Iron ions-sequestrable and antioxidative carbon dot-based nano-formulation with nitric oxide release for Parkinson's disease treatment.

Nondestructive penetration of the blood-brain barrier (BBB) to specifically prevent iron deposition and the generation of reactive oxygen species (ROS) shows great potential for treating Parkinson's disease (PD). However, effective agents with distinct mechanisms of action remain scarce. Herein, a N-doping carbon dot (CD) emitting red light was prepared, which can sacrifice ROS and produce nitric oxide (NO) owing to its surface N-involved groups conjugated to the sp2-hybrided π-system. Meanwhile, CD can chelate iron ions, thus depressing the catalytic Fe cycle and *OH detaching to inhibit the Fenton reaction. By modifying lactoferrin (Lf) via polyethylene glycol (PEG), the resulting CD-PEG-Lf (CPL) can nondestructively cross the BBB, targeting the dopaminergic neurons via both NO-mediated reversible BBB opening and Lf receptor-mediated transportation. Accordingly, it can serve as an antioxidant, reducing oxidative stress via its unique iron chelation, free radical sacrificing, and synergy with iron reflux prevention originating from Lf. Thus, it can significantly reduce brain inflammation and improve the behavioral performance of PD mice. Additionally, CPL can image the PD via its red fluorescence. Finally, this platform can be metabolized out of the brain through cerebrospinal fluid circulation without causing obvious side effects, promising a robust treatment for PD.

Screening of efficient salicylaldoxime reactivators for DFP and paraoxon-inhibited acetylcholinesterase.

Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.

Spiro-Josiphos Ligands for the Ir-Catalyzed Asymmetric Synthesis of Chiral Amines under Hydrogenation Conditions.

Transition metal-catalyzed asymmetric hydrogenation possesses unparalleled advantages to prepare chiral amines. Here we reported a novel ligand that combined Josiphos and a spirobiindane scaffold and simultaneously investigated its application in Ir-catalyzed asymmetric hydrogenation for the synthesis of chiral amines. Excellent catalytic activity (5000 TON), high enantioselectivity (up to 99% ee), and broad substrate scope (different C═N substrates) make it highly promising for both academic research and industrial applications.

Highly Enantioselective Ir-Catalyzed Hydrogenation of Pyrazolo[1,5-a]pyrimidine for the Synthesis of Zanubrutinib.

A highly enantioselective catalytic reduction of pyrazolo[1,5-a]pyrimidine to zanubrutinib has been realized by the Ir/(R)-t-Bu-FcPhox complex. This chiral product could be obtained in up to >99% ee in the asymmetric transformation without any other additives, providing a new route for the asymmetric synthesis of zanubrutinib.

Naotaifang III Protects Against Cerebral Ischemia Injury Through LPS/TLR4 Signaling Pathway in the Microbiota-Gut-Brain Axis.

Background: Ischemic stroke (IS) is a leading cause of mortality worldwide. Naotaifang III is a new Chinese herbal formula to treat IS. Previous studies have shown that Astragali Radix, Puerariae Lobatae Radix, Chuanxiong Rhizoma, and Rhei Radix Et Rhizoma in Naotaifang III were able to regulate the imbalance of intestinal microbiota during cerebral ischemia injury. Methods: Rats were randomly divided into sham operation group, normal control group, middle cerebral artery occlusion (MCAO) group, intestinal microbiota imbalance MCAO group, Naotaifang III group, and normal bacteria transplantation group, with 15 rats in each group. Then, neurological function scores and cerebral infarction volume were detected; haematoxylin and eosin staining and Golgi silver staining were used to observe morphological changes in brain tissue. Meanwhile, the lipopolysaccharide (LPS) and cerebral cortex interleukin (IL)-1ß were detected by enzyme-linked immunosorbent assay (ELISA); the expressions of Toll-like receptor (TLR)-4 and nuclear factor kappa-B (NF-κB) proteins were detected by immunofluorescence and Western blot. The cecal flora was detected by 16S rDNA. The results showed that gut dysbiosis aggravated cerebral ischemic injury and significantly increased the expression of LPS, TLR4, NF-κB, and IL-1ß, which could be significantly reversed by Naotaifang III or normal bacterial transplantation. Naotaifang III may exert a protective effect on neuroinflammatory injury after MCAO through the LPS/TLR4 signaling pathway in the microbe-gut-brain axis. In summary, Naotaifang III may induce anti-neuroinflammatory molecular mechanisms and signaling pathways through the microbe-gut-brain axis. Results: The results showed that gut dysbiosis aggravated cerebral ischemic injury and significantly increased the expression of LPS, TLR4, NF-κB, and IL-1ß, which could be significantly reversed by Naotaifang III or normal bacterial transplantation. Naotaifang III may exert a protective effect on neuroinflammatory injury after MCAO through the LPS/TLR4 signaling pathway in the microbe-gut-brain axis. Conclusion: Naotaifang III may induce anti-neuroinflammatory molecular mechanisms and signaling pathways through the microbe-gut-brain axis.

The Interplay between Mitochondrial Dysfunction and Ferroptosis during Ischemia-Associated Central Nervous System Diseases.

Cerebral ischemia, a leading cause of disability and mortality worldwide, triggers a cascade of molecular and cellular pathologies linked to several central nervous system (CNS) disorders. These disorders primarily encompass ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and other CNS conditions. Despite substantial progress in understanding and treating the underlying pathological processes in various neurological diseases, there is still a notable absence of effective therapeutic approaches aimed specifically at mitigating the damage caused by these illnesses. Remarkably, ischemia causes severe damage to cells in ischemia-associated CNS diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including mitochondrial permeability transition pore (MPTP) opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of ischemia-associated CNS diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in cerebral ischemia have not yet been clarified. Thus, we analyzed the underlying mechanism between mitochondrial dysfunction and ferroptosis in ischemia-associated CNS diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of ROS and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of ischemia-associated CNS diseases.

The mechanism of intestinal microbiota regulating immunity and inflammation in ischemic stroke and the role of natural botanical active ingredients in regulating intestinal microbiota: A review.

Intestinal microbiota is a unique ecosystem, known as the "second genome" of human beings. With the widespread application of next generation sequencing (NGS), especially 16 S rRNA and shotgun sequencing, numerous studies have shown that dysregulation of intestinal microbiota is associated with many central nervous system diseases. Ischemic stroke (IS) is a cerebrovascular disease with high morbidity and mortality. Brain damage in IS affects intestinal function, and intestinal dysfunction further aggravates brain damage, forming a vicious circle of mutual interference in pathology. The microbiota-gut-brain axis study based on the intestinal microbiota has opened up broader ideas for exploring its pathogenesis and risk factors, and also provided more possibilities for the selection of therapeutic targets for this type of drug. This review discussed the application of NGS technology in the study of intestinal microbiota and the research progress of microbiota-gut-brain axis in recent years, and systematically sorts out the literature on the relationship between ischemic stroke and intestinal microbiota. It starts with the characteristics of microbiota-gut-brain axis' bidirectional regulation, respectively discusses the high risk factors of IS under intestinal microbiota imbalance and the physiological and pathological changes of intestinal microbiota after IS, and summarizes the related targets, in order to provide reliable reference for the treatment of IS from intestinal microbiota. In addition, natural botanical active ingredients have achieved good results in the treatment of IS based on regulating the homeostasis of gut microbiota, providing new evidence for studying the potential targets and therapies of IS based on the microbiota-gut-brain axis.

Sensitive CTC analysis and dual-mode MRI/FL diagnosis based on a magnetic core-shell aptasensor.

Synergizing the sensitive circulating tumor cell (CTC) capture, detection, release and the specific magnetic resonance/fluorescence (MR/FL) imaging for accurate cancer diagnosis is of great importance for cancer treatment. Herein, EcoR1-responsive complementary pairing of two ssDNA with a fluorescent P0 aptamer, which can specifically bind with the overexpressed MUC1 protein on cancer cells, was covalently modified to SiO2@C-coated magnetic nanoparticles for preparing a special nanoparticle-mediated FL turn-on aptasensor (FSC-D-P0). This aptasensor can selectively capture/enrich CTC and thus achieve sensitive CTC detection/imaging in even the blood due to its stable targeting, unique magnetic properties and the regulated interactions between the quencher and the fluorescent groups. Meanwhile, FSC-D-P0 can release the captured CTC for further downstream analysis upon the EcoR1 enzyme-triggered cleavage of the double-stranded DNA (dsDNA). Most importantly, this aptasensor can distinctly avoid false positivity of MRI via multiple targeting mechanisms. Thus, the sensitive CTC capture, detection, release and accurate MR/FL imaging were synergistically combined into a single platform with good biocompatibility, promising a robust pattern for clinical tumor diagnosis in vitro and in vivo.

A Space-Time Conversion Vehicle for Programmed Multi-Drugs Delivery into Pancreatic Tumor to Overcome Matrix and Reflux Barriers.

The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.

Facile access to chiral chromanone-2-carboxylic acids enabled by rhodium-catalyzed chemo- and enantioselective hydrogenation.

Rh-catalyzed highly chemo- and enantioselective hydrogenation of chromone-2-carboxylic acids was successfully established for the first time, providing a wide range of enantiopure chromanone-2-carboxylic acids with excellent results (up to 97% yield and 99% ee) and high efficiency (up to 10 000 TON). The carboxylic group in the substrate was demonstrated to play a vital role and an enantio-induction mode was elucidated by DFT calculation. This hydrogenation protocol provided straightforward access to various bioactive chromanoids.

Discovery of Novel Non-Oxime Reactivators Showing In Vivo Antidotal Efficiency for Sarin Poisoned Mice.

A family of novel efficient non-oxime compounds exhibited promising reactivation efficacy for VX and sarin inhibited human acetylcholinesterase was discovered. It was found that aromatic groups coupled to Mannich phenols and the introduction of imidazole to the ortho position of phenols would dramatically enhance reactivation efficiency. Moreover, the in vivo experiment was conducted, and the results demonstrated that Mannich phenol L10R1 (30 mg/kg, ip) could afford 100% 48 h survival for mice of 2*LD50 sarin exposure, which is promising for the development of non-oxime reactivators with central efficiency.

Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor.

Exploiting zeolitic imidazolate framework (ZIF)-based nanoparticles to synergistically enhance starvation-combined chemotherapy strategies remains an urgent demand. Herein, glucose oxidase (GOX) and doxorubicin (DOX) were facilely incorporated into ZIFs for starvation-combined chemotherapy. The as-prepared DOX/GOX-loaded ZIF (DGZ) exhibited uniform size with good dispersity, effective protection of the GOX activity, and stable delivery of the drugs into tumor. Correspondingly, it could achieve the glucose- and pH-responsive degradation and thus the controllable drug release. As a result, the acidification of glucose accompanied with reactive oxygen species (ROS) production was observed for the starvation-enhanced chemotherapy and the improved degradation. Most importantly, adjustable Zn2+ release was achieved with the biodegradation of DGZ, which thus contributed to an augmented therapeutic outcome via the Zn2+-induced mitochondrial dysfunction and antioxidation dyshomeostasis. These findings, synergized with the enhancement of starvation-combined chemotherapy by inhibiting the mitochondrial energy metabolism and boosting the ROS accumulation using pristine ZIF-based nanoparticles, provide a new insight into the metal-organic framework-based nanomedicine for further cancer treatments.

Tumor-derived Exosome Promotes Metastasis via Altering its Phenotype and Inclusions.

Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.

Molecular modeling-guided optimization of acetylcholinesterase reactivators: A proof for reactivation of covalently inhibited targets.

Covalent drugs have been intensively studied in some very important fields such as anti-tumor and anti-virus, including the currently global-spread SARS-CoV-2. However, these drugs may interact with a variety of biological macromolecules and cause serious toxicology, so how to reactivate the inhibited targets seems to be imperative in the near future. Organophosphate was an extreme example, which could form a covalent bound easily with acetylcholinesterase and irreversibly inhibited the enzyme, causing high toxicology. Some nucleophilic oxime reactivators for organophosphate poisoned acetylcholinesterase had been developed, but the reactivation process was still less understanding. Herein, we proposed there should be a pre-reactivated pose during the reactivating process and compounds whose binding pose was easy to transfer to the pre-reactivated pose might be efficient reactivators. Then we refined the previous reactivators based on the molecular dynamic simulation results, the resulting compounds L7R3 and L7R5 were proven as much more efficient reactivators for organophosphate inhibited acetylcholinesterase than currently used oximes. This work might provide some insights for constructing reactivators of covalently inhibited targets by using computational methods.

Iridium-Catalyzed Asymmetric Hydrogenation of Sterically Hindered Cyclic Imines for Enantioselective Synthesis of Tetrahydroisoquinolines.

An efficient enantioselective hydrogenation of sterically hindered cyclic imines catalyzed by the Ir-tBu-ax-Josiphos complex has been described, producing a series of useful chiral bulky tetrahydroisoquinoline analogs in high isolated yields (85-96%) with good to excellent enantioselectivities (74-99% ee). This transformation provided highly straightforward access to the useful derivatives of tetrahydroisoquinolines, which are of great potential value in drug molecule and natural product research.

Highly Chemo- and Enantioselective Hydrogenation of 2-Substituted-4-oxo-2-alkenoic Acids.

The highly chemo- and enantioselective hydrogenation of (E)-2-substituted-4-oxo-2-alkenoic acids was established for the first time using the Rh/JosiPhos complex, affording a series of chiral α-substituted-γ-keto acids with excellent results (up to 99% yield and >99% ee) and high efficiency (up to 3000 TON). In addition, the importance of this methodology was further demonstrated by a concise and gram-scale synthesis of the anti-inflammatory drug (R)-flobufen.

Publisher Correction: Eliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Concise asymmetric synthesis of two natural oxacyclododecindione-type macrolactones from industrial waste.

(S)-5-Methyl-tetrahydropyran-2-one 1 is a by-product in the production of key intermediates of steroidal hormones. Asymmetric synthesis of natural oxacyclododecindione-type macrolactones 2 and 3 has been realized for the first time from (S)-1 in seven and eight steps with 37% and 27% overall yield, respectively.

Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer.

Engineered exosomes have become popular drug delivery carriers for cancer treatment. This is partially due to the interesting property, i.e. exosome organotropism, which plays an important role in organ distribution post systemic administration. Here, we demonstrated that breast cancer (MDA-MB-231) cell-derived exosomes (231-Exo) could be specifically internalized by non-small cell lung cancer cells via a specific interaction between overexpressed integrin ß4 (on exosomes) and surfactant protein C (SPC) on the cancer cells. We showed that 231-Exo was capable of recognizing A549 cells in blood and effectively escaping from the immune surveillance system in vitro. Once loaded with microRNA molecules in the exosome carriers, the resulting, miRNA-126 loaded 231-Exo (miRNA-231-Exo) strongly suppressed A549 lung cancer cell proliferation and migration through the interruption of the PTEN/PI3K/AKT signaling pathway. Intravenous administration of the miRNA-126 laden exosomes led to an effective lung homing effect in mice. When tested in a lung metastasis model, miRNA-231-Exo resulted in an efficacious effect in inhibiting the formulation of lung metastasis in vivo. Collectively, our data demonstrated the possibility of using the organotropism feature of exosomes in exosome carrier design, generating a potent anti-metastasis effect in a mouse model.

Eliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles.

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi's sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.