Toxic warhead-armed antibody for targeted treatment of glioblastoma.

Glioblastoma is a fatal intracranial tumor with a poor prognosis, exhibiting uninterrupted malignant progression, widespread invasion throughout the brain leading to the destruction of normal brain tissue and inevitable death. Monoclonal antibodies alone or conjugated with cytotoxic payloads to treat patients with different solid tumors showed effective. This treatment strategy is being explored for patients with glioblastoma (GBM) to obtain meaningful clinical responses and offer new drug options for the treatment of this devastating disease. In this review, we summarize clinical data (from pubmed.gov database and clinicaltrial.gov database) on the efficacy and toxicity of naked antibodies and antibody-drug conjugates (ADCs) against multiple targets on GBM, elucidate the mechanisms that ADCs act at the site of GBM lesions. Finally, we discuss the potential strategies for ADC therapies currently used to treat GBM patients.

The Neuropharmacological Effects of Magnolol and Honokiol: A Review of Signal Pathways and Molecular Mechanisms.

Magnolol and honokiol are natural lignans with good physiological effects. As the main active substances derived from Magnolia officinalis, their pharmacological activities have attracted extensive attention. It is reported that both of them can cross the blood-brain barrier (BBB) and exert neuroprotective effects through a variety of mechanisms. This suggests that these two ingredients can be used as effective therapeutic compounds to treat a wide range of neurological diseases. This article provides a review of the mechanisms involved in the therapeutic effects of magnolol and honokiol in combating diseases, such as cerebral ischemia, neuroinflammation, Alzheimer's disease, and brain tumors, as well as psychiatric disorders, such as anxiety and depression. Although magnolol and honokiol have the pharmacological effects described above, their clinical potential remains untapped. More research is needed to improve the bioavailability of magnolol and honokiol and perform experiments to examine the therapeutic potential of magnolol and honokiol.

The neuroprotective and antidiabetic effects of trigonelline: A review of signaling pathways and molecular mechanisms.

The global epidemic of diabetes has brought heavy pressure on public health. New effective anti-diabetes strategies are urgently needed. Trigonelline is the main component of fenugreek, which has been proved to have a good therapeutic effect on diabetes and diabetic complications. Trigonelline achieves amelioration of diabetes, the mechanisms of which include the modulation of insulin secretion, a reduction in oxidative stress, and the improvement of glucose tolerance and insulin resistance. Besides, trigonelline has been reported to be a neuroprotective agent against many neurologic diseases including Alzheimer's disease, Parkinson's disease, stroke, and depression. Concerning the potential therapeutic effects of trigonelline, comprehensive clinical trials are warranted to evaluate this valuable molecule.

Photobiomodulation (800 nm Light-Emitting Diode) Treatment Promotes Bone Mesenchymal Stem Cell Proliferation Via Long Noncoding RNA MEG3-MicroRNA-217-5P Pathway.

Background: Patients with osteoporosis (OP) have a high risk of bone fracture. Abnormal bone mesenchymal stem cell (BMSC) differentiation is an essential process of OP development. In recent years, photobiomodulation has been shown to effectively promote BMSC proliferation. However, the mechanism by which photobiomodulation promotes BMSC proliferation is unclear. Long noncoding RNAs (lncRNAs) are essential mediators in multiple biological processes. The lncRNA maternally expressed gene 3 (MEG3) is a novel lncRNA gene and is related to cell proliferation. Studies have indicated that MEG3 serves as a promotor in BMSC proliferation. Objective: To investigate the effects and mechanisms of 800 nm light-emitting diode (LED) photobiomodulation in BMSC proliferation. Materials and methods: The BMSCs collected from mouse tibias and femurs were irradiated by 800 nm LED for 180 sec. CCK-8 assay was used to detect the cell viability. A dual-luciferase reporter assay was used to determine IncRNA MEG3 acted as a miR-217-5p sponge. We used reverse transcription-polymerase chain reaction (RT-PCR) and western blot to detect the mRNA and protein levels of MEG3, miR-217-5p, Notch2, Hes1, Hey2. Results: In the present study, we revealed that photobiomodulation (800 nm LED) could increase the mRNA level of MEG3, and protein levels of Notch2, Hes1, and Hey2. Moreover, we also identified that upregulated MEG3 could act as a miR-217-5p sponge to activate the Notch signaling pathway. Conclusions: The current study revealed the MEG3-related mechanism of photobiomodulation treatment in OP and identified potential gene therapies for OP.

Model-Free Optimal Tracking Control of Nonlinear Input-Affine Discrete-Time Systems via an Iterative Deterministic Q-Learning Algorithm.

In this article, a novel model-free dynamic inversion-based Q-learning (DIQL) algorithm is proposed to solve the optimal tracking control (OTC) problem of unknown nonlinear input-affine discrete-time (DT) systems. Compared with the existing DIQL algorithm and the discount factor-based Q-learning (DFQL) algorithm, the proposed algorithm can eliminate the tracking error while ensuring that it is model-free and off-policy. First, a new deterministic Q-learning iterative scheme is presented, and based on this scheme, a model-based off-policy DIQL algorithm is designed. The advantage of this new scheme is that it can avoid the training of unusual data and improve data utilization, thereby saving computing resources. Simultaneously, the convergence and stability of the designed algorithm are analyzed, and the proof that adding probing noise into the behavior policy does not affect the convergence is presented. Then, by introducing neural networks (NNs), the model-free version of the designed algorithm is further proposed so that the OTC problem can be solved without any knowledge about the system dynamics. Finally, three simulation examples are given to demonstrate the effectiveness of the proposed algorithm.

Synthesis, Characterization, and Bioactivities of Polysaccharide Metal Complexes: A Review.

Natural polysaccharides are critical to a wide range of fields (e.g., medicine, food production, and cosmetics) for their various remarkable physical properties and biological activities. However, the bioactivities of naturally acquired polysaccharides may be unsatisfactory and limit their further applications. It is generally known that the chemical structure exhibited by polysaccharides lays the material basis for their biological activities. Accordingly, possible structural modifications should be conducted on polysaccharides for their enhancement. Recently, polysaccharides complexed with metal ions (e.g., Fe, Zn, Mg, Cr, and Pt) have been reported to be possibly used to improve their bioactivities. Moreover, since the properties exhibited by metal ions are normally conserved, polysaccharides may be endowed with new applications. In this review, the synthesis methods, characterization methods, and bioactivities of polysaccharide metal complexes are summarized specifically. Then, the application prospects and limitations of these complexes are analyzed and discussed.

Ginsenosides in central nervous system diseases: Pharmacological actions, mechanisms, and therapeutics.

The nervous system is one of the most complex physiological systems, and central nervous system diseases (CNSDs) are serious diseases that affect human health. Ginseng (Panax L.), the root of Panax species, are famous Chinese herbs that have been used for various diseases in China, Japan, and Korea since ancient times, and remain a popular natural medicine used worldwide in modern times. Ginsenosides are the main active components of ginseng, and increasing evidence has demonstrated that ginsenosides can prevent CNSDs, including neurodegenerative diseases, memory and cognitive impairment, cerebral ischemia injury, depression, brain glioma, multiple sclerosis, which has been confirmed in numerous studies. Therefore, this review summarizes the potential pathways by which ginsenosides affect the pathogenesis of CNSDs mainly including antioxidant effects, anti-inflammatory effects, anti-apoptotic effects, and nerve protection, which provides novel ideas for the treatment of CNSDs.

Therapeutic effect of baicalin on inflammatory bowel disease: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Baicalin (BI) is an important biologically active flavonoid isolated from the root of Scutellaria radix (Huang Qin). Traditionally Scutellaria radix was the common drug of dysentery. As the main flavonoid compound, there is a distribution tendency of baicalin to the intestinal tract and it has a protective effect on the gastrointestinal tract. AIM OF THE REVIEW: This review aims to compile up-to-date and comprehensive information on the efficacy of baicalin in vitro and in vivo, about treating inflammatory bowel disease. Relevant information on the therapeutic potential of baicalin against inflammatory bowel disease was collected from the Web of Science, Pubmed and so on. Additionally, a few books and magazines were also consulted to get the important information. RESULTS: The mechanisms of baicalin against inflammatory bowel disease mainly include anti-inflammation, antioxidant, immune regulation, maintenance of intestinal barrier, maintenance of intestinal flora balance. Also, BI can relieve parts of extraintestinal manifestations (EIMs), and prevent colorectal cancer. CONCLUSION: Baicalin determined the promising therapeutic prospects as potential supplementary medicines for the treatment of IBD.

The role of TRPV channels in osteoporosis.

As the world's population ages, the treatment of osteoporosis is a major problem to be addressed. The cause of osteoporosis remains unclear. Ca2+ is not only an important component of bones but also plays a key role in osteoporosis treatment. Transient receptor potential vanilloid (TRPV) channels are one of the TRP channel families that is widely distributed in various organs, playing an important role in the physiological regulation of the human body. Bone formation and bone absorption may require Ca2+ transport via TRPV channels. It has been proven that the TRPV subtypes 1, 2, 4, 5, 6 (TRPV1, TRPV2, TRPV4, TRPV5, TRPV6) may affect bone metabolism balance through selective regulation of Ca2+. They significantly regulate osteoblast/osteoclast proliferation, differentiation and function. The purpose of this review is to explore the mechanisms of TRPV channels involved in regulation of the differentiation of osteoblasts and osteoclasts, as well as to discuss the latest developments in current researches, which may provide new clues and directions for an in-depth study of osteoporosis and other related bone metabolic diseases.

The antihypertensive potential of flavonoids from Chinese Herbal Medicine: A review.

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

Bilobalide: A review of its pharmacology, pharmacokinetics, toxicity, and safety.

Bilobalide is a natural sesquiterpene trilactone from Ginkgo biloba leaves. It has good water solubility and is widely used in food and pharmaceutical fields. In the last decade, a plethora of studies on the pharmacological activities of bilobalide has been conducted and demonstrated that bilobalide possessed an extensive range of pharmacological activities such as neuroprotective, antioxidative, antiinflammatory, anti-ischemic, and cardiovascular protective activities. Pharmacokinetic studies indicated that bilobalide may have the characteristics of rapid absorption, good bioavailability, wide distribution, and slow elimination. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and safety studies of bilobalide in the last decade with an emphasis on its neuroprotective and antiinflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.

Bergapten: A review of its pharmacology, pharmacokinetics, and toxicity.

Bergapten is a natural furocoumarin, also known as 5-methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However，bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood-brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes-induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.

Silencing long non-coding RNA MEG8 inhibits the proliferation and induces the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Even though long non-coding RNA (lncRNA) MEG8 plays vital roles in carcinogenesis of malignances, its roles and mechanisms in hemangioma remain unknown. Therefore, we evaluate the oncogenic roles of MEG8 in hemangioma. Small interfering RNA (siRNA)-mediated depletion of MEG8 inhibited the proliferation and increased MDA level in human hemangioma endothelial cells (HemECs). The inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) abolished the MEG8 silence induced cell viability loss. Knockdown of MEG8 increased the miR-497-5p expression and reduced the mRNA and protein levels of NOTCH2. Using a dual-luciferase assay, we confirmed the binding between MEG8 and miR-497-5p, and between the miR-497-5p and 3'UTR of NOTCH2. We further found that silencing MEG8 significantly decreased the expressions of SLC7A11 and GPX4 both in mRNA and protein level and had no effect on the level of AIFM2. Importantly, blocking miR-497-5p abrogated the effects of MEG8 loss on cell viability, MDA level and expression levels of NOTCH2, SLC7A11 and GPX4 in HemECs. Taken together, our results suggested that knockdown of long non-coding RNA MEG8 inhibited the proliferation and induced the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Association between enterovirus infection and clinical type 1 diabetes mellitus: systematic review and meta-analysis of observational studies.

Numerous animal models and epidemiological and observational studies have demonstrated that enterovirus (EV) infection could be involved in the development of clinical type 1 diabetes mellitus (T1DM), but its aetiology is not fully understood. Therefore, we reviewed the association between EV infection and clinical T1DM. We searched PubMed and Embase from inception to April 2021 and reference lists of included studies without any language restrictions in only human studies. The correlation between EV infection and clinical T1DM was calculated as the pooled odds ratio (OR) and 95% confidence intervals (CIs), analysed using random-effects models. Subgroup and sensitivity analyses were performed to evaluate the robustness of the associations. A total of 25 articles (22 case-control studies and three nested case-control studies) met the inclusion criterion including 4854 participants (2948 cases and 1906 controls) with a high level of statistical heterogeneity (I2 = 80%, P < 0.001) mainly attributable to methods of EV detection, study type, age distribution, source of EV sample and control subjects. Meta-analysis showed a significant association between EV infection and clinical T1DM (OR 5.75, 95% CI 3.61-9.61). There is a clinically significant association between clinical T1DM and EV infection.

Path Planning of Mobile Robot With Improved Ant Colony Algorithm and MDP to Produce Smooth Trajectory in Grid-Based Environment.

This approach has been derived mainly to improve quality and efficiency of global path planning for a mobile robot with unknown static obstacle avoidance features in grid-based environment. The quality of the global path in terms of smoothness, path consistency and safety can affect the autonomous behavior of a robot. In this paper, the efficiency of Ant Colony Optimization (ACO) algorithm has improved with additional assistance of A* Multi-Directional algorithm. In the first part, A* Multi-directional algorithm starts to search in map and stores the best nodes area between start and destination with optimal heuristic value and that area of nodes has been chosen for path search by ACO to avoid blind search at initial iterations. The path obtained in grid-based environment consist of points in Cartesian coordinates connected through line segments with sharp bends. Therefore, Markov Decision Process (MDP) trajectory evaluation model is introduced with a novel reward policy to filter and reduce the sharpness in global path generated in grid environment. With arc-length parameterization, a curvilinear smooth route has been generated among filtered waypoints and produces consistency and smoothness in the global path. To achieve a comfort drive and safety for robot, lateral and longitudinal control has been utilized to form a set of optimal trajectories along the reference route, as well as, minimizing total cost. The total cost includes curvature, lateral and longitudinal coordinates constraints. Additionally, for collision detection, at every step the set of optimal local trajectories have been checked for any unexpected obstacle. The results have been verified through simulations in MATLAB compared with previous global path planning algorithms to differentiate the efficiency and quality of derived approach in different constraint environments.

Mobile Robot Path Planning Based on Ant Colony Algorithm With A* Heuristic Method.

This paper proposes an improved ant colony algorithm to achieve efficient searching capabilities of path planning in complicated maps for mobile robot. The improved ant colony algorithm uses the characteristics of A* algorithm and MAX-MIN Ant system. Firstly, the grid environment model is constructed. The evaluation function of A* algorithm and the bending suppression operator are introduced to improve the heuristic information of the Ant colony algorithm, which can accelerate the convergence speed and increase the smoothness of the global path. Secondly, the retraction mechanism is introduced to solve the deadlock problem. Then the MAX-MIN ant system is transformed into local diffusion pheromone and only the best solution from iteration trials can be added to pheromone update. And, strengths of the pheromone trails are effectively limited for avoiding premature convergence of search. This gives an effective improvement and high performance to ACO in complex tunnel, trough and baffle maps and gives a better result as compare to traditional versions of ACO. The simulation results show that the improved ant colony algorithm is more effective and faster.

Broadening the scope of sortagging.

Sortases are enzymes occurring in the cell wall of Gram-positive bacteria. Sortase A (SrtA), the best studied sortase class, plays a key role in anchoring surface proteins with the recognition sequence LPXTG covalently to oligoglycine units of the bacterial cell wall. This unique transpeptidase activity renders SrtA attractive for various purposes and motivated researchers to study multiple in vivo and in vitro ligations in the last decades. This ligation technique is known as sortase-mediated ligation (SML) or sortagging and developed to a frequently used method in basic research. The advantages are manifold: extremely high substrate specificity, simple access to substrates and enzyme, robust nature and easy handling of sortase A. In addition to the ligation of two proteins or peptides, early studies already included at least one artificial (peptide equipped) substrate into sortagging reactions - which demonstrates the versatility and broad applicability of SML. Thus, SML is not only a biology-related technique, but has found prominence as a major interdisciplinary research tool. In this review, we provide an overview about the use of sortase A in interdisciplinary research, mainly for protein modification, synthesis of protein-polymer conjugates and immobilization of proteins on surfaces.

Sortase-Mediated Ligation of Purely Artificial Building Blocks.

Sortase A (SrtA) from Staphylococcus aureus has been often used for ligating a protein with other natural or synthetic compounds in recent years. Here we show that SrtA-mediated ligation (SML) is universally applicable for the linkage of two purely artificial building blocks. Silica nanoparticles (NPs), poly(ethylene glycol) and poly(N-isopropyl acrylamide) are chosen as synthetic building blocks. As a proof of concept, NP⁻polymer, NP⁻NP, and polymer⁻polymer structures are formed by SrtA catalysis. Therefore, the building blocks are equipped with the recognition sequence needed for SrtA reaction-the conserved peptide LPETG-and a pentaglycine motif. The successful formation of the reaction products is shown by means of transmission electron microscopy (TEM), matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF MS), and dynamic light scattering (DLS). The sortase catalyzed linkage of artificial building blocks sets the stage for the development of a new approach to link synthetic structures in cases where their synthesis by established chemical methods is complicated.