Synthesis of gem-Difluorohomoallyl Amines via a Transition-Metal-Free Defluorinative Alkylation of Benzyl Amines with Trifluoromethyl Alkenes.

A mild and transition-metal-free defluorinative alkylation of benzyl amines with trifluoromethyl alkenes is reported. The features of this protocol are easy-to-obtain starting materials, a wide range of substrates, and functional group tolerance as well as high atom economy, thus offering a strategy to access a variety of gem-difluorohomoallyl amines, which are extensively distributed in pharmaceuticals and bioactive agents, with excellent chemoselectivity. The primary products can be further transformed to a diversity of 2-fluorinated pyrroline compounds.

N-Containing triterpenoid saponins from Mussaenda densiflora and identification of heinsiagenin A as a potent immunosuppressant.

Eleven triterpenoid saponins, including five new compounds, which were named densiflorasides A - E (1 - 5), were isolated from aerial parts of Mussaenda densiflora (Rubiaceae). Their structures were elucidated based on spectroscopic and single-crystal X-ray diffraction analyses and chemical methods. All the isolated compounds and the aglycone heinsiagenin A were evaluated for their immunosuppressive and antiosteoclastogenic activities in vitro. Compounds 6 - 8 and heinsiagenin A inhibited osteoclastogenesis, with IC50 values ranging from 8.24 to 17.7 µM. Furthermore, compounds 3, 6 - 8, and heinsiagenin A significantly inhibited T-cell proliferation, with IC50 values ranging from 2.56 to 8.60 µM, and compounds 3 - 5 and 11 inhibited the proliferation of B lymphocytes, with IC50 values ranging from 1.29 to 8.49 µM. Further in vivo experiments indicated that heinsiagenin A could significantly attenuate IMQ-induced psoriasis and DSS-induced colitis in mice.

Synthesis and biological evaluation of pyrazole-fused oleanolic acid derivatives as novel inhibitors of inflammatory and osteoclast differentiation.

A series of pyrazole-fused oleanolic acid derivatives were designed and synthesized. The modification of these analogues focused on the substituents screening on the pyrazole ring. The cytotoxicity of these compounds and their anti-inflammatory activities via inhibiting interleukin-1ß (IL-1ß) production were evaluated in RAW264.7 cells. Most of the derivatives showed significantly improved potency compared with oleanolic acid. Among them, compound 7n exhibited the most potent anti-inflammatory activity on decreasing IL-1ß production with low cytotoxicity. Moreover, the further study found 7n could inhibit RANKL-induced osteoclast differentiation on bone marrow-derived macrophages (BMMs). These findings may provide a potential direction for the drug development of osteoarthritis.

Adipose-derived mesenchymal stem cell-incorporated PLLA porous microspheres for cartilage regeneration.

BACKGROUND: In facial plastic surgery, patients with nasal deformity are often treated by rib cartilage transplantation. In recent years, cartilage tissue engineering has developed as an alternative to complex surgery for patients with minor nasal defects via injection of nasal filler material. In this study, we prepared an injectable nasal filler material containing poly-L-lactic acid (PLLA) porous microspheres (PMs), hyaluronic acid (HA) and adipose-derived mesenchymal stem cells (ADMSCs). METHODS: We seeded ADMSCs into as-prepared PLLA PMs using our newly invented centrifugation perfusion technique. Then, HA was mixed with ADMSC-incorporated PLLA PMs to form a hydrophilic and injectable cell delivery system (ADMSC-incorporated PMH). RESULTS: We evaluated the biocompatibility of PMH in vitro and in vivo. PMH has good injectability and provides a favorable environment for the proliferation and chondrogenic differentiation of ADMSCs. In vivo experiments, we observed that PMH has good biocompatibility and cartilage regeneration ability. CONCLUSION: In this study, a injectable cell delivery system was successfully constructed. We believe that PMH has potential application in cartilage tissue engineering, especially in nasal cartilage regeneration.

Reversible SAHH inhibitor ameliorates MIA-induced osteoarthritis of rats through suppressing MEK/ERK pathway.

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

When Learning Goal Orientation Leads to Learning From Failure: The Roles of Negative Emotion Coping Orientation and Positive Grieving.

Considering failure is a common result in project management, how to effectively learn from failure has becoming a more and more important topic for managers. Drawing on the goal orientation theory and grief recovery theory, the purpose of this paper is to clarify the impact of learning goal orientation on learning from failure. Furthermore, this paper examines the mediating effect of two negative emotion coping orientations (restoration orientation and loss orientation) and the moderating effect of positive grieving in this relationship. The results indicated that: (1) A learning goal orientation is positively related to learning from failure; (2) As a dual-path mediation model, restoration orientation and loss orientation mediate the relationship between a learning goal orientation and learning from failure; and (3) Positive grieving negatively moderates the relationship between a loss orientation and learning from failure.

When Error Learning Orientation Leads to Learning From Project Failure: The Moderating Role of Fear of Face Loss.

As the importance of failure is widely recognized, there is increasing research interest in the antecedents of learning from failure. Basing on affective event theory, the current study cast light on individuals' cognition of error and proposed that employees with higher levels of error learning orientation tend to show more positive grieving after project failure, which in turn increases their learning from failure. Using a sample of 752 employees from 140 project teams, we found empirical evidence to support this theoretical model. Our results indicated that positive grieving mediated the relationship between error learning orientation and learning from failure. Besides, the relationship between error learning orientation and positive grieving is more positive for employees with lower levels of fear of face loss. Our findings help enrich the antecedents of learning from failure by shedding light on how and when error learning orientation matters. Theoretical and practical implications are discussed.

When Project Commitment Leads to Learning from Failure: The Roles of Perceived Shame and Personal Control.

Facing a remarkably changing world, researchers have gradually shifted emphasis from successful experiences to failures. In the current study, we build a model to explore the relationship between project commitment and learning from failure, and test how emotion (i.e., perceived shame after failure) and cognition (i.e., attribution for failure) affect this process. After randomly selecting 400 firms from the list of high-tech firms reported by the Beijing Municipal Science and Technology Commission, we use a two-wave investigation of the employees, and the final sample consists of 140 teams from 58 companies in the technology industry in mainland China. The results provide evidence for the positive role of personal control attribution in the relationship between project commitment and learning from failure. However, in contrast to previous studies, perceived shame, as the negative emotion after failed events, could bring desirable outcomes during this process. Based on the results, we further expand a model to explain the behavioral responses after failure, and the implications of our findings for research and practice are discussed. The failures and reverses which await men - and one after another sadden the brow of youth - add a dignity to the prospect of human life, which no Arcadian success would do. -Henry David Thoreau.