Biocatalytic Hydrogen-Borrowing Cascade in Organic Synthesis.

Biocatalytic hydrogen borrowing represents an environmentally friendly and highly efficient synthetic method. This innovative approach involves converting various substrates into high-value-added products, typically via a one-pot, two/three-step sequence encompassing dehydrogenation (intermediate transformation) and hydrogenation processes employing the hydride shuffling between NAD(P)+ and NAD(P)H. Represented key transformations in hydrogen borrowing include stereoisomer conversion within alcohols, conversion between alcohols and amines, conversion of allylic alcohols to saturated carbonyl counterparts, and α,ß-unsaturated aldehydes to saturated carboxylic acids, etc. The direct transformation methodology and environmentally benign characteristics of hydrogen borrowing have contributed to its advancements in fine chemical synthesis or drug developments. Over the past decades, the hydrogen borrowing strategy in biocatalysis has led to the creation of diverse catalytic systems, demonstrating substantial potential for straightforward synthesis as well as asymmetric transformations. This perspective serves as a detailed exposition of the recent advancements in biocatalytic reactions employing the hydrogen borrowing strategy. It provides insights into the potential of this approach for future development, shedding light on its promising prospects in the field of biocatalysis.

[Protective effects of Moutan Cortex polysaccharides components on renal injury in diabetic nephropathy rats].

This study investigated the protective effects of Moutan Cortex polysaccharides components(MCPC) on the renal tissues of diabetic nephropathy(DN) rats and explored their regulation effect on inflammatory response and oxidative stress. The DN rat model was induced by high-glucose and high-fat diet combined with streptozotocin(STZ), and then the rats were randomly divided into control group, model group, positive group and MCPC high(120 mg·kg~(-1)·d~(-1)), low(60 mg·kg~(-1)·d~(-1)) dose groups. After 12 weeks treatment, blood was taken from the orbit of the rats, and then they were sacrificed before the kidney tissues were collected. The serum and tissues were detected for related biochemical indicators and pathological changes of the kidney. Immunohistochemical methods were used to determine the expression of FN and ColⅣ in the kidney tissue of DN rats. Compared with the model group, blood glucose, serum creatinine, blood urea nitrogen and 24 h urine protein in the MCPC high-dose group were significantly reduced(P<0.01). The results of HE, PAS, Masson staining showed that glomerular basement membrane thickening, Bowman's capsule narrowing and inflammatory cell infiltration in DN rats were improved in the MCPC high-dose group; the activity of T-SOD and GSH-Px in serum significantly increased(P<0.001), and the expression level of FN significantly decreased(P<0.001). The high-dose MCPC treatment could effectively inhibit the abnormal expression of Col Ⅳ(P<0.001) and significantly reduce the levels of AGEs and RAGE in serum(P<0.001), the content of VCAM-1 and IL-1ß in serum(P<0.001), and the levels of IL-1ß mRNA in kidney tissue(P<0.001), but failed to effectively reduce VCAM-1 mRNA levels in kidney tissues. The high-dose MCPC could significantly improve pathological injury of renal tissue and related renal indicators in DN rats, and achieve renal protection in DN rats mainly by regulating oxidative stress and inflammatory factors.

Stereoselective Synthesis of ß-Branched Aromatic α-Amino Acids by Biocatalytic Dynamic Kinetic Resolution*.

ß-Branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a stereoselective fashion, and contemporary methods for the synthesis of such compounds often rely on the use of rare-transition-metal catalysts with designer ligands. Herein, we report a highly diastereo- and enantioselective biocatalytic transamination method to prepare a broad range of aromatic ß-branched α-amino acids. Mechanistic studies show that the transformation proceeds through dynamic kinetic resolution that is unique to the optimal enzyme. To highlight its utility and practicality, the biocatalytic reaction was applied to the synthesis of several sp3 -rich cyclic fragments and the first total synthesis of jomthonic acid A.

The impact of multi-person virtual reality competitive learning on anatomy education: a randomized controlled study.

BACKGROUND: Anatomy is one of the core subjects in medical education. Students spend considerable time and effort on learning the requisite anatomy knowledge. This study explored the effect of a multiple-player virtual reality (VR) gaming system on anatomy learning. METHODS: 18 participants were randomly assigned into 3 learning conditions: (1) a textbook reading control group (CG), (2) a single-player VR (SP) group; and (3) a multiple-player VR (MP) group. The participants studied anatomy for 5 days, and completed a multiple-choice test on Days 1, 5, and 12. In the VR environment, the participants used handheld controllers to move the simulated tissues. The mission of the game was to complete puzzles of a human body. The SP and MP groups filled out a motivation inventory on Day 5. The scores on the multiple-choice test, the correct assembly rates, and the motivation inventory scores were analyzed using the 2-way ANOVA or independent t-test to compare group differences. RESULTS: There was a significant interaction effect of group and timepoint (p = 0.003) in the multiple-choice test. In the CG, the scores on Day 1, Day 5, and Day 12 were significantly different (p < 0.001). The scores on Day 5 were significantly higher than those on Day 1 (p < 0.001). Although the scores declined slightly on Day 12, they were still significantly higher than those on Day 1 (p < 0.001). The SP and MP groups had similar results (p < 0.001, p < 0.001). The differences between the groups were only significant on Day 12 (p = 0.003), not Day 5 (p = 0.06). On Day 12, the scores of the MP group were higher than those of the CG (p = 0.002). The SP group and MP group had high scores on the interest, competence, and importance subscales of the motivation inventory. Both VR groups considered the system to be fun and beneficial to their learning. However, the MP group reported higher stress levels than the SP group. CONCLUSION: The results indicated that the proposed VR learning system had a positive impact on the anatomy learning. Although the between-player competition caused higher stress levels for the VR groups, the stress could have been a mediator of their learning outcomes. TRIAL REGISTRATION: ETRD, ETRD-D-19-00573. Registered 20 December 2018, http://www.edah.org.tw/irb/index.htm.

Divergent synthesis of complex diterpenes through a hybrid oxidative approach.

Polycyclic diterpenes exhibit many important biological activities, but de novo synthetic access to these molecules is highly challenging because of their structural complexity. Semisynthetic access has also been limited by the lack of chemical tools for scaffold modifications. We report a chemoenzymatic platform to access highly oxidized diterpenes by a hybrid oxidative approach that strategically combines chemical and enzymatic oxidation methods. This approach allows for selective oxidations of previously inaccessible sites on the parent carbocycles and enables abiotic skeletal rearrangements to additional underlying architectures. We synthesized a total of nine complex natural products with rich oxygenation patterns and skeletal diversity in 10 steps or less from ent-steviol.

[Practice and development of structural characteristics and quality control of multi-dimensional structure of basic components of genuine material of Moutan Cortex].

Traditional Chinese medicine is the product of clinical medication practice of the Chinese nation for thousands of years. Its material basis is the key to reveal the essence of the roles of traditional Chinese medicine, and the fundamental guarantee to solve the difficulties in the quality control of traditional Chinese medicine. However, the material basis of traditional Chinese medicine is to exert the overall pharmacodynamic effect through multi-targets, multi-approaches and mutual cooperation, resulting in unclear quality control index. In recent years, the quality control standards of traditional Chinese medicine have experienced great changes by shifting the focus from the appearance characteristics to the internal material basis, which however is limited to the control of a single com-ponent or multiple components. In other words, the intrinsic effectiveness and safety could not be guaranteed without the characteristics of the integrity of traditional Chinese medicine. With Moutan Cortex as an example, this paper analyzed the evolution of Moutan Cortex quality standards based on Chinese Pharmacopoeia, and comprehensively summarized the material basis of Moutan Cortex. Based on the theory of "component structure", this study analyzed current quality control of the material basis of Moutan Cortex and its preparations, and expounded the development trend of multi-dimensional quality control, so as to lay a foundation for establishing a more rational quality control system for traditional Chinese medicine in the future.

[Structural characteristics of pharmacodynamical components in genuine Moutan Cortex].

Guided by the theory of "component structure", we analyzed the structural characteristics of pharmacodynamical components in genuine Moutan Cortex. The compositions of organic small molecules were determined by high performance liquid chromatography(HPLC) for 20 batches of genuine Moutan Cortex and 12 batches of non-genuine Moutan Cortex. By means of similarity analysis, clustering analysis(CA), principal component analysis(PCA) and orthogonal partial least-squares discriminant analysis(OPLS-DA), the elements in structural characteristics of the pharmacodynamical components were extracted as follows: terpene glycosides components(oxidized paeoniflorin, paeoniflorin,galloyl paeoniflorin, benzoyloxy paeoniflorinand benzoyl paeoniflorin), tannin components(1,3,6-tri-O-galloside acyl glucose, pentagalloyl glucose), and phenolic acid components(methyl gallate, paeonol). The contents and quantity ratios of terpene glycoside component, tannin component and phenolic acid components in genuine Moutan Cortex were determined as 14.1, 12.5, 21.7 mg·g~(-1), 1.00∶0.89∶1.54. The contents and quantity ratios of the oxidized paeoniflorin, paeoniflorin and benzoylpaeoniflorin in the terpene glycoside components were characteristic and determined as 2.05, 7.05, 3.30 mg·g~(-1), 1.00∶3.44∶1.61. The unique structural characteristics of genuine Moutan Cortex provide scientific basis for the formulation of quality standards.

Stereoselective access to [5.5.0] and [4.4.1] bicyclic compounds through Pd-catalysed divergent higher-order cycloadditions.

Medium-sized rings, including those embedded in bridged and fused bicyclic scaffolds, are common core structures of myriad bioactive molecules. Among various synthetic strategies towards their synthesis, intermolecular higher-order cycloaddition provides great potential to build complex medium-sized rings from simple building blocks. Unfortunately, such transformations are often plagued with competitive reaction pathways and low levels of site- and stereoselectivity. Herein, we report catalyst-controlled divergent access to three classes of medium-sized bicyclic compounds in high efficiency and stereoselectivity, by palladium-catalysed cycloadditions of tropones with γ-methylidene-δ-valerolactones. Mechanistic studies and density functional theory calculations disclosed that the divergent reactions stem from the different reaction profiles of the diastereomeric intermediates. While one undergoes either O- or C-allylation to provide [5.5.0] or [4.4.1] bicyclic compounds, the unique conformation of the other diastereomer allows an unconventional alkene isomerization to deliver bridgehead alkene-containing bicyclo[4.4.1] compounds. The conversion of these products to diverse complex polycyclic scaffolds has also been demonstrated.

Scaling relationships and volcano plots of homogeneous transition metal catalysis.

Linear scaling relationships and volcano plots have served as powerful tools for catalyst design and screening in heterogeneous catalysis. Recently, this approach has been introduced in homogeneous catalysis. Seminal reports found that the complicated thermodynamic and kinetic energy profiles of homogeneous catalysis can be successfully described by using very limited energetic descriptors based on linear scaling relationships. This is demonstrated in a number of important catalytic transformations including C-C cross-coupling, N2 reduction, CO2 hydrogenation and alkene hydroformylation. This Frontier highlights the noteworthy impact of scaling relationships and volcano plots on the understanding and design of homogeneous catalysis and discusses the perspectives on the future development of this area.

Reactivity Profiles of Diazo Amides, Esters, and Ketones in Transition-Metal-Free C-H Insertion Reactions.

Vinyl cations derived from diazo ketones participate in transition-metal-free C-H insertion reactions, but the corresponding amide and ester analog exhibit divergent reactivity profiles. Whereas cations formed from diazo ketones undergo a rearrangement and C-H insertion sequence, those from diazo amides do so less efficiently and tend to be competitively trapped before the insertion step occurs. Diazo esters undergo several rearrangement steps and fail to insert. DFT calculations reveal that this disparity stems from two factors: differing levels of electrostatic stabilization of the initially formed vinyl cation by the adjacent carbonyl oxygen and predistortion of the ketone and amide systems toward C-H insertion. The computational data is in strong agreement with experimental results, and this study explains how structural and electronic factors determine the outcome of reactions of diazo carbonyl-derived vinyl cations.

Palladium-Titanium Relay Catalysis Enables Switch from Alkoxide-π-Allyl to Dienolate Reactivity for Spiro-Heterocycle Synthesis.

Reported herein is the divergent syntheses of [5,5] and [6,5] spiro-heterocycles under Lewis-acid-assisted palladium catalysis. In particular, an unprecedented switch from alkoxide-π-allyl to dienolate reactivity was achieved by the use of palladium-titanium relay catalysis, and represents umpolung reactivity of vinylethylene carbonates. This method uses a simple procedure and commercially available catalysts, and delivers both classes of spiro-heterocycles, bearing three contiguous stereocenters, in high yield and uniformly excellent diastereoselectivity.

Pd-Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten-Membered Heterocycles.

We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten-membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd-SIPHOX catalyst, a wide range of benzofuran- as well as indole-fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten-membered heterocycles was also discovered.

Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation.

The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.

Methotrexate-induced epidermal necrosis: A case series of 24 patients.

BACKGROUND: Methotrexate-induced epidermal necrosis (MEN) is a rare but life-threatening cutaneous reaction that mimics Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To investigate the clinicopathology, risk factors, and prognostic factors of MEN. METHODS: We enrolled 24 patients with MEN and 150 controls and analyzed the demographics, pathology, and plasma concentrations of methotrexate (MTX). RESULTS: Patients with MEN showed extensive skin necrosis (mean, 33.2% total body surface area) but no target lesions. The histopathology displayed keratinocyte dystrophy. Early signs of MEN included painful skin erosions, oral ulcers, and leukopenia/thrombocytopenia. Although 79.2% patients received leucovorin treatment, there was 16.7% mortality. Risk factors for MEN included older age (>60 years), chronic kidney disease, and high initial dosage of MTX without folic acid supplementation. Renal insufficiency delayed MTX clearance. Severe renal disease and leukopenia predicted poor prognosis in MEN, but none of the SCORe of Toxic Epidermal Necrosis criteria were associated with mortality of MEN. LIMITATIONS: The study was limited by the small sample size. CONCLUSION: MEN exhibited distinct clinicopathologic features from SJS/TEN. Recognition of the early signs and prognostic factors is important, because the rapid institution of leucovorin may be helpful. To reduce the risk of MEN, physicians should avoid prescribing MTX to high-risk patients and titrate the dosage slowly upward with folic acid supplementation.

Construction of Nine-Membered Heterocycles through Palladium-Catalyzed Formal [5+4] Cycloaddition.

The first catalytic formal [5+4] cycloaddition to prepare nine-membered heterocycles is presented. Under palladium catalysis, the reaction of N-tosyl azadienes and substituted vinylethylene carbonates (VECs) proceeds smoothly to produce benzofuran-fused heterocycles in uniformly high efficiency. Highly diastereoselective functionalization of the nine-membered heterocycles through peripheral attack is also demonstrated.

Toward evidence-based practice in acne: consensus of an Asian Working Group.

Acne vulgaris is common throughout the world and often perceived by both patients and clinicians as an inconsequential disease of adolescence. In reality, however, acne is a chronic medical disease that lasts for years and causes a considerable impact on quality of life. Many patients with acne experience emotional problems due to their disease, which can lead to reduced social interactions and even a lower likelihood of employment. Little has been written specifically about acne in Asian patients in the English-language medical published work, perhaps due to an assumption that the management of acne is the same in all populations. A group of acne experts from nine Asian countries and the USA met to review and discuss acne care within the Asia-Pacific region, focusing on evidence-based medicine. This group developed a care algorithm using results of clinical trials as well as knowledge of practice patterns.

Prurigo pigmentosa: a clinicopathological study and analysis of associated factors.

BACKGROUND: Prurigo pigmentosa (PP), a rare inflammatory disease of the skin, is mostly reported in the ethnic Japanese population. Its pathogenesis remains unclear. The chronic and recurrent nature of PP implies a possible role of viral infection in the pathogenesis. The anti-inflammatory mechanism of doxycycline, which is well documented as a good treatment for PP, is related to the suppression of interleukin expression. METHODS: We identified and retrospectively analyzed 16 biopsy-proven and criteria-matched patients over a seven year period at a single medical center. DNA extracted from formalin-fixed, paraffin-embedded specimens was analyzed for herpes simplex virus-1 (HSV-1), HSV-2, and human herpes virus-6 (HHV-6) DNA by polymerase chain reaction. Immunohistochemistry was performed to determine the interleukin-6 (IL-6) and interleukin-8 (IL-8) expression in PP skin lesions. RESULTS: Clinicopathological findings in the ethnic Chinese population are similar to those reported in Japanese studies. All patients had a good response to doxycycline treatment, with a mean duration of use of 2.4 weeks. However, recurrence was noted in six patients. HSV-1, HSV-2, and HHV-6 DNA in PP skin lesions were negative. Immunohistochemistry showed IL-6 (P = 0.035) to be more strongly expressed in PP skin lesions. There was no statistical significance of elevated IL-8 expression in PP (P = 0.123). CONCLUSIONS: Prurigo pigmentosa is not uncommon in the ethnic Chinese population. There was no evidence of herpes virus DNA in PP skin lesions. Increased expression of IL-6 in PP skin lesions may explain the effects of doxycycline in terms of its anti-inflammatory properties.

Intravenous immunoglobulin-induced, non-eczematous, vesiculobullous eruptions in Stevens-Johnson syndrome.

Intravenous immunoglobulin (IVIG) has emerged as a promising treatment that interrupts the progression of Stevens-Johnson syndrome (SJS). Our patient experienced an uncommon adverse effect, non-eczematous, vesiculobullous eruptions, after treatment with IVIG. These new lesions developed rapidly on the palms while most previous SJS bullous lesions subsided. A skin biopsy of these new lesions showed an intracorneal vesicle, without epidermal necrosis, with inflammatory cell infiltration. IVIG-induced, vesiculobullous eruptions are discussed, along with their possible pathogenesis. With the increasing use of IVIG for treatment of bullous dermatoses, recognition of this rare adverse effect is important for prompt differential diagnosis.

Bullous pemphigoid in a renal transplant recipient: a case report and review of the literature.

Bullous pemphigoid (BP) is an autoimmune disease with chronic, recurrent bullous eruptions. BP has been reported to be associated with drugs, physical stimuli, malignancies, and immune abnormalities. Its association with renal transplant is rare and only four cases have been reported. We present a case of BP in a 52-year-old man with chronic hepatitis B and C infection who underwent a cadaveric renal transplant 13 years earlier. His graft was still functioning well when BP appeared. The occurrence of BP in our patient might be a result of drugs (furosemide or tacrolimus), viruses, or renal allograft. As the patient was receiving regular T-cell immunosuppressant therapy, his BP lesions were recalcitrant to corticosteroid treatment. We discuss the pathogenesis and treatment of such patients.