FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31--demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31--demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against and, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Notably, 9-deoxo-31--demethyl-FK506 and 31--demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31--demethyl-FK506 for further evaluation of its antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31--demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of -infected mice, confirming the synergistic antifungal efficacy between these two agents.

A reduction in the strong immunosuppressive activity of FK506 ( 1) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (7) exhibited a >900-fold reduction in the in vitro immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. 7 exhibited robust synergistic antifungal activity with fluconazole. FK506 ( 1) is a 23-membered macrolide produced by several Streptomyces species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506binding protein (FKBP) 12, and the resulting FKBP12−FK506 complex interacts with a Ca 2+ -calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12−FK506−CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as Cryptococcus neoformans, Candida albicans, and Aspergillus f umigatus. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.

It is increasingly agreed upon that cognitive and audiological factors are associated with self-perceived hearing handicap in old adults. This study aimed to compare self-perceived hearing handicap among mild cognitive impairment (MCI) subgroups and a cognitively normal elderly (CNE) group and determine which factors (i.e., demographic, audiometric, or neuropsychological factors) are correlated with self-perceived hearing handicap in each group. A total of 46 MCI patients and 39 hearing threshold-matched CNE subjects participated in this study, and their age ranged from 55 to 80 years. The MCI patients were reclassified into two groups: 16 with frontal-executive dysfunction (FED) and 30 without FED. All subjects underwent audiometric, neuropsychological, and self-perceived hearing handicap assessments. The Korean version of the Hearing Handicap Inventory for the Elderly (K-HHIE) was administered to obtain the hearing handicap scores for each subject. After controlling for age, years of education, and depression levels, we found no significant differences in the K-HHIE scores between the MCI and the CNE groups. However, after we classified the MCI patients into the MCI with FED and MCI without FED groups, the MCI with FED group scored significantly higher than did both the MCI without FED and the CNE groups. In addition, after controlling for depression levels, significant partial correlations of hearing handicap scores with frontal-executive function scores and speech-in-noise perception performance were found in the MCI groups. In the CNE group, the hearing handicap scores were related to peripheral hearing sensitivity and years of education. In summary, MCI patients with FED are more likely to experience everyday hearing handicap than those without FED and cognitively normal old adults. Although educational level and peripheral hearing function are related to self-perceived hearing handicap in cognitively normal old adults, speech-in-noise perception and frontal-executive function are mainly associated with hearing handicap in patients with MCI.

Background: Healthy aging is characterized by declines in language function and it is important to differentiate language comprehension difficulties due to pathological aging (i.e., mild cognitive impairment) from those due to normal aging. The purposes of this study were to review the literature on characteristics of language comprehension in normal elderly and the mild cognitive impaired, and to compare their performances on different language domains. Methods: A comprehensive literature search identified numerous studies on language comprehension in both groups, and we analyzed them according to each language domain. Results: The results indicated that the normal elderly show more difficulties in the comprehension of grammatically or lexically complex sentences and in text/discourse comprehension than words or simple sentences. Compared to normal elderly, MCI shows significantly lower performance on text/discourse comprehension and other tasks demanding higher cognitive function. In both groups, there are many different factors affecting language comprehension, such as hearing sensitivity, speech rate, literacy, and cognition. Conclusions: The results may provide insight into useful language comprehension tasks for differential diagnosis between normal aging and MCI. Further research on various compensatory strategies in daily life to facilitate language comprehension for both groups is warranted. 서 론 노화는 연령 증가와 함께 나타나는 신체적, 생리적 기능의 점차적 인 퇴보이다. 노화가 진행됨에 따라 관찰될 수 있는 인지 기능의 저 하는 크게 다음의 두 가지로 나눌 수 있다. 하나는 정상적인 노화 과 정으로 인한 생리적인 인지 기능 저하이며, 다른 하나는 경도인지장 애(mild cognitive impairment, MCI)나 알츠하이머병(Alzheimer' s disease, AD)과 같은 병적인 인지 기능 장애이다[1]. MCI나 AD에서는 인지 기능과 더불어 언어 능력이 저하되는 것으로 잘 알려져 있다. 이에 비해서, 정상적인 노화로 인해 나타나는 언어 기능 저하에 대 해서는 아직까지 논란이 많다[2]. 일반적으로 노화가 진행될수록 언 어 능력이 저하된다는 견해가 받아들여지나, 특정 언어 능력의 저 하가 다양한 인지 능력, 청력, 문해 능력, 메시지의 특성 등의 영향을 받은 결과일 수 있으므로 해석상 주의가 필요하다[3]. 노년기의 언어능력을 다룬 연구들을 살펴보면, 언어 산출과 관련 된 연구는 구어 유창성(word fluency)이나 이름대기(naming) 능력 등을 중심으로 비교적 활발하게 이루어지고 있으나, 언어 이해와 관련된 연구는 부족한 실정이다. 그 이유로는 언어 산출에 비해 언 어 이해의 측정이 어려우며[4], 널리 통용되는 객관적인 검사 도구 의 종류도 제한적이기 때문이다. 언어 이해력은 외부로부터 주어진 여러 유형의 언어적 자극(청각적 또는 시각적 자극)을 지각하고 처 리하여 정보를 해석하는 능력이다. 청각적 언어 이해(즉, 언어 듣기 이해)는 청각적 처리(auditory processing)와 말소리 인식(speech perception)이라는 과정을 거쳐서 비로소 도달한다. 한편, 시각적 언어 이해(즉, 언어 읽기 이해)는 철자법(orthography)에 대한 지식이나 음 운론(phonology), 형태론(morphology)적 인식이 관여한다. 음운론 Dementia and Neurocognitive Disorders 2014; 13: 51-62 http://dx.

Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36−C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105-and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.