Showing papers in "Biomedicines in 2021"

Advances in Nanomaterial-Mediated Photothermal Cancer Therapies: Toward Clinical Applications.

Abstract: Photothermal therapy (PTT) has attracted extensive research attention as a noninvasive and selective treatment strategy for numerous cancers. PTT functions via photothermal effects induced by converting light energy into heat on near-infrared laser irradiation. Despite the great advances in PTT for cancer treatment, the photothermal therapeutics using laser devise only or non-specific small molecule PTT agents has been limited because of its low photothermal conversion efficiency, concerns about the biosafety of the photothermal agents, their low tumor accumulation, and a heat resistance of specific types of cancer. Using nanomaterials as PTT agents themselves, or for delivery of PTT agents, offers improved therapeutic outcomes with fewer side effects through enhanced photothermal conversion efficiency, accumulation of the PTT agent in the tumor tissue, and, by extension, through combination with other therapies. Herein, we review PTT’s current clinical progress and present the future outlooks for clinical applications. To better understand clinical PTT applications, we describe nanomaterial-mediated photothermal effects and their mechanism of action in the tumor microenvironment. This review also summarizes recent studies of PTT alone or in combination with other therapies. Overall, innovative and strategically designed PTT platforms are promising next-generation noninvasive cancer treatments to move closer toward clinical applications.

Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Abstract: Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway.

Abstract: The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses and chronic diseases. KYN, kynurenic acid, xanthurenic acid and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2,3-dioxygenases and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric disorders, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia and autism spectrum disorder.

Long-Term Impact of COVID-19: A Systematic Review of the Literature and Meta-Analysis

Abstract: Background: The long-term impact of COVID-19 is still unknown. This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond 3 months post infection. Methods: A systematic search was performed on PubMed, Web of Science, and Ovid MEDLINE on 22 May 2021, to identify studies that reported persistent effects of COVID-19 beyond 3 months follow-up. Data on the proportion of patients who had the outcome were collected and analyzed using a one-group meta-analysis. Results: Data were extracted from 24 articles that presented information on a total of 5323 adults, post-infection, between 3 to 6 months after symptom onset or hospital discharge. The pooled prevalence of CT abnormalities was 59% (95% CI 44–73, I2 = 96%), abnormal lung function was 39% (95% CI 24–55, I2 = 94%), fatigue was 38% (95% CI 27–49, I2 = 98%), dyspnea was 32% (95% CI 24–40, I2 = 98%), chest paint/tightness was 16% (95% CI 12–21, I2 = 94%), and cough was 13%, (95% CI 9–17, I2 = 94%). Decreased functional capacity and HRQoL were found in 36% (95% CI 22–49, I2 = 97%) and 52% (95% CI 33–71, I2 = 94%), respectively. On average, 8 out of 10 of the patients had returned to work or reported no work impairment. Conclusion: Post-COVID-19 patients may experience persistent respiratory symptoms, fatigue, decreased functional capacity and decreased quality of life up to 6 months after infection. Further studies are needed to establish the extent to which post-COVID-19 effects continue beyond 6 months, how they interact with each other, and to clarify their causes and their effective management.

Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans

Abstract: The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients.

Current FDA-Approved Therapies for High-Grade Malignant Gliomas

Abstract: The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.

Neuroinflammation in Alzheimer's Disease.

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

Modern Wound Dressings: Hydrogel Dressings

Abstract: Chronic wounds do not progress through the wound healing process in a timely manner and are considered a burden for healthcare system; they are also the most common reason for decrease in patient quality of life. Traditional wound dressings e.g., bandages and gauzes, although highly absorbent and effective for dry to mild, exudating wounds, require regular application, which therefore can cause pain upon dressing change. In addition, they have poor adhesional properties and cannot provide enough drainage for the wound. In this regard, the normalization of the healing process in chronic wounds is an extremely urgent task of public health and requires the creation and implementation of affordable dressings for patients with chronic wounds. Modern wound dressings (WDs) are aimed to solve these issues. At the same time, hydrogels, unlike other types of modern WDs (foam, films, hydrocolloids), have positive degradation properties that makes them the perfect choice in applications where a targeted delivery of bioactive substances to the wound is required. This mini review is focused on different types of traditional and modern WDs with an emphasis on hydrogels. Advantages and disadvantages of traditional and modern WDs as well as their applicability to different chronic wounds are elucidated. Furthermore, an effectiveness comparison between hydrogel WDs and the some of the frequently used biotechnologies in the field of regenerative medicine (adipose-derived mesenchymal stem cells (ADMSCs), mesenchymal stem cells, conditioned media, platelet-rich plasma (PRP)) is provided.

Roles of XBP1s in Transcriptional Regulation of Target Genes.

Abstract: The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease.

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance.

Abstract: Copper (Cu) is a vital element required for cellular growth and development; however, even slight changes in its homeostasis might lead to severe toxicity and deleterious medical conditions. Cancer patients are typically associated with higher Cu content in serum and tumor tissues, indicating increased demand of cancer cells for this micronutrient. Cu is known to readily cycle between the +1 and +2 oxidation state in biological systems. The mechanism of action of Cu complexes is typically based on their redox activity and induction of reactive oxygen species (ROS), leading to deadly oxidative stress. However, there are a number of other biomolecular mechanisms beyond ROS generation that contribute to the activity of anticancer Cu drug candidates. In this review, we discuss how interfering with intracellular Cu balance via either diet modification or addition of inorganic Cu supplements or Cu-modulating compounds affects tumor development, progression, and sensitivity to treatment modalities. We aim to provide the rationale for the use of Cu-depleting and Cu-overloading conditions to generate the best possible patient outcome with minimal toxicity. We also discuss the advantages of the use of pre-formed Cu complexes, such as Cu-(bis)thiosemicarbazones or Cu-N-heterocyclic thiosemicarbazones, in comparison with the in situ formed Cu complexes with metal-binding ligands. In this review, we summarize available clinical and mechanistic data on clinically relevant anticancer drug candidates, including Cu supplements, Cu chelators, Cu ionophores, and Cu complexes.

Emerging SARS-CoV-2 Variants of Concern (VOCs): An Impending Global Crisis.

Abstract: The worldwide battle against the SARS-CoV-2 virus rages on, with millions infected and many innocent lives lost. The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a beta coronavirus that belongs to the Coronaviridae family. Many clinically significant variants have emerged, as the virus's genome is prone to various mutations, leading to antigenic drift and resulting in evasion of host immune recognition. The current variants of concern (VOCs) include B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617/B.1.617.2 (Delta), and P.1 (Gamma). The emerging variants contain various important mutations on the spike protein, leading to deleterious consequences, such as immune invasion and vaccine escape. These adverse effects result in increased transmissibility, morbidity, and mortality and the evasion of detection by existing or currently available diagnostic tests, potentially delaying diagnosis and treatment. This review discusses the key mutations present in the VOC strains and provides insights into how these mutations allow for greater transmissibility and immune evasion than the progenitor strain. Continuous monitoring and surveillance of VOC strains play a vital role in preventing and controlling the virus's spread.

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

Abstract: Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence cSCC could be in situ (eg, Bowen’s disease) or an invasive form A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes Thus, cSCC development is a gradual process with several histological- and pathological-defined stages Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC Surgical excision is the first-line treatment for invasive cSCC Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC Furthermore, the implementation of prevention measures has been useful in patient management

Natural Photosensitizers in Antimicrobial Photodynamic Therapy.

Abstract: Health problems and reduced treatment effectiveness due to antimicrobial resistance have become important global problems and are important factors that negatively affect life expectancy. Antimicrobial photodynamic therapy (APDT) is constantly evolving and can minimize this antimicrobial resistance problem. Reactive oxygen species produced when nontoxic photosensitizers are exposed to light are the main functional components of APDT responsible for microbial destruction; therefore, APDT has a broad spectrum of target pathogens, such as bacteria, fungi, and viruses. Various photosensitizers, including natural extracts, compounds, and their synthetic derivatives, are being investigated. The main limitations, such as weak antimicrobial activity against Gram-negative bacteria, solubility, specificity, and cost, encourage the exploration of new photosensitizer candidates. Many additional methods, such as cell surface engineering, cotreatment with membrane-damaging agents, nanotechnology, computational simulation, and sonodynamic therapy, are also being investigated to develop novel APDT methods with improved properties. In this review, we summarize APDT research, focusing on natural photosensitizers used in in vitro and in vivo experimental models. In addition, we describe the limitations observed for natural photosensitizers and the methods developed to counter those limitations with emerging technologies.

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

Abstract: As a public health emergency of international concern, the highly contagious coronavirus disease 2019 (COVID-19) pandemic has been identified as a severe threat to the lives of billions of individuals. Lung cancer, a malignant tumor with the highest mortality rate, has brought significant challenges to both human health and economic development. Natural products may play a pivotal role in treating lung diseases. We reviewed published studies relating to natural products, used alone or in combination with US Food and Drug Administration-approved drugs, active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lung cancer from 1 January 2020 to 31 May 2021. A wide range of natural products can be considered promising anti-COVID-19 or anti-lung cancer agents have gained widespread attention, including natural products as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, shiraiachrome A, resveratrol, and baicalein) or lung cancer (daurisoline, graveospene A, deguelin, and erianin) or in combination with FDA-approved anti-SARS-CoV-2 agents (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and anti-lung cancer agents (curcumin and cisplatin, celastrol and gefitinib). Natural products have demonstrated potential value and with the assistance of nanotechnology, combination drug therapies, and the codrug strategy, this “natural remedy” could serve as a starting point for further drug development in treating these lung diseases.

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma.

Abstract: Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.

Meningioma: A Review of Epidemiology, Pathology, Diagnosis, Treatment, and Future Directions.

Abstract: Meningiomas are the most common intracranial tumor, making up more than a third of all primary central nervous system (CNS) tumors. They are mostly benign tumors that can be observed or preferentially treated with gross total resection that provides good outcomes. Meningiomas with complicated histology or in compromising locations has proved to be a challenge in treating and predicting prognostic outcomes. Advances in genomics and molecular characteristics of meningiomas have uncovered potential use for more accurate grading and prediction of prognosis and recurrence. With the study and detection of genomic aberrancies, specific biologic targets are now being trialed for possible management of meningiomas that are not responsive to standard surgery and radiotherapy treatment. This review summarizes current epidemiology, etiology, molecular characteristics, diagnosis, treatments, and current treatment trials.

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study.

Abstract: Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p < 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Pancreatic cancer signaling pathways, genetic alterations, and tumor microenvironment: The barriers affecting the method of treatment.

Abstract: Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

Abstract: The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease However, its low in vivo bioavailability calls for modifications to its molecular structure In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM) Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145) The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro

Application of CAR-T Cell Therapy beyond Oncology: Autoimmune Diseases and Viral Infections

Abstract: Adoptive cell transfer (ACT) has long been at the forefront of the battle with cancer that began last century with the therapeutic application of tumor-infiltrating lymphocytes (TILs) against melanoma. The development of novel ACT approaches led researchers and clinicians to highly efficient technologies based on genetically engineered T lymphocytes, with chimeric antigen receptor (CAR)-T cells as the most prominent example. CARs consist of an extracellular domain that represents the single-chain variable fragment (scFv) of a monoclonal antibody (mAb) responsible for target recognition and the intracellular domain, which was built from up to several signaling motifs that mediated T cell activation. The number of potential targets amenable for CAR-T cell therapy is expanding rapidly, which means that the tremendous success of this approach in oncology could be further translated to treating other diseases. In this review, we outlined modern trends and recent developments in CAR-T cell therapy from an unusual point of view by focusing on diseases beyond cancer, such as autoimmune disorders and viral infections, including SARS-CoV-2.

Inflammatory Mediators and Pain in Endometriosis: A Systematic Review.

Abstract: Background: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients’ personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators’ synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. Objectives: patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. Data Sources: three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords ‘inflammation, pain, and endometriosis’ between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. Data Extraction: two authors independently extracted data from articles, using predefined criteria. Results: the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. Conclusions: inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.

Abstract: Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Abstract: Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.

Dopamine in Health and Disease: Much More Than a Neurotransmitter

Abstract: Dopamine is derived from an amino acid, phenylalanine, which must be obtained through the diet. Dopamine, known primarily to be a neurotransmitter involved in almost any higher executive action, acts through five types of G-protein-coupled receptors. Dopamine has been studied extensively for its neuronal handling, synaptic actions, and in relation to Parkinson's disease. However, dopamine receptors can be found extra-synaptically and, in addition, they are not only expressed in neurons, but in many types of mammalian cells, inside and outside the central nervous system (CNS). Recent studies show a dopamine link between the gut and the CNS; the mechanisms are unknown, but they probably require cells to act as mediators and the involvement of the immune system. In fact, dopamine receptors are expressed in almost any cell of the immune system where dopamine regulates various processes, such as antigen presentation, T-cell activation, and inflammation. This likely immune cell-mediated linkage opens up a new perspective for the use of dopamine-related drugs, i.e., agonist-antagonist-allosteric modulators of dopamine receptors, in a variety of diseases.

Mitochondrial Dysfunction in Alzheimer's Disease: A Biomarker of the Future?

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use.

Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients.

Abstract: Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage.

Retinal Microvascular Impairment in COVID-19 Bilateral Pneumonia Assessed by Optical Coherence Tomography Angiography.

Abstract: The purpose of this study was to evaluate the presence of retinal and microvascular alterations in COVID-19 patients with bilateral pneumonia due to SARS-COV-2 that required hospital admission and compare this with a cohort of age- and sex-matched controls. COVID-19 bilateral pneumonia patients underwent retinal imaging 14 days after hospital discharge with structural optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) measurements. Vessel density (VD) and foveal avascular zone (FAZ) area were evaluated in the superficial, deep capillary plexus (SCP, DCP), and choriocapillaris (CC). After exclusion criteria, only one eye per patient was selected, and 50 eyes (25 patients and 25 controls) were included in the analysis. COVID-19 patients presented significantly thinner ganglion cell layer (GCL) (p = 0.003) and thicker retinal nerve fiber layer (RNFL) compared to controls (p = 0.048), and this RNFL thickening was greater in COVID-19 cases with cotton wool spots (CWS), when compared with patients without CWS (p = 0.032). In both SCP and DCP, COVID-19 patients presented lower VD in the foveal region (p < 0.001) and a greater FAZ area than controls (p = 0.007). These findings suggest that thrombotic and inflammatory phenomena could be happening in the retina of COVID-19 patients. Further research is warranted to analyze the longitudinal evolution of these changes over time as well as their correlation with disease severity.

Advances and Limitations of Antibody Drug Conjugates for Cancer.

Abstract: The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate.

Abstract: Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.