Hydrogen Sulfide Exerted a Pro-Angiogenic Role by Promoting the Phosphorylation of VEGFR2 at Tyr797 and Ser799 Sites in Hypoxia-Reoxygenation Injury.

The protective effects of hydrogen sulfide (H2S) against ischemic brain injury and its role in promoting angiogenesis have been established. However, the specific mechanism underlying these effects remains unclear. This study is designed to investigate the regulatory impact and mechanism of H2S on VEGFR2 phosphorylation. Following expression and purification, the recombinant His-VEGFR2 protein was subjected to LC-PRM/MS analysis to identify the phosphorylation sites of VEGFR2 upon NaHS treatment. Adenovirus infection was used to transfect primary rat brain artery endothelial cells (BAECs) with the Ad-VEGFR2WT, Ad-VEGFR2Y797F, and Ad-VEGFR2S799A plasmids. The expression of VEGFR2 and recombinant Flag-VEGFR2, along with Akt phosphorylation, cell proliferation, and LDH levels, was assessed. The migratory capacity and tube-forming potential of BAECs were assessed using wound healing, transwell, and tube formation assays. NaHS notably enhanced the phosphorylation of VEGFR2 at Tyr797 and Ser799 sites. These phosphorylation sites were identified as crucial for mediating the protective effects of NaHS against hypoxia-reoxygenation (H/R) injury. NaHS significantly enhanced the Akt phosphorylation, migratory capacity, and tube formation of BAECs and upregulated the expression of VEGFR2 and recombinant proteins. These findings suggest that Tyr797 and Ser799 sites of VEGFR2 serve as crucial mediators of H2S-induced pro-angiogenic effects and protection against H/R injury.

The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse.

PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.

Extraction of high inverted mesiodentes via the labial, palatal and subperiostal intranasal approach：A clinical prospective study.

The aim of this study is to provide criteria for the choice of the surgical approach for extraction of high inverted mesiodens. The operation statistics, life quality of postoperative patients, and the operative injury/recovery were compared and analysed. The laser Doppler blood flowmetry, laser speckle contrast imaging, and electric pulp testing were explored to detect the postoperative pulp and gingiva blood supply of adjacent teeth. For the clinician's primary concerns, the surgical time, the volume of osteotomy, and the amount of bleeding in the labial approach group (The p values are 0.0001, <0.0001, and 0.0131, respectively.) and intranasal approach group (All p values were <0.0001.) were significantly less than that in the palatal approach group. However, from the patient's perspective, the postoperative swelling in the labial approach was far more than that in the intranasal approach group (p =0.0044), with unsurprisingly lower satisfaction (p <0.0001). There were no significant differences in pulp and gingival blood supply of adjacent teeth and jaw development. Trauma was manageable in all patients. Within the limitations of the study it seems that extraction of mesiodens by the intranasal approach achieves a delicate balance between reducing surgical trauma and optimizing postoperative recovery.

Effects of modified triangular flap for third molar extraction on distal periodontal health of second molar: A randomized controlled study.

Objective: The aim of this study was to assess the effect of flap design for impacted mandibular third molar extraction on the distal periodontal tissue of their neighbors clinically, immunologically, and microbiologically. Study design: This randomized controlled study comprised 100 patients who were allocated randomly to receive either a triangular flap or a modified triangular flap. The distal periodontal pocket depth, plaque index, bleeding on probing, the presence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia, and the level of interleukin-1ß, interleukin-8 and matrix metalloproteinase-8 of adjacent second molars were measured at baseline, and 1, 4 and 8 weeks after surgery. Results: After 1 and 4 weeks, distal periodontal conditions of adjacent second molars deteriorated, along with an increase in subgingival microbiota and inflammatory factors in both groups. And compared to the modified triangular flap group, the triangular flap group significantly increased (p < 0.05). Prevotella intermedia, interleukin-1ß and probing depth were positively correlated in both groups. After 8 weeks, they returned to the preoperative level. Conclusions: In this study, both flap designs for impacted mandibular third molar extractions was associated with worse clinical periodontal indices, increased inflammatory biomarkers of gingival crevicular fluid, and more subgingival pathogenic microbiota within 4 weeks. But compared with the triangular flap, the modified triangular flap was better for distal periodontal health of adjacent second molars, which provides certain directions for clinical treatment.

Design and Evaluation of Paeonol-Loaded Liposomes in Thermoreversible Gels for Atopic Dermatitis.

Paeonol (PAE) is a hydrophobic drug. In this study, we encapsulated paeonol in a lipid bilayer of liposomes (PAE-L), which delayed drug release and increased drug solubility. When PAE-L was dispersed in gels (PAE-L-G) based on a poloxamer matrix material for local transdermal delivery, we observed amphiphilicity, reversible thermal responsiveness, and micellar self-assembly behavior. These gels can be used for atopic dermatitis (AD), an inflammatory skin disease, to change the surface temperature of the skin. In this study, we prepared PAE-L-G at an appropriate temperature for the treatment of AD. We then assessed the gel's relevant physicochemical properties, in vitro cumulative drug release, and antioxidant properties. We found that PAE-loaded liposomes could be designed to increase the drug effect of thermoreversible gels. At 32 °C, PAE-L-G could change from solution state to gelatinous state at 31.70 ± 0.42 s, while the viscosity was 136.98 ± 0.78 MPa.S and the free radical scavenging rates on DPPH and H2O2 were 92.24 ± 5.57% and 92.12 ± 2.71%, respectively. Drug release across the extracorporeal dialysis membrane reached 41.76 ± 3.78%. In AD-like mice, PAE-L-G could also relieve skin damage by the 12th day. In summary, PAE-L-G could play an antioxidant role and relieve inflammation caused by oxidative stress in AD.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

The novel delivery-exosome application for diagnosis and treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic degenerative disease characterized by persistent systemic synovitis, with a high risk of stiffness, pain, and swelling. It may affect the other extra-articular tissues. There is no ideal treatment for this disease at present, and it can only be controlled by medication to alleviate the prognosis. Exosomes are small vesicles secreted by various cells in the organism under normal or pathological conditions, and play a role in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and so on. Due to the adverse effects of conventional drugs and treatments in the treatment of RA, exosomes, as a nanocarrier with many advantages, can have a great impact on the loading of drugs for the treatment of RA. This article reviews the role of exosomes in the pathogenesis of RA and the progress of exosome-based therapy for RA.

Cu-catalysed enantioselective radical heteroatomic S-O cross-coupling.

The transition-metal-catalysed cross-coupling reaction has established itself as one of the most reliable and practical synthetic tools for the efficient construction of carbon-carbon/heteroatom (p-block elements other than carbon) bonds in both racemic and enantioselective manners. In contrast, development of the corresponding heteroatom-heteroatom cross-couplings has so far remained elusive, probably due to the under-investigated and often challenging heteroatom-heteroatom reductive elimination. Here we demonstrate the use of single-electron reductive elimination as a strategy for developing enantioselective S-O coupling under Cu catalysis, based on both experimental and theoretical results. The reaction manifests its synthetic potential by the ready preparation of challenging chiral alcohols featuring congested stereocentres, the expedient valorization of the biomass-derived feedstock glycerol, and the remarkable catalytic 4,6-desymmetrization of inositol. These results demonstrate the potential of enantioselective radical heteroatomic cross-coupling as a general chiral heteroatom-heteroatom formation strategy.

The Effect of Arthroscopic Extra-Articular Entire Coracohumeral Ligament Release for Patients with Recalcitrant Frozen Shoulder.

OBJECTIVE: The thickened coracohumeral ligament (CHL) is an important part of the typical manifestations and magnetic resonance imaging of frozen shoulder. However, only a few clinical studies with limited cases on arthroscopic extra-articular entire CHL release exist in the literature. This study was to evaluate the effect of arthroscopic extra-articular entire CHL release for patients with recalcitrant frozen shoulder. METHODS: From February 2014 to February 2020, 81 cases of recalcitrant frozen shoulder patients treated with surgery in a single-center shoulder department and followed for more than 2 years were analyzed. Arthroscopic 360° capsular release was performed with intra-articular partial release (IPR group) or additional extra-articular entire release (IPR + EER group) of CHL. The same rehabilitation program was performed after surgery in both groups. Visual analogue scale (VAS) for pain, range of motion (ROM), and the Constant-Murley scoring system was evaluated before operation, at 3 months after operation, 6 months after operation, and the final follow-up. T-test, Mann-Whitney U-test and chi-squared test were used to compared data. RESULTS: There were 39 patients in the IPR group, with an average follow-up of 29.2 months. A total of Forty-two patients in the IPR + EER group completed a mean follow-up of 25.7 months. All incisions healed in stages. There were significant differences in Constant-Murley shoulder score, VAS score, and ROM before operation and at the final follow-up in both groups (both P < 0.001). The VAS score of the IPR + EER group was lower than that of the IPR group at 3 months after surgery (P < 0.05), and 6 months after operation (P < 0.05). External rotation, internal rotation, and abduction of ROMs and Constant-Murley shoulder score were significantly greater in the IPR + EER group at 3 months (P < 0.001, P < 0.05, P < 0.001, P < 0.05, respectively) and 6 months after operation (P < 0.001, P < 0.05, P < 0.001, P < 0.05, respectively). At the last follow-up, there was no significant difference in forward flexion, internal rotation, and abduction of ROMs, VAS, and the Constant-Murley shoulder score between the IPR and IPR + EER groups. The external rotation of the IPR + EER group was still greater than that of the IPR group at the last follow-up (P < 0.001). CONCLUSION: Arthroscopic extra-articular entire coracohumeral ligament release could solve early pain of shoulder joint, recover shoulder joint functions effectively, and achieve a satisfactory efficacy in the treatment of recalcitrant frozen shoulder.

Percutaneous Electroosmosis of Berberine-Loaded Ca2+ Crosslinked Gelatin/Alginate Mixed Hydrogel.

Flexible conductive hydrogel has been driven by scientific breakthroughs and offers a wide variety of applications, including sensors, electronic skins, biomedicine, energy storage, etc. Based on the mixed-ion crosslinking method, gelatin and sodium alginate (Gel-Alg) composite hydrogels were successfully prepared using Ca2+ crosslinking. The migration behavior of berberine hydrochloride (BBH) in the matrix network structure of Gel-Alg hydrogel with a certain pore size under an electric field was studied, and the transdermal effect of berberine hydrochloride under an electric field was also studied. The experimental results show that Gel-Alg has good flexibility and conductivity, and electrical stimulation can enhance the transdermal effect of drugs. Gel-Alg composite hydrogel may be a new material with potential application value in future biomedical directions.

Ligustrazine as an Extract from Medicinal and Edible Plant Chuanxiong Encapsulated in Liposome-Hydrogel Exerting Antioxidant Effect on Preventing Skin Photoaging.

Long-term sunlight exposure will cause the accumulation of free radicals in the skin and lead to oxidative damage and aging, antioxidant drugs have gradually become the focus of research, but there is little research on antioxidant drugs for percutaneous treatment. The purpose of this study was to prepare ligustrazine hydrochloride (TMPZ)-loaded liposome-hydrogel (TMPZ-LG), evaluate its antioxidant properties, and apply it on the skin of mice to observe whether it had preventive and therapeutic effect on the irradiation under the ultraviolet rays, in an attempt to make it into a new kind of delivery through the skin. TMPZ-LG was prepared by the combination of film dispersion and sodium carboxymethylcellulose (2%, CMC-Na) natural swelling method. The release rates in vitro permeation across the dialysis membrane and ex vivo transdermal had both reached 40%; the scavenging effect of TMPZ-LG on 1,1-diphenyl-2-picrylhydrazyl (DPPH) and H2O2 were 65.57 ± 4.13% and 73.06 ± 5.65%; the inhibition rate of TMPZ-LG on malondialdehyde (MDA) production in liver homogenate and anti-low density lipoprotein (LDL) oxidation experiments ex vivo were 15.03 ± 0.9% and 21.57 ± 1.2%. Compared with untreated mice, the skin pathological symptoms of mice coated with TMPZ-LG were significantly reduced after ultraviolet irradiation, and there was statistical significance. The results showed TMPZ-LG could exert good antioxidant activity in vitro and ex vivo; therefore, it is feasible to prevent and treat skin oxidation.

The Fabrication of Docetaxel-Containing Emulsion for Drug Release Kinetics and Lipid Peroxidation.

Docetaxel (DTX)-based formulation development is still confronted with significant challenges, due to its refractory solubility and side effects on normal tissues. Inspired by the application of the transdermal drug delivery model to topical treatment, we developed a biocompatible and slow-release DTX-containing emulsion via self-assembly prepared by a high-speed electric stirring method and optimized the formulation. The results of accelerated the emulsion stability experiment showed that the emulsion prepared at 10,000 rpm/min had a stability of 89.15 ± 2.05%. The ADME, skin irritation, skin toxicity and molecular interaction between DTX and excipients were predicted via Discovery Studio 2016 software. In addition, DTX addition in oil or water phases of the emulsion showed different release rates in vitro and ex vivo. The DTX release ex vivo of the DTX/O-containing emulsion and the DTX/W-containing emulsion were 45.07 ± 5.41% and 96.48 ± 4.54%, respectively. In vitro antioxidant assays and anti-lipid peroxidation models revealed the antioxidant potential of DTX. However, DTX-containing emulsions could maintain and even enhance the antioxidant effect, both scavenging free radicals in vitro and inhibiting the process of lipid peroxidation.

A humanized 4-1BB-targeting agonistic antibody exerts potent antitumor activity in colorectal cancer without systemic toxicity.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety. METHODS: The antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. RESULTS: HuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity. CONCLUSIONS: This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

In Vitro Evaluation of Kaempferol-Loaded Hydrogel as pH-Sensitive Drug Delivery Systems.

The purpose of this study was to prepare and evaluate kaempferol-loaded carbopol polymer (acrylic acid) hydrogel, investigate its antioxidant activity in vitro, and compare the effects on drug release under different pH conditions. Drug release studies were conducted in three different pH media (pH 3.4, 5.4, and 7.4). The kaempferol-loaded hydrogel was prepared by using carbopol 934 as the hydrogel matrix. The morphology and viscosity of the preparation were tested to understand the fluidity of the hydrogel. The antioxidant activity of the preparation was studied by scavenging hydrogen peroxide and 2,2-diphenyl-1-picrilhidrazil (DPPH) radicals in vitro and inhibiting the production of malondialdehyde in mouse tissues. The results showed that kaempferol and its preparations had high antioxidant activity. In vitro release studies showed that the drug release at pH 3.4, 5.4, and 7.4 was 27.32 ± 3.49%, 70.89 ± 8.91%, and 87.9 ± 10.13%, respectively. Kaempferol-loaded carbopol hydrogel displayed greater swelling and drug release at higher pH values (pH 7.4).

Copper-Catalyzed anti-Selective Radical 1,2-Alkylarylation of Terminal Alkynes.

A copper-catalyzed highly anti-selective radical 1,2-alkylarylation of terminal alkynes with aryl boronic acids and alkyl bromides has been established. The reaction exhibits high compatibility with a wide range of terminal alkynes and diverse aryl boronic acids, thus providing facile access to various stereodefined trisubstituted alkenes in high yield under mild reaction conditions. Preliminary mechanistic investigations support the formation of alkyl radicals and their subsequent addition to alkynes in the reaction.

Study on the controlled release and synergistic anti-oxidant activity in vitro and ex vivo of ligustrazine hydrochloride encapsulated into liposomes.

Ligustrazine with good antioxidant activity is one of the main active components of chuanxiong. We designed ligustrazine hydrochloride-loaded liposomes (LTH-L) by the thin film dispersion method. The particle size and zeta potential of liposomes was 118±10.61nm and -39.3±3.7mV, entrapment efficiency (EE%) was 75.05±10.67%. In vitro permeation across the dialysis membrane, the release rate (R%) of ligustrazine hydrochloride (LTH) and LTH-L were reached 80% and 60%. Ex Vivo transdermal behavior experiment showed the R% of LTH and LTH-L were between 30%-40%, the R% of LTH-L was slightly lower, because liposomes played the role on the sustained and controlled release of LTH. In addition, LTH, LTH-L and BL reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH) solution for two hours, the scavenge rates (SR%) were 55.06±2.73%, 11.3±0.03% and 37.25±1.12% respectively (P<0.001) and the SR% of LTH, LTH-L and BL reacted with H2O2 were 4.13±0.02%, 0.52±0.01% and 75.15±6.10%. The inhibit rate (IR%) of LTH, LTH-L and BL on malondialdehyde (MDA) in liver homogenate were 35.44±1.79%, 1.22±0.01% and 17.92±0.29% (P<0.001), the IR% were 30.82±0.93%, 1.7±0.01% and 25.19±0.60% (P<0.001) in anti-low density lipoprotein (LDL) oxidation experiments, perhaps LTH prepared into LTH-L can play a better antioxidant role.

Evaluation method on seismic risk of substation in strong earthquake area.

Frequent earthquakes in strong earthquake areas pose a great threat to the safety operation of electric power facilities. There exists a pressing research need to develop an assessment method for the seismic risk of substations, i.e., the hubs of power system networks. In this study, based on Incremental Dynamic Analysis (IDA), Probabilistic Seismic Demand Model (PSDM) and reliability theory, a vulnerability model for a substation is obtained, based on considering the relationships between Peak Ground Acceleration (PGA) and four seismic damage states (complete, extensive, moderate, and slight.) via a probabilistic approach. After an earthquake, the scope of influence and PGA distribution are evaluated using information recorded by the seismic observation stations, based on using interpolation or an empirical formula for the PGA attenuation. Therefore, the seismic risk can be evaluated by combining ground motion evaluation and the pre-built vulnerability model. The Wuqia- Kashgar area of Xinjiang was selected as the study area; it is an Earthquake-prone area, and one of the starting points for new energy transmission projects in China. Under a hypothetical earthquake (MS 7.9), the seismic risk of the substations was evaluated. The results show that: this method is able to give the probabilities of the four damage states of the substations, four substations close to the epicenter only have a probability of slight damage (45%-88%) and other substations are safer.

Effects of Impacted Lower Third Molar Extraction on Periodontal Tissue of the Adjacent Second Molar.

The extraction of impacted lower third molars (ILTM) is one of the most common procedures in oral-maxillofacial surgery. Being adjacent to lower second molars, most impacted lower third molars often lead to distal periodontal defects of adjacent second molars. Several symptoms may occur after extraction, such as periodontal pocket formation, loss of attachment, alveolar bone loss and even looseness of second molar resulting in extraction. The distal periodontal defects of second molars are affected by many factors, including periodontal conditions, age, impacted type of third molars, and intraoperative operations. At present, several studies have suggested that dentists can reduce the risk of periodontal defects of the second molar after ILTM extraction through preoperative evaluation, reasonable selection of flap design, extraction instruments and suture type, and necessary postoperative interventions. This review summarizes the research progress on the influence factors, interventions methods and some limitations of distal periodontal defects of adjacent second molar after extraction of impacted mandibular third molars, with the aim of opening up future directions for studying effects of ILTM extraction on periodontal tissue of the adjacent second molar.

Investigation on the Preparation, Characteristics, and Controlled Release Model of Paeonol-Loaded Liposome in Carbomer Hydrogel.

OBJECTIVE: Paeonol is a phenolic compounce that is volatile. In order to decrease its volatility and achieve controlled release, paeonol-loaded liposome in carbomer hydrogel was prepared by coating with soybean phospholipid via ethanol injection method and then added into the carbomer hydrogel. METHODS: The quality of paeonol-loaded liposome in carbomer hydrogel was evaluated by the degree of roundness, particle size distribution, zeta potential, entrapment efficiency (filtration method and chitosan neutralization method), viscosity, infrared spectrum, etc. Furthermore, the diffusion from paeonolloaded liposome in hydrogel was studied in vitro. RESULTS: The results showed that the average particle size of paeonol-loaded liposome was about 401 nm, the potential was -17.8 mV, and the entrapment efficiency was above 45%. The viscosity of paeonol- loaded liposome in hydrogel was 23.972×10-3 Pa*s, and the diffusion rate from paeonol-loaded liposome in hydrogel in vitro was obviously slower than that from the other paeonol preparations. CONCLUSION: The conclusions could be drawn that paeonol-loaded liposome in hydrogel was a kind of novel preparation, and its diffusion in vitro had obvious controlled-release characteristics, which further proved that it might improve the bioavailability of paeonol.

Desymmetrization of unactivated bis-alkenes via chiral Brønsted acid-catalysed hydroamination.

Although great success has been achieved in catalytic asymmetric hydroamination of unactivated alkenes using transition metal catalysis and organocatalysis, the development of catalytic desymmetrising hydroamination of such alkenes remains a tough challenge in terms of attaining a high level of stereocontrol over both remote sites and reaction centers at the same time. To address this problem, here we report a highly efficient and practical desymmetrising hydroamination of unactivated alkenes catalysed by chiral Brønsted acids with both high diastereoselectivity and enantioselectivity. This method features a remarkably broad alkene scope, ranging from mono-substituted and gem-/1,2-disubstituted to the challenging tri- and tetra-substituted alkenes, to provide access to a variety of diversely functionalized chiral pyrrolidines bearing two congested tertiary or quaternary stereocenters with excellent efficiency under mild and user-friendly synthetic conditions. The key to success is indirect activation of unactivated alkenes by chiral Brønsted acids via a concerted hydroamination mechanism.