Herbal Medicine for Postpartum Pain: A Systematic Review of Puerperal Wind Syndrome (Sanhupung).

Mothers in the postpartum period often experience musculoskeletal disorders and pain, impacting their ability to care for themselves and their infants. Conventional treatments have limitations, prompting interest in alternative options like herbal medicine. This systematic review aimed to confirm the effectiveness and safety of herbal medicine treatment to improve maternal health in patients with postpartum pain (puerperal wind syndrome). We searched eight electronic databases for randomized controlled trials (RCTs) to evaluate the effects of herbal medicines on puerperal wind syndrome. Nine RCTs, including 652 patients, were selected. Following a meta-analysis of RCTs, both herbal medicine and combination treatments improved the visual analog scale scores, total effective rate, scores of Traditional Chinese Medicine syndromes, Oswestry Disability Index, and quality of life in patients with role-emotional puerperal wind syndrome. All adverse events were minor, and the incidence rate was not high compared with that of the control group. In conclusion, herbal medicine supports the improvement in pain, other systemic symptoms, and the quality of life of patients with puerperal wind syndrome. Moreover, no serious side effects were observed; therefore, herbal medicines appear to be safe. It can be the preferred treatment option for puerperal wind syndrome, which is currently managed symptomatically.

Biochemical and functional characterization of skeletal muscle cells differentiated from tonsil-derived mesenchymal stem cells.

INTRODUCTION/AIMS: Human tonsils are a readily accessible source of stem cells for the potential treatment of skeletal muscle disorders. We reported previously that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into skeletal muscle cells (SKMCs), which renders TMSCs promising candidates for cell therapy for skeletal muscle disorders. However, the functional properties of the myocytes differentiated from mesenchymal stem cells have not been clearly evaluated. In this study we investigated whether myocytes differentiated from TMSCs (skeletal muscle cells derived from tonsil mesenchymal stem cells [TMSC-SKMCs]) exhibit the functional characteristics of SKMCs. METHODS: To test the insulin reactivity of TMSC-SKMCs, the expression of glucose transporter 4 (GLUT4) and phosphatidylinositol 3-kinase/Akt was analyzed after the cells were treated for 30 minutes with 100 nmol/L insulin in normal or high-glucose medium. We also examined whether these cells formed a neuromuscular junction (NMJ) when cocultured with motor neurons, and whether they were stimulated by electrical signals using whole-cell patch clamping. RESULTS: Skeletal muscle cells derived from tonsil mesenchymal stem cells expressed SKMC markers, such as MYOD, MYH3, MYH8, TNNI1, and TTN, at high levels, and exhibited a multinucleated cell morphology and a myotube-like shape. The expression of the acetylcholine receptor and GLUT4 was confirmed in TMSC-SKMCs. In addition, these cells exhibited insulin-mediated glucose uptake, NMJ formation, and transient changes in cell membrane action potential, all of which are representative functions of human SKMCs. DISCUSSION: Tonsil-derived mesenchymal stem cells can be functionally differentiated into SKMCs and may have potential for clinical application for the treatment of skeletal muscle disorders.

Alkylidene Carbene from Silyl Vinyl Iodide Provides Mechanistic Insights on Trimethylenemethane Diyl-Mediated Tandem Cyclizations.

We describe a method to generate alkylidene carbenes via tetramethylammonium-fluoride-induced desilylation of silyl vinyl iodides. The reversible carbene generation from an iodovinyl anion enabled us to unearth mechanistic aspects of the trimethylenemethane (TMM) diyl cyclization reaction that could not be explored via previous methods. We observed that a slow diyl-diylophile cycloaddition can induce the reversible formation of an alkylidene carbene from the TMM diyl intermediate via a retro-cyclopropanation at ambient temperature.

On the Erosion of Enantiopurity of Rhodonoids via Their Asymmetric Total Synthesis.

Rhodonoid natural products are found in nature as a scalemic mixture. This interesting phytochemical feature is presumed to originate from a reversible electrocyclic ring opening of the chromene core present in the biogenetic precursors of rhodonoids. Herein, we systematically investigated factors that are responsible for this racemization event. This eventually led us to complete the asymmetric total synthesis of rhodonoids A, C, D, and G.

Nm23-H1 activator phenylbutenoid dimer exerts cytotoxic effects on metastatic breast cancer cells by inducing mitochondrial dysfunction only under glucose starvation.

Mitochondrial oxidative phosphorylation (OXPHOS) has become an attractive target in anti-cancer studies in recent years. In this study, we found that a small molecule phenylbutenoid dimer NMac1 (Nm23-H1 activator 1), (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, a previously identified anti-metastatic agent, has novel anti-proliferative effect only under glucose starvation in metastatic breast cancer cells. NMac1 causes significant activation of AMPK by decreasing ATP synthesis, lowers mitochondrial membrane potential (MMP, ΔΨm), and inhibits oxygen consumption rate (OCR) under glucose starvation. These effects of NMac1 are provoked by a consequence of OXPHOS complex I inhibition. Through the structure-activity relationship (SAR) study of NMac1 derivatives, NMac24 was identified as the most effective compound in anti-proliferation. NMac1 and NMac24 effectively suppress cancer cell proliferation in 3D-spheroid in vivo-like models only under glucose starvation. These results suggest that NMac1 and NMac24 have the potential as anti-cancer agents having cytotoxic effects selectively in glucose restricted cells.

A Free Radical Cyclization Catalyzed by Ruthenium Hydride Species.

A photolytically generated ruthenium hydride species catalyzing a free radical cyclization reaction was developed. As the new methodology ensures reproducibility of the free radical reaction of trialkyltin hydrides and a fast hydrogen transfer to the radical intermediates, the methodology provides fast quenching of radical intermediates and thus suppresses rearrangement of radical intermediates before the hydride quench. By offering new reactivity and selectivity to the trialkyltin hydride mediated free radical cyclization reactions, the methodology will find wide range of applications in organic synthesis.

Development of Carbazole Derivatives Compounds against Candida albicans: Candidates to Prevent Hyphal Formation via the Ras1-MAPK Pathway.

Morphogenesis contributes to the virulence of the opportunistic human fungal pathogen Candida albicans. Ras1-MAPK pathways play a critical role in the virulence of C. albicans by regulating cell growth, morphogenesis, and biofilm formation. Ume6 acts as a transcription factor, and Nrg1 is a transcriptional repressor for the expression of hyphal-specific genes in morphogenesis. Azoles or echinocandin drugs have been extensively prescribed for C. albicans infections, which has led to the development of drug-resistant strains. Therefore, it is necessary to develop new molecules to effectively treat fungal infections. Here, we showed that Molecule B and Molecule C, which contained a carbazole structure, attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that Molecule B and Molecule C inhibit morphogenesis through repressing protein and RNA levels of Ras/MAPK-related genes, including UME6 and NRG1. Furthermore, we determined the antifungal effects of Molecule B and Molecule C in vivo using a candidiasis murine model. We anticipate our findings are that Molecule B and Molecule C, which inhibits the Ras1/MAPK pathway, are promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.

Total Synthesis of (±)-Jujuyane.

The first total synthesis of (±)-jujuyane, a cyclooctanoid natural product, was accomplished from a (5 + 3) dimerization product of oxidopyrylium ylide that forms the cyclooctanoid core structure along with inherited stereochemical bias. Selective functional group modifications of the highly oxygenated dimeric structure, followed by the tactical functional group manipulation around the eight-membered carbocyclic core, enabled the total synthesis of (±)-jujuyane, which will serve a guide for future applications of oxidopyrylium dimers to the natural product total synthesis.

Receptor protein tyrosine phosphatase delta is not essential for synapse maintenance or transmission at hippocampal synapses.

Members of the leukocyte common antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family, comprising PTPσ, PTPδ and LAR, are key hubs for presynaptic assembly and differentiation in vertebrate neurons. However, roles of individual LAR-RPTP members have not been investigated using member-specific conditional knockout mice. Here, we show that loss of PTPδ had no overt effect on synapse development in mouse cultured hippocampal neurons. Moreover, loss of PTPδ in presynaptic CA1 hippocampal neurons did not influence neurotransmitter release in subicular pyramidal neurons, suggesting that PTPδ is not critical for presynaptic function in vivo. Our results demonstrate that PTPδ is not essential for synapse maintenance or transmission, at least in the mouse hippocampus, and underscore the importance of using sophisticated genetic approaches to confirm the roles of synaptic proteins.

PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses.

Leukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. In the current study, we analyzed the synaptic role of PTPσ using newly generated, single conditional knockout (cKO) mice targeting PTPσ. We found that the number of synapses was reduced in PTPσ cKO cultured neurons in association with impaired excitatory synaptic transmission, abnormal vesicle localization, and abnormal synaptic ultrastructure. Strikingly, loss of presynaptic PTPσ reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. Furthermore, loss of presynaptic PTPσ in hippocampal CA1 pyramidal neurons had no impact on postsynaptic glutamate receptor responses in subicular pyramidal neurons. Postsynaptic PTPσ deletion had no effect on excitatory synaptic strength. Taken together, these results demonstrate that PTPσ is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.

Calsyntenin-3 interacts with both α- and ß-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways.

Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, using LC-MS/MS-based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, we show that ß-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive ß-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits, including Schaffer collateral afferents.

Au(I)-Catalyzed Cyclization of Epoxyalkynes to Allylic Alcohol Containing Spiroketals and Application to the Total Synthesis of (-)-Alotaketal A.

A gold-catalyzed tandem spiroketalization of epoxyalkynes accompanied by epoxide rearrangement into the corresponding allylic alcohol was developed for the construction of functionalized spiroketals. This new synthetic methodology for unsaturated spiroketals warranted a facile total synthesis of alotaketal A from carvone via a corresponding epoxyalkyne precursor.

Biosynthetically Inspired Syntheses of Secu'amamine A and Fluvirosaones A and B.

Presented here is a concise synthesis of secu'amamine A, and fluvirosaones A and B from readily available allosecurinine and viroallosecurinine. The key C2-enamine derivative of (viro)allosecurinine, the presumed biosynthetic precursors of these natural products, was accessed, for the first time, by a VO(acac)2 -mediated regioselective Polonovski reaction. Formal hydration and 1,2-amine shift of this pluripotent enamine compound afforded secu'amamine A. Formal oxidative [3+2] cycloaddition reaction between this enamine and TMS-substituted methallyl iodide reagent paved the way to the precursors of fluvirosaones A and B. The relative stereochemistry at the C2 position of these advanced intermediates governs the fate of 1,2-amine shift leading to fluvirosaones A and B. The syntheses of potential biosynthetic precursors and investigations of their chemical reactivities have provided insights regarding the biogenesis of these natural products.

Synthetic Strategies for (-)-Cannabidiol and Its Structural Analogs.

(-)-Cannabidiol ((-)-CBD), a non-psychoactive phytocannabinoid from Cannabis, and its structural analogs have received growing attention in recent years because of their potential therapeutic benefits, including neuroprotective, anti-epileptic, anti-inflammatory, anxiolytic, and anti-cancer properties. (-)-CBD and its analogs have been obtained mainly based on extraction from the natural source; however, the conventional extraction-based methods have some drawbacks, such as poor quality control along with purification difficulty. Chemical-synthetic strategies for (-)-CBD could tackle these issues, and, additionally, generate novel (-)-CBD analogs that exhibit advanced biological activities. This review concisely summarizes the historic and recent milestones in the synthetic strategies for (-)-CBD and its analogs.

Cu(OTf)2-Promoted 1,4-Addition of Alkyl Bromides to Dehydroalanine.

Zn/Cu(OTf)2-mediated addition of alkyl bromides to dehydroalanine (Dha) derivatives including dipeptides and tripeptides in good to high yields under an aqueous medium was developed. This protocol allows selective and biocompatible access to various amino acid units from Dha derivatives.

(+)-Dimericbiscognienyne A: Total Synthesis and Mechanistic Investigations of the Key Heterodimerization.

The first total synthesis of (+)-dimericbiscognienyne A is described. Key to the successful access to (+)-dimericbiscognienyne A was a biosynthetically inspired Diels-Alder reaction between two differential epoxyquinoid monomers and the subsequent intramolecular hemiacetal formation. The selective formation of the natural product among other possible diastereomers during the late-stage [4+2] cycloaddition reaction was investigated by DFT calculations and experimental control studies.

Small molecule activator of Nm23/NDPK as an inhibitor of metastasis.

Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.

Active maintenance of endothelial cells prevents kidney fibrosis.

BACKGROUND: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. METHODS: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. RESULTS: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system. CONCLUSION: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT.

Total Synthesis of (-)-Phorbaketal A.

A convergent asymmetric total synthesis of phorbaketal A was achieved in 10 steps through a Au(I)-catalyzed intramolecular spiroketalization reaction of an alkyne diol intermediate prepared from (R)-carvone and geranial. The spiroketalization reaction was regio- and stereoselective and was accompanied by isomerization of an exo-olefin into the trisubstituted olefin to form a unique spiroketal structure of phorbaketals.