Double Swords in One: Novel Selective PI3/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp.

The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure-activity relationship studies of a series of small-molecule PI3/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3/110β with VHL ligands. Among them, and exhibited rapid and efficient degradation ability for the target proteins in MDR cells.

Folate receptor-targeted pH-sensitive liposomes loaded with TGX-221 against prostate cancer by inhibiting PI3K/110β signaling.

Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility.

Exosomes-encapsulated biomimetic polydopamine carbon dots with dual-targeting effect alleviate motor and non-motor symptoms of Parkinson's disease via anti-neuroinflammation.

Currently, the clinical drugs for Parkinson's disease (PD) only focus on motor symptoms, while non-motor symptoms like depression are usually neglected. Even though, the efficacy of existing neurotherapeutic drugs is extremely poor which is due to the blood brain barrier (BBB). Therefore, a biomimetic polydopamine carbon dots (PDA C-dots) at 2-4 nm was synthesized, while exosomes from macrophages were applied to encapsulate PDA C-dots for improving their BBB-crossing ability and inflammation-targeting effect.

Doxorubicin-Loaded Liposome with the Function of "Killing Two Birds with One Stone" against Glioma.

The blood-brain barrier (BBB) continues to be one of the main clinical obstacles in the treatment of glioma. Current chemotherapies always bring many different side effects, some even permanent. To date, nanomaterial-based vehicles have shown great potential in treating glioma.

Characterization, in vitro digestibility, antioxidant activity and intestinal peristalsis in zebrafish of Dioscorea opposita polysaccharides.

The soluble crude polysaccharides from Dioscorea opposita (DOP1 and DOP2) were prepared and characterized. DOP1 and DOP2 obtained carbohydrate (65.71% and 70.

A Triple-Targeted Rutin-Based Self-Assembled Delivery Vector for Treating Ischemic Stroke by Vascular Normalization and Anti-Inflammation via ACE2/Ang1-7 Signaling.

Changes in the cerebral microenvironment caused by acute ischemic stroke-reperfusion are the main obstacle to the recovery of neurological function and an important cause of stroke recurrence after thrombolytic therapy. The intracerebral microenvironment after ischemia-reperfusion reduces the neuroplasticity of the penumbra and ultimately leads to permanent neurological damage. To overcome this challenge, we developed a triple-targeted self-assembled nanodelivery system, which combines the neuroprotective drug rutin with hyaluronic acid through esterification to form a conjugate, and then connected SS-31, a small peptide that can penetrate the blood brain barrier and target mitochondria.

A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3/-Catenin and TGF-/Smad2/3 Signaling Pathways.

Hepatocellular carcinoma (HCC) is a disease with high morbidity, high mortality, and low cure rate. Hyaluronic acid (HA) is widely adopted in tissue engineering and drug delivery. 5-(4-Hydroxyphenyl)-3H-1, 2-dithiol-3-thione (ADT-OH) is one of commonly used HS donors.

A multi-bioresponsive self-assembled nano drug delivery system based on hyaluronic acid and geraniol against liver cancer.

Herein, a multi-bioresponsive self-assembled nano-drug delivery system (HSSG) was constructed by conjugating the anticancer drug Geraniol (GER) to hyaluronic acid (HA) via a disulfide bond. The HSSG NPs displayed a uniform spherical shape with an average diameter of ∼110 nm, maintained high stability, and realized controlled drug release in the tumor microenvironment (pH/glutathione/hyaluronidase). Results of fluorescence microscopy and flow cytometry verified that HSSG NPs were selectively uptaken by human hepatocellular carcinoma cell lines HepG2 and Huh7 via CD44 receptor-mediated internalization.

A Water-Soluble Quercetin Conjugate with Triple Targeting Exerts Neuron-Protective Effect on Cerebral Ischemia by Mitophagy Activation.

The existing treatments for ischemic stroke cannot meet the clinical needs so far. Quercetin (QT) is an effective apoptosis inhibitor and antioxidant flavonoid, but its water solubility is poor and has no targeting. In this study, QT is modified with hyaluronic acid (HA) to form a water-soluble conjugate HA-QT, which can specifically bind to CD44 receptors and response to hyaluronidase.

Research progress of stem cell therapy for endometrial injury.

Endometrial damage is an important factor leading to infertility and traditional conventional treatments have limited efficacy. As an emerging technology in recent years, stem cell therapy has provided new hope for the treatment of this disease. By comparing the advantages of stem cells from different sources, it is believed that menstrual blood endometrial stem cells have a good application prospect as a new source of stem cells.

Whole Genome Transcriptomic Analysis of Ovary Granulosa Cells Revealed an Anti-Apoptosis Regulatory Gene DLGAP5 in Polycystic Ovary Syndrome.

The mechanisms underlining pathogenesis of polycystic ovary syndrome (PCOS) remain largely unknown. Dysfunction of ovarian granulosa cells plays an important role. The present study performed the lncRNA and mRNA profiling by whole genome transcriptomic sequencing of ovary granulosa cells from women with PCOS and investigated the potential role of differentially expressed gens (DEGs) in the pathomechanism of PCOS.

Exposure of particulate matter (PM) induces neurodevelopmental toxicity in zebrafish embryos.

Particulate matter with 10 μm or less in diameter (PM) exposure is a major threat to health and environment around the world. Even though a number of clinical and experimental studies have focused on the cardiopulmonary effects of PM, its impact on neurovascular development and the underlying toxicity is relatively less studied. The present study is therefore undertaken to evaluate the potential toxic effects of PM on neurodevelopment and the associated gene expression profiles in the zebrafish embryo/larvae.

Bisindole compound 4ae ameliorated cognitive impairment in rats with vascular dementia by anti-inflammation effect via microglia cells.

Neuroinflammation is considered as an important mechanism of vascular dementia (VaD). Our primary study showed that the bisindole analogue (2-(2-(bis(5-chloro-1H-indol-3-yl)methyl)phenoxy)aniline, compound 4ae) had great anti-inflammation in zebrafish. Rat model of permanent occlusion of the bilateral common carotid arteries (2-vessel occlusion, 2VO) was utilized to evaluate the neuroprotective effect of 4ae.

Curcumin Derivative Cur20 Attenuated Cerebral Ischemic Injury by Antioxidant Effect and HIF-1α/VEGF/TFEB-Activated Angiogenesis.

In this paper, a curcumin derivative Cur20 was synthesized for better hydrolytic stability, which showed a higher angiogenic effect on zebrafish model than curcumin. In order to reveal the potential effects on neuroprotection, a mouse model of vascular dementia (VaD) induced by permanent right common carotid artery occlusion (rUCCAO) was established. After two weeks of curcumin administration, the cognitive function of mice was detected by Morris water maze and Y maze.

Transdermal Delivery of Adipocyte Phospholipase A2 siRNA using Microneedles to Treat Thyroid Associated Ophthalmopathy-Related Proptosis.

Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune disease occurring in patients with thyroid disease. Patients with TAO-related proptosis is largely due to excessive orbital adipose tissue Adipocyte phospholipase A2 (AdPLA) is one of the most important regulatory factors in adipocyte lipolysis, which may be associated with TAO-related proptosis. Thus, silencing AdPLA by RNA interference may be beneficial for the treatment of TAO.

HMGB1 promoted P-glycoprotein at the blood-brain barrier in MCAO rats via TLR4/NF-κB signaling pathway.

P-glycoprotein (P-gp) is located on the luminal surface of brain vascular endothelium and its status may determine the delivery of the agents into the brain tissues. Previous study showed that upregulation of P-gp at the blood-brain barrier (BBB) after ischemic stroke were mediated by nuclear factor-B (NF-kB) and tumour necrosis factor-α (TNF-α). Based on middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD) in co-culture of rat brain microvessel endothelial cells (rBMECs) and astrocytes system, the present data indicated that potentiated P-gp expression and activity in brain microvessels or rBMECs were associated with the increase in high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4) and activation of NF-kB and that HMGB1 can release from nucleus to the cytoplasm in activated astrocytes, then into the medium.

What and How Can Physical Activity Prevention Function on Parkinson's Disease?

Aim: This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson's disease (PD) and providing theoretical guidance for the prevention and treatment of PD.

Methods: Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method.

Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway.

Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish.

Hepatotoxicity Induced by Isoniazid-Lipopolysaccharide through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis Pathways in Zebrafish.

Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understand the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in levels of hepatotoxicity from INH between normal zebrafish and zebrafish in an inflammatory state to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis, and expression levels of certain genes.

Polyamine analogue QMA attenuated ischemic injury in MCAO rats via ERK and Akt activated Nrf2/HO-1 signaling pathway.

Previous research showed N-(quinolin-2-ylmethy) butane-1, 4-diamine (QMA), a polyamine analogue, was efficacious in the prevention of oxidative injury in models of cerebral ischemia. The present study manifested that pretreatment with QMA attenuated ischemic damage accompanying up regulation of Nuclear factor erythroid 2‑related factor (Nrf2), Heme oxygenase‑1 (HO‑1), p-ERK and p-Akt in cerebral cortex tissues of middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD)-treated PC12 cells. Further more, treatment with LY294002 (specific PI3K inhibitor), PD98059 (specific ERK inhibitor), brusatol (specific Nrf2 inhibitor) and SnPP (specific HO-1 inhibitor) deprived almost all the effects of QMA in MCAO rats and OGD-treated PC12 cells.

Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.

A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE).

Transplantation of Human Umbilical Cord Blood Mononuclear Cells Attenuated Ischemic Injury in MCAO Rats via Inhibition of NF-κB and NLRP3 Inflammasome.

Accumulated evidence displayed that transplantation of stem cells may be a promising approach for the treatment of neurological disorders. However, the underlying mechanisms remain to be well elucidated. Moreover, some investigators cannot reproduce similar results as the previous.

Triterpenoids from exert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen species induction and P-glycoprotein inhibition.

Triterpenoids from the have been shown cytotoxicity on a broad spectrum of human tumor cells. In the present study, we extracted triterpenoids AA-5 (1) and AA-6 (2) from stems of , and studied their cytotoxicity in multidrug resistant (MDR) MCF-7/ADM cells. After 48 h treatment, AA-5 (1) and AA-6 (2) significantly increased mitochondrial-mediated apoptosis by enhancing reactive oxygen species (ROS) with depressed mitochondrial membrane potential and caspase-9 activities.