Enhanced oral and pulmonary delivery of biomacromolecules via amplified transporter targeting.

Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptake→intracellular transport→basolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.

Lipoic acid-mediated oral drug delivery system utilizing changes on cell surface thiol expression for the treatment of diabetes and inflammatory diseases.

Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.

Determination of Maximum Tolerable Cold Ischemia Time in a Mouse Model of Cervical Heterotopic Uterus Transplantation.

BACKGROUND: Uterus transplantation (UTx) is an emerging treatment for uterine factor infertility. Determining the maximum tolerable cold ischemia time is crucial for successful UTx. However, the limit for cold ischemia in the uterus is unclear. This study aimed to examine cold ischemia's effects on mouse uteri and identify the maximum cold ischemia duration that uteri can endure. METHODS: We systematically assessed the tolerance of mouse uteri to extended cold ischemia, 24 h, 36 h, and 48 h, using the cervical heterotopic UTx model. Multiple indicators were used to evaluate ischemia-reperfusion injury, including reperfusion duration, macroscopic examination, oxidative stress, inflammation, and histopathology. The function of transplants was evaluated through estrous cycle monitoring and embryo transfer. RESULTS: Mouse uteri subjected to 48 h of cold ischemia exhibited significant delays and insufficiencies in reperfusion, substantial tissue necrosis, and loss of the estrous cycle. Conversely, uteri that underwent cold ischemia within 36 h showed long survival, regular estrous cycles, and fertility. CONCLUSIONS: Our study demonstrated that mouse uteri can endure at least 36 h of cold ischemia, extending the known limits for cold ischemia and providing a pivotal reference for research on the prevention and treatment of cold ischemic injury in UTx.

Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and accounts for more than 90% of primary liver cancer. The advent of immune checkpoint inhibitor (ICI)-related therapies combined with angiogenesis inhibition has revolutionized the treatment of HCC in late-stage and unresectable HCC, as ICIs alone were disappointing in treating HCC. In addition to the altered immune microenvironment, abnormal lipid metabolism in the liver has been extensively characterized in various types of HCC. Stains are known for their cholesterol-lowering properties and their long history of treating hypercholesterolemia and reducing cardiovascular disease risk. Apart from ICI and other conventional therapies, statins are frequently used by advanced HCC patients with dyslipidemia, which is often marked by the abnormal accumulation of cholesterol and fatty acids in the liver. Supported by a body of preclinical and clinical studies, statins may unexpectedly enhance the efficacy of ICI therapy in HCC patients through the regulation of inflammatory responses and the immune microenvironment. This review discusses the abnormal changes in lipid metabolism in HCC, summarizes the clinical evidence and benefits of stain use in HCC, and prospects the possible mechanistic actions of statins in transforming the immune microenvironment in HCC when combined with immunotherapies. Consequently, the use of statin therapy may emerge as a novel and valuable adjuvant for immunotherapies in HCC.

QTL-seq analysis identified the genomic regions of plant height and days to heading in high-latitude rice.

Introduction: Rice (Oryza sativa L.) is one of the most extensive crops in the world. China's Heilongjiang Province is the northernmost rice-growing region in the world. However, rice cultivars suitable for growth in low-latitude regions may not mature normally due to their distinct climate and short frost-free period. It is necessary to precisely determine the frost-free period for each region to make the best use of the rice growth stage so as to ensure the maturity and yield of different rice cultivars in Heilongjiang Province. The time span of the heading stage is a key parameter for evaluating the adaptability of a rice cultivar to a specific rice-growing region. Given the above facts, it is of high importance to study the associated genes and sites controlling days to heading (DH) and plant height (PH) of rice in Heilongjiang Province. Bulked segregant analysis (BSA) combined with high-throughput sequencing can effectively exclude interferences from background genomic differences, making it suitable for analyzing the associated sites of complex agronomic traits in early generations. Methods: In this study, an F3 segregating population was obtained by crossing two main cultivars that are grown under different temperatures and day-light conditions in Heilongjiang. Two pools of extreme phenotypes were built for the DH and PH of the population. For SNP and InDel variants obtained from whole-genome resequencing in the pools, an association analysis was performed using the Euclidean distance (ED) algorithm and the SNP/InDel index algorithm. Results: The intersection of SNP and InDel regions associated with the phenotypes was considered to obtain the final associated sites. After excluding interferences from the cloned genes on chromosomes 2 and 7, a total length of 6.34 Mb on chromosomes 1, 3, and 10 and 3.16 Mb on chromosomes 1 and 10 were left associated with PH and DH, respectively. Then, we performed a gene annotation analysis for candidate genes in the remaining regions using multiple genome annotation databases. Our research provides basic data for subsequent gene mapping and cloning. Discussion: By mining more genetic loci associated with the days to heading and plant height of rice, we may provide abundant genetic resources for refined molecular breeding in Heilongjiang Province.

Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs.

Exosomes, as promising vehicles, have been widely used in the research of oral drug delivery, but the generally low drug loading efficiency of exosomes seriously limits its application and transformation. In this study, we systematically investigated the effects of drug loading methods and physicochemical properties (lipophilicity and molecular weight) on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions. Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method, drug lipophilicity, drug molecular weight and exosome/drug proportions. Of note, we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes, which was attributed to the efficient loading capacity and sustained release behavior. Furthermore, milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs (octreotide, exendin-4 and salmon calcitonin). Collectively, our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

Effect of azithromycin combined with ambroxol in children with Mycoplasma pneumoniae pneumonia.

OBJECTIVE: This study was designed to investigate the clinical efficacy of azithromycin combined with ambroxol in children with Mycoplasma pneumoniae pneumonia (MPP). METHODS: The clinical data of 103 children with MPP treated in Fuyang District Hospital of Traditional Chinese Medicine of Hangzhou from December 2020 to August 2021 were selected and retrospectively analyzed, and these children were divided into a control group (n=51, azithromycin treatment) and a study group (n=52, azithromycin plus ambroxol treatment) according to the different treatment methods. The immunoglobulin level, pulmonary function score, treatment efficacy, serum cytokine level, disappearance time of signs and symptoms, and myocardial enzyme indices were observed and compared between the two groups. Univariate and multivariate analyses were conducted to screen the factors affecting the prognosis of MPP patients. RESULTS: After treatment, the study group showed significantly lower levels of immunoglobulin E, immunoglobulin G, immunoglobulin M and immunoglobulin A; higher pulmonary function scores, and lower levels of interleukin-6, human interferon-gamma, and monocyte chemoattractant protein-4 compared with the control group (all P < 0.05). The total incidence of adverse reactions such as nausea, diarrhea, abdominal pain, and vomiting was 15.38% in the study group, which was slightly lower than that in the control group (17.65%), exhibiting no significant difference (P > 0.05). The disappearance time of cough and lung rales, time required to restore to a normal body temperature, and hospital stay in the study group were shorter than those in the control group (P < 0.05). After treatment, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme in the study group were lower than those in the control group (all P < 0.05). The course of disease before admission, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anemia, albumin < 30 g/L, drug initiation time, pulmonary consolidation, and complications involving multiple systems were the main factors affecting the efficacy of azithromycin combined with ambroxol in the treatment of MPP. CONCLUSION: Azithromycin combined with ambroxol can effectively improve the immunoglobulin level and lung function, reduce the level of inflammatory factors, improve the therapeutic effect, shorten the recovery process, and reduce the degree of myocardial damage, which is effective in the treatment of MPP and is worth promoting.

Merging Alkene Isomerization Enables Difunctionalization of Cyclic Enamines toward Ring-Fused Aminal Synthesis.

Here we report a Pd-catalyzed isomerization of alicyclic allyl amine to achieve the unprecedented α,ß-difunctionalization of synthetically inaccessible trisubstituted cyclic enamine. The dual role of in situ formed enamine intermediate allows for the intermolecular formal [4 + 2] reaction with acrylamide or isatoic anhydride to simultaneously construct the C-C bond and C-N bond, thus realizing the expedient construction of [4.3.0]-aminal with excellent diastereoselectivity and high atom economy.

Catalytic Asymmetric Diarylation of Internal Acyclic Styrenes and Enamides.

Enantioselective transformations of olefins are among the most important strategies for the asymmetric synthesis of organic compounds. Chemo-, diastereo-, and stereoselective control of reactions with internal acyclic alkenes for the construction of functionalized acyclic alkanes still remain a persistent challenge. Here, we report a palladium-catalyzed asymmetric regiodivergent Heck-type diarylation of internal acyclic alkenes. The 1,2-diarylation of two accessible acyclic alkenes, cinnamyl carbamates and enamides with diazonium salts and aromatic boronic acids, furnishes products containing vicinal stereogenic centers via the stereospecific formation of carbonyl coordination-assisted transient palladacycles. Moreover, the asymmetric migratory diarylation of enamides enables the formation of incontiguous stereocenters by an interrupted diastereoselective 1,3-chain-walking process. This protocol streamlines access to highly functionalized multisubstituted enantioenriched carbamates and amine derivatives which are embedded in the key biologically active motifs.

TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling.

Cholinergic and sympathetic counter-regulatory networks control numerous physiological functions, including learning/memory/cognition, stress responsiveness, blood pressure, heart rate, and energy balance. As neurons primarily utilize glucose as their primary metabolic energy source, we generated mice with increased glycolysis in cholinergic neurons by specific deletion of the fructose-2,6-phosphatase protein TIGAR. Steady-state and stable isotope flux analyses demonstrated increased rates of glycolysis, acetyl-CoA production, acetylcholine levels, and density of neuromuscular synaptic junction clusters with enhanced acetylcholine release. The increase in cholinergic signaling reduced blood pressure and heart rate with a remarkable resistance to cold-induced hypothermia. These data directly demonstrate that increased cholinergic signaling through the modulation of glycolysis has several metabolic benefits particularly to increase energy expenditure and heat production upon cold exposure.

The association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility: a systematic review and meta-analysis.

During recent decades, the association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility remains doubtful. We conducted this meta-analysis to evaluate the association between mutations in USP26 and male infertility according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021225251). PubMed, Web of Science, and Scopus were systematically searched for comparative clinical studies, which were written in English and provided eligible data. Studies were included when they compared USP26 mutations in azoospermic, oligozoospermic, and asthenozoospermic patients with controls with normal sperm parameter values or whose partners had experienced spontaneous pregnancy. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated with random effect models. Overall, twelve studies with 3927 infertility patients and 4648 healthy controls were included. The association between overall USP26 mutations and infertility was not significant (OR = 1.60, 95% CI: 0.51-5.01). For specific mutations, the pooled ORs were 1.65 (95% CI: 1.02-2.69) for cluster mutation (including 370-371insACA, 494T>C, and 1423C>T), 1.80 (95% CI: 0.35-9.15) for c.576G>A, 1.43 (95% CI: 0.79-2.56) for c.1090C>T, and 3.59 (95% CI: 2.30-5.59) for c.1737G>A. Our results suggest that several mutations (cluster mutation, c.1737G>A) may play roles in male infertility, while others (c.576G>A and c.1090C>T) do not show notable associations with male infertility. More high-quality clinical researches are needed for validation.

Multi-Task Transformer with Adaptive Cross-Entropy Loss for Multi-Dialect Speech Recognition.

At present, most multi-dialect speech recognition models are based on a hard-parameter-sharing multi-task structure, which makes it difficult to reveal how one task contributes to others. In addition, in order to balance multi-task learning, the weights of the multi-task objective function need to be manually adjusted. This makes multi-task learning very difficult and costly because it requires constantly trying various combinations of weights to determine the optimal task weights. In this paper, we propose a multi-dialect acoustic model that combines soft-parameter-sharing multi-task learning with Transformer, and introduce several auxiliary cross-attentions to enable the auxiliary task (dialect ID recognition) to provide dialect information for the multi-dialect speech recognition task. Furthermore, we use the adaptive cross-entropy loss function as the multi-task objective function, which automatically balances the learning of the multi-task model according to the loss proportion of each task during the training process. Therefore, the optimal weight combination can be found without any manual intervention. Finally, for the two tasks of multi-dialect (including low-resource dialect) speech recognition and dialect ID recognition, the experimental results show that, compared with single-dialect Transformer, single-task multi-dialect Transformer, and multi-task Transformer with hard parameter sharing, our method significantly reduces the average syllable error rate of Tibetan multi-dialect speech recognition and the character error rate of Chinese multi-dialect speech recognition.

Comparative short-term outcomes of robotic-assisted surgery for older patients with non-small cell lung cancer: a propensity matched study.

To investigate comparative short-term outcomes of robotic-assisted surgery (RAS) versus video-assisted thoracoscopic surgery (VATS) for older non-small cell lung cancer (NSCLC) patients. Patients ≥ 65 years old with stage I-III NSCLC operated with RAS or VATS from 2016 to 2018 were consecutively included. Propensity score-matched (PSM) method was implemented to balance inter-group biases. Totally 376 participants (224 with VATS and 152 with RAS) were included. After PSM, a cohort (144 with VATS and 107 with RAS) was generated with balanced baseline characteristics. RAS was significantly superior over VATS in the majority of perioperative outcomes, such as operating time (120.8 vs. 165.1 min), conversion rate (0.0% vs. 19.4%), and length of stay (8.6 vs. 10.8 days). RAS versus VATS was significantly associated with comparable rates of postoperative complications (OR 0.642, 95% CI 0.311-1.327), except the rate of pneumonia (OR 0.161, 95% CI 0.048-0.544). RAS leads to analogous postoperative complications and seemingly accelerates the recovery time of older NSCLC patients compared with VATS.

Stable DNA Aptamer-Metal-Organic Framework as Horseradish Peroxidase Mimic for Ultra-Sensitive Detection of Carcinoembryonic Antigen in Serum.

Carcinoembryonic antigen (CEA) is an important broad-spectrum tumor marker. For CEA detection, a novel type of metal-organic framework (MOF) was prepared by grafting CEA aptamer-incorporated DNA tetrahedral (TDN) nanostructures into PCN-222 (Fe)-based MOF (referred as CEAapt-TDN-MOF colloid nanorods). The synthesized CEAapt-TDN-MOF is a very stable detection system due to the vertex phosphorylated TDN structure at the interface, possessing a one-year shelf-life. Moreover, it exhibits a significant horseradish peroxidase mimicking activity due to the iron porphyrin ring, which leads to a colorimetric reaction upon binding toward antibody-captured CEA. Using this method, we successfully achieved the highly specific and ultra-sensitive detection of CEA with a limit of detection as low as 3.3 pg/mL. In addition, this method can detect and analyze the target proteins in clinical serum samples, effectively identify the difference between normal individuals and patients with colon cancer, and provide a new method for the clinical diagnosis of tumors, demonstrating a great application potential.

Risk factors of conversion in robotic- and video-assisted pulmonary surgery for non-small cell lung cancer.

BACKGROUND: This study aimed to investigate risk factors of conversion to thoracotomy for patients with non-small cell lung cancer (NSCLC) underwent robotic- (RATS) or video-assisted thoracoscopic surgery (VATS). METHODS: A retrospective review was conducted to included consecutive participants from January 2016 to December 2018. Three groups [mini-invasive, conversion, and up-front open thoracotomy (OT) groups] and two series of comparison (conversion versus mini-invasive, and conversion versus OT) were generated. Propensity score-matched analysis (1:1) was conducted to verify outcomes of complications and perioperative factors. Multivariate binary logistic regression analysis was used to identify potential risk factors of conversion. RESULTS: 1177 patients (912 in mini-invasive group, 180 in conversion group, and 85 in OT group) were included. The overall conversion rate was 16.5%. Robotic approach resulted in dramatically lower conversion rate compared to VATS (2.4% vs 25.1%, p < 0.001). After propensity adjustment, no significant difference of complication rates was identified when comparing conversion group with mini-invasive and OT groups. Multivariate regression analyses shown that robotic approach (odd ratio (OR) = 0.037, 95% confidential interval (CI) 0.016-0.087), tumor size < 5 cm (OR = 0.274, 95% CI 0.152-0.493), no chief symptom(OR = 0.311, 95% CI 0.178-0.545), body mass index < 25 kg/m2 (OR = 0.537, 95% CI 0.343-0.842), and lobectomy (OR = 0.079, 95% CI 0.017-0.370) were independent protectors of conversion. CONCLUSIONS: Seven demographic factors might be recognized as independent predictors of conversion. For patients with highly risk of conversion, robotic approach is recommended to perform mini-invasive pulmonary surgery over VATS.

Ti3+ doped V2O5/TiO2 catalyst for efficient selective catalytic reduction of NOx with NH3.

The effect of self-doping Ti3+ into V2O5/TiO2 catalysts on the activity of the catalysts was assessed by the selective catalytic reduction of NOX with NH3 (NH3-SCR). 0.2-V2O5/TiO2 (Al(acac)3:TBOT = 0.2%) catalyst had the highest catalytic activity at low-temperature range. The as-prepared catalysts are characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), H2 temperature-programmed reduction (H2-TPR), NH3 temperature-programmed desorption (NH3-TPD), surface area and pore structure. XPS and EPR were used to confirm the existence of Ti3+ and oxygen vacancy in the catalysts. The specific surface area, surface acidity, reducibility and valence state of the active components of the catalysts are significantly affected by the self-doping of Ti3+. This work would lead to a new strategic design of Ti3+ self-doped catalysts with fine structure and that can efficiently improve low-temperature SCR performance.

A bi-enzymatic cascade to yield pyruvate as co-substrate for L-tyrosine production.

L-Tyrosine is a versatile compound used in the fine chemical, pharmaceutical, and functional food industries. Here, we report a bi-enzymatic cascade involving alanine racemase (ALR) and D-amino acid oxidase (DAAO) to produce pyruvate, as co-substrate for L-tyrosine production, from the cheap substrate L-alanine. The BpALR (ALR from Bacillus pseudofirmus) was used as a whole-cell biocatalyst, converting L-alanine to D, L-alanine. The FsDAAO (DAAO from Fusarium solani) was immobilized to oxidize the D-alanine generated in the first step to pyruvate. Both systems were combined as a continuous-flow reactor for maximized L-alanine-to-pyruvate conversion rates. The optimal parameters and appropriate conditions for FsDAAO immobilization were investigated. The pyruvate concentration of 86.6 g/L was achieved within 17 h. Subsequently, a whole-cell biocatalyst system for L-tyrosine production, catalyzed by the tyrosine phenol-lyase (TPL) from Erwinia herbicola (EhTPL), was developed, and a fed-batch approach was applied with phenol and the pyruvate produced with the ALR/DAAO system mentioned above. The concentration of phenol and pyruvate in the reactor should not exceed 7.5 g/L and 10 g/L, respectively. Significantly, the L-tyrosine concentration of 152.5 g/L was achieved within 10 h, demonstrating the great potential for high-efficiency production of L-tyrosine through the approach we established in this paper. Graphical abstract KEY POINTS: • A specific bioreactor system for pyruvate produced from l-alanine was developed • The appropriate condition for immobilization of FsDAAO was investigated • A fed-batch process was established to produce l-tyrosine with recombinant E. coli • The bi-enzymatic cascade was successfully used for l-tyrosine production at low cost.

Palladium-Catalyzed Secondary Benzylic Imidoylative Reactions.

Reported herein is a palladium-catalyzed secondary benzylic imidoylative Negishi reaction leveraging the sterically bulky aromatic isocyanides as the imine source. This method allows the facile access of alkyl-, (hetero)aryl-, and alkynylzinc reagents to afford various α-substituted phenylacetone products under mild acidic hydrolysis, which are ubiquitous motifs in many pharmaceuticals and biologically active compounds. The diastereoselective reduction of imine can be accomplished to provide the expedient conversion of secondary benzylic halide into α-substituted phenethylamine derivatives with high atom economy.