU No. 2625295 dated 12.07.2017) was reproduced. The total activity of free radical oxidation and the antioxidant potential of the body were monitored by the biochemiluminescence method, and markers of collagen metabolism were recorded. Results. The study revealed a sharp predominance of oxidative processes and the inability of the antioxidant potential to suppress free radical peroxidation, as evidenced by the persistently high levels of total luminescence intensity and biohemiluminescence light sum that persist throughout the experiment, despite dynamic changes. Reactive oxygen species in conditions of progressive chronic inflammation have a damaging effect on collagen fibers, which means they lead to the inevitable destruction of the periodontal complex, which is expressed in the growth of CO and PSO. In addition, there is a significant direct correlation between the dynamics of the intensity of free radical oxidation and the indicators of collagen metabolism. Conclusion. Thus, oxidative stress, progressing against the background of periodontitis, leads to disorganization of connective tissue structures of the periodontal. In turn, the study confirms the validity of the use of markers of the intensity of free radical oxidation and collagen metabolism to diagnose the severity of the disease and prognosis, as well as the need for the use of antioxidant drugs as part of complex therapy.

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies.

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.

Crocetin: A Systematic Review.

Crocetin is an aglycone of crocin naturally occurring in saffron and produced in biological systems by hydrolysis of crocin as a bioactive metabolite. It is known to exist in several medicinal plants, the desiccative ripe fruit of the cape jasmine belonging to the Rubiaceae family, and stigmas of the saffron plant of the Iridaceae family. According to modern pharmacological investigations, crocetin possesses cardioprotective, hepatoprotective, neuroprotective, antidepressant, antiviral, anticancer, atherosclerotic, antidiabetic, and memory-enhancing properties. Although poor bioavailability hinders therapeutic applications, derivatization and formulation preparation technologies have broadened the application prospects for crocetin. To promote the research and development of crocetin, we summarized the distribution, preparation and production, total synthesis and derivatization technology, pharmacological activity, pharmacokinetics, drug safety, drug formulations, and preparation of crocetin.

Knowledge and Attitude of Taif University Students on Stem Cell Banking

Abstract: Background and Objectives: The awareness of university students is pivotal to the adaptation of new therapeutic technologies in combating illness and disorders. Stem cells are unique and effective in treating several pathological conditions. This study was an effort to determine the knowledge and attitude of Taif University students toward the banking of stem cells through the donation of umbilical cord blood (UCB). Materials and Methods: The study used a self-administered questionnaire that consisted of items on demographics, knowledge characteristics, and attitude towards banking of UCB as a source of stem cells for the purpose of achieving advanced therapeutic outcomes. The questionnaire was administered to only female students at Taif University during the academic year 2020-21. Both descriptive and inferential analysis were done using SPSSIBM 25 to analyze the data. Results: A total of 604 female students of Taif University responded to our questionnaire. Although most of the participants (70%) lacked sufficient knowledge (less than or equal to 2 out of 4), their attitudes were motivating, with more than 60% rated better than adequate (more than or equal to 3 out of 4). Many study participants have shown an interest in donating umbilical cord stem cells to treat other patients and for research purposes. Conclusion: Students with good knowledge of umbilical cord blood donation and those who are more educated showed a greater level of willingness to participate in banking and donation of stem cells. Therefore, raising awareness about stem cell banking and its importance among young undergraduates, especially female students, is imperative. Key words: Knowledge, Attitude, Taif University, Awareness campaigns, Umbilical Cord blood.

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.