Discovery of an Imine Reductase for Reductive Amination of Carbonyl Compounds with Sterically Challenging Amines.

The synthesis of structurally diverse amines is of fundamental significance in the pharmaceutical industry due to the ubiquitous presence of amine motifs in biologically active molecules. Biocatalytic reductive amination for amine production has attracted great interest owing to its synthetic advantages. Herein, we report the direct synthesis of a wide range of sterically demanding secondary amines, including several important active pharmaceutical ingredients and pharmaceutical intermediates, via reductive amination of carbonyl substrates and bulky amine nucleophiles employing imine reductases. Key to success for this route is the identification of an imine reductase from Penicillium camemberti with unusual substrate specificity and its further engineering, which empowered the accommodation of a broad range of sterically demanding amine nucleophiles encompassing linear alkyl and (hetero)aromatic (oxy)alkyl substituents and the formation of final amine products with up to >99% conversion. The practical utility of the biocatalytic route has been demonstrated by its application in the preparative synthesis of the anti-hyperparathyroidism drug cinacalcet.

Interleukin-17 is involved in neuropathic pain and spinal synapse plasticity on mice.

Neuropathic pain seriously affects people's life, but its mechanism is not clear. Interleukin-17 (IL-17) is a proinflammation cytokine and involved in pain regulation. Our previous study found that IL-17 markedly enhanced the excitatory activity of spinal dorsal neurons in mice spinal slices. The present study attempts to explore if IL-17 contributes to neuropathic pain and spinal synapse plasticity. A model of spared nerve injury (SNI) was established in C57BL/6 J mice and IL-17a mutant mice. The pain-like behaviors was tested by von Frey test and dynamic mechanical stimuli, and the expression of IL-17 and its receptor, IL-17RA, was detected by immunohistochemical staining. C-fiber evoked field potentials were recorded in vivo. In the spinal dorsal horn, IL-17 predominantly expressed in the superficial spinal astrocytes and IL-17RA expressed mostly in neurons and slightly in astrocytes. The SNI-induced static and dynamic allodynia was significantly prevented by pretreatment of neutralizing IL-17 antibody (intrathecal injection, 2 µg/10 µL) and attenuated in IL-17a mutant mice. Post-treatment of IL-17 neutralizing antibody also partially relieved the established mechanical allodynia. Moreover, spinal long-term potentiation (LTP) of C-fiber evoked field potentials, a substrate for central sensitization, was suppressed by IL-17 neutralizing antibody. Intrathecal injection of IL-17 recombinant protein (0.2 µg/10 µL) mimicked the mechanical allodynia and facilitated the spinal LTP. These data implied that IL-17 in the spinal cord played a crucial role in neuropathic pain and central sensitization.

[A long-term follow-up study of deep penile vein resection patients].

OBJECTIVE: To study the five-year postoperative effect of the ligation and resection of the deep penile vein for the patient of erectile dysfunction (ED) caused by penile venous leakage. METHODS: Sixteen ED patients received deep penile vein ligation and resection. Observations of the penile erection had been recorded for 5 years after surgery. RESULTS: Eight cases demonstrated erectile hypofunction after 18 months postoperatively and total ED after 21-30 months of which 6 were improved by chemotherapy, and 2 showed no improvement. Seven cases remained normal and 1 case get out of touch at the 24th month postoperatively. CONCLUSIONS: The ligation and resection of the deep penile vein can be considered as an easy and effective method to treat patients of ED caused by penile venous leakage.

[Hemodynamometry of erectile dysfunction].

OBJECTIVE: To study the clinical causes of the erectile dysfunction (ED). METHODS: One hundred and thirty cases of ED were examined by hemonamometry and cavernosography with vasodilating agent. The data about penile brachial index, intracavernous pressure, maintenance flow rate, and pressure loss change were obtained and the status of the penile veins was detected. RESULTS: Among 130 patients with ED, 39 had venous leakage including penile arterial insufficiency simultaneous venous leakage in 15 patients. Various leakage sites were observed by using cavernosography. Twenty-eight patients showed deep dorsal veins only and the remaining crural veins. CONCLUSION: Hemodynamometry is effective to diagnose the cause of ED.