Accurate Cutting-Force Measurement with Smart Tool Holder in Lathe.

Cutting force in lathe work is closely related to tool wear and affects the turning quality. Direct measurement of the cutting force by measuring the strain of the tool holder is challenging because the tool holder design aims to be highly rigid in order to undertake large cutting forces. Accordingly, the most popular dynamometer designs modify the standard tool holder by decreasing the structural rigidity of the holder, which reduces the machining precision and is not widely accepted. In order to solve the issue of the low stiffness of the dynamometer reducing the machining precision, in this paper, the ultra-low strain on the tool holder was successfully detected by the highly sensitive semiconductor strain gauges (SCSG) adjacent to the blade cutting insert. However, the cutting process would generate much heat, which increases the force measuring area temperature of the tool holder by about 30 °C. As a result, the readout drifted significantly with the temperature changes due to the high temperature coefficient of SCSG. To solve this problem, the temperature on the tool holder was monitored and a BP neural network was proposed to compensate for temperature drift errors. Our methods improved the sensitivity (1.14 × 10-2 mV/N) and the average relative error of the BP neural network prediction (≤1.48%) while maintaining the original stiffness of the tool holder. The smart tool holder developed possesses high natural frequency (≥6 kHz), it is very suitable for dynamic cutting-force measurement. The cutting experiment data in the lathe work show comparable performance with the traditional dynamometers and the resolution of the smart tool holder is 2 N (0.25% of total range).

D3PM: a comprehensive database for protein motions ranging from residue to domain.

BACKGROUND: Knowledge of protein motions is significant to understand its functions. While currently available databases for protein motions are mostly focused on overall domain motions, little attention is paid on local residue motions. Albeit with relatively small scale, the local residue motions, especially those residues in binding pockets, may play crucial roles in protein functioning and ligands binding. RESULTS: A comprehensive protein motion database, namely D3PM, was constructed in this study to facilitate the analysis of protein motions. The protein motions in the D3PM range from overall structural changes of macromolecule to local flip motions of binding pocket residues. Currently, the D3PM has collected 7679 proteins with overall motions and 3513 proteins with pocket residue motions. The motion patterns are classified into 4 types of overall structural changes and 5 types of pocket residue motions. Impressively, we found that less than 15% of protein pairs have obvious overall conformational adaptations induced by ligand binding, while more than 50% of protein pairs have significant structural changes in ligand binding sites, indicating that ligand-induced conformational changes are drastic and mainly confined around ligand binding sites. Based on the residue preference in binding pocket, we classified amino acids into "pocketphilic" and "pocketphobic" residues, which should be helpful for pocket prediction and drug design. CONCLUSION: D3PM is a comprehensive database about protein motions ranging from residue to domain, which should be useful for exploring diverse protein motions and for understanding protein function and drug design. The D3PM is available on www.d3pharma.com/D3PM/index.php .

Comparisons of Isolation Methods, Structural Features, and Bioactivities of the Polysaccharides from Three Common Panax Species: A Review of Recent Progress.

Panax spp. (Araliaceae family) are widely used medicinal plants and they mainly include Panax ginseng C.A. Meyer, Panax quinquefolium L. (American ginseng), and Panax notoginseng (notoginseng). Polysaccharides are the main active ingredients in these plants and have demonstrated diverse pharmacological functions, but comparisons of isolation methods, structural features, and bioactivities of these polysaccharides have not yet been reported. This review summarizes recent advances associated with 112 polysaccharides from ginseng, 25 polysaccharides from American ginseng, and 36 polysaccharides from notoginseng and it compares the differences in extraction, purification, structural features, and bioactivities. Most studies focus on ginseng polysaccharides and comparisons are typically made with the polysaccharides from American ginseng and notoginseng. For the extraction, purification, and structural analysis, the processes are similar for the polysaccharides from the three Panax species. Previous studies determined that 55 polysaccharides from ginseng, 18 polysaccharides from American ginseng, and 9 polysaccharides from notoginseng exhibited anti-tumor activity, immunoregulatory effects, anti-oxidant activity, and other pharmacological functions, which are mediated by multiple signaling pathways, including mitogen-activated protein kinase, nuclear factor kappa B, or redox balance pathways. This review can provide new insights into the similarities and differences among the polysaccharides from the three Panax species, which can facilitate and guide further studies to explore the medicinal properties of the Araliaceae family used in traditional Chinese medicine.

Exploring Conformational Change of Adenylate Kinase by Replica Exchange Molecular Dynamic Simulation.

Replica exchange molecular dynamics (REMD) simulation is a popular enhanced sampling method that is widely used for exploring the atomic mechanism of protein conformational change. However, the requirement of huge computational resources for REMD, especially with the explicit solvent model, largely limits its application. In this study, the availability and efficiency of a variant of velocity-scaling REMD (vsREMD) was assessed with adenylate kinase as an example. Although vsREMD achieved results consistent with those from conventional REMD and experimental studies, the number of replicas required for vsREMD (30) was much less than that for conventional REMD (80) to achieve a similar acceptance rate (∼0.2), demonstrating high efficiency of vsREMD to characterize the protein conformational change and associated free-energy profile. Thus, vsREMD is a highly efficient approach for studying the large-scale conformational change of protein systems.

Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations.

The substitution of methyl (Me or -CH3) by trifluoromethyl (TFM or -CF3) is frequently used in medicinal chemistry. However, the exact effect of -CH3/-CF3 substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that -CH3 is substituted by -CF3, and the statistical results showed that the replacement of -CH3 with -CF3 does not improve bioactivity on average. Yet, 9.19% substitution of -CH3 by -CF3 could increase the biological activity by at least an order. A PDB survey revealed that -CF3 prefers Phe, Met, Leu, and Tyr, while -CH3 prefers Leu, Met, Cys, and Ile. If we substitute the -CH3 by -CF3 near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 -CH3/-CF3 pairs of protein-ligand complexes and found that the -CH3/-CF3 substitution does achieve a large energy gain in some systems, although the mean energy difference is subtle, which is consistent with the statistical survey. The -CF3 substitution on the benzene ring could be particularly effective at gaining binding energy. The maximum improvements in energy achieved -4.36 kcal/mol by QM/MM calculation. Moreover, energy decompositions from MM/GBSA calculations showed that the large energy gains for the -CH3/-CF3 substitution are largely driven by the electrostatic energy or the solvation free energy. These findings may shed some light on the biological activity profile for -CH3/-CF3 substitution, which should be useful for further drug discovery and drug design.

Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.

The enoyl-acyl carrier protein reductase InhA of Mycobacterium tuberculosis is an attractive, validated target for antituberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure-based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski's rule and avoidance of PAINS-like properties and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 µg/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 µM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e., in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA.

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors.

Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanism of reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI thioethers were stereoselectively oxidized to (R)- and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion. By comparing the area under the plasma concentration-time curve ratios of thioether to rabeprazole under different routes of administration and blood sampling site, it was determined that thioether was mainly formed in the liver rather than the intestine. The formation rate of PPI thioethers in liver subcellular fractions was significantly higher than that in buffers. Sulfhydryl-blocking agents, such as N-ethylmaleimide, menadione, and ethacrynic acid, inhibited the reductive metabolism of PPIs in vitro, and their corresponding glutathione conjugates were observed. Similar amounts of thioethers were formed in glutathione solutions as in liver subcellular fractions, indicating that biologic reducing agents, instead of reductases, accelerated the reductive metabolism of PPIs. The reduction rates in glutathione solutions were ordered as follows: rabeprazole > omeprazole > lansoprazole > pantoprazole, which was consistent with the natural bond orbital charges of sulfur atoms in these compounds. In conclusion, PPIs were transformed into thioethers by biologic reducing agents in liver, and thioethers continued to be oxidized to two enantiomers, leading to chiral inversion. Furthermore, inhibiting oxidative metabolism of PPIs enhanced reductive metabolism and chiral inversion.

D3Pockets: A Method and Web Server for Systematic Analysis of Protein Pocket Dynamics.

The intrinsic dynamic properties of the ligand-binding pockets of proteins are important for the protein function mechanism and thus are useful to drug discovery and development. Few methods are available to study the dynamic properties, such as pocket stability, continuity, and correlation. In this work, we develop a method and web server, namely, D3Pockets, for exploring the dynamic properties of the protein pocket based on either molecular dynamics (MD) simulation trajectories or conformational ensembles. Application of D3Pockets on five target proteins as examples, namely, HIV-1 protease, BACE1, L-ABP, GPX4, and GR, uncovers more information on the dynamic properties of the ligand-binding pockets, which should be helpful to understanding protein function mechanism and drug design. The D3Pockets web server is available at http://www.d3pharma.com/D3Pocket/index.php .

Halogen bonding in differently charged complexes: basic profile, essential interaction terms and intrinsic σ-hole.

Studies on halogen bonds (XB) between organohalogens and their acceptors in crystal structures revealed that the XB donor and acceptor could be differently charged, making it difficult to understand the nature of the interaction, especially the negatively charged donor's electrophilicity and positively charged acceptor's nucleophilicity. In this paper, 9 XB systems mimicking all possibly charged halogen bonding interactions were designed and explored computationally. The results revealed that all XBs could be stable, with binding energies after removing background interaction as strong as -1.2, -3.4, and -8.3 kcal mol-1 for Cl, Br, and I involved XBs respectively. Orbital and dispersion interactions are found to be always attractive while unidirectional intermolecular electron transfer from a XB acceptor to a XB donor occurs in all XB complexes. These observations could be attributed to the intrinsic σ-hole of the XB donor and the intrinsic electronic properties of the XB acceptor regardless of their charge states. Intramolecular charge redistribution inside both the donor and the acceptor is found to be system-dependent but always leads to a more stable XB. Accordingly, this study demonstrates that the orbital-based origin of halogen bonds could successfully interpret the complicated behaviour of differently charged XB complexes, while electrostatic interaction may dramatically change the overall bonding strength. The results should further promote the application of halogens in all related areas.

Rh(III)-Catalyzed Redox-Neutral Unsymmetrical C-H Alkylation and Amidation Reactions of N-Phenoxyacetamides.

A Rh(III)-catalyzed unsymmetrical C-H alkylation and amidation of N-phenoxyacetamides with diazo compounds has been developed under mild and redox-neutral conditions, producing dinitrogen as the only byproduct. The reaction represents the first example of one-step, unsymmetrical difunctionalization of two ortho-C-H bonds. Experimental and computational studies support that N-phenoxyacetamides most likely undergo an initial ortho-C-H alkylation with diazo compounds via a Rh(III)-catalyzed C-H activation, and the resulting Rh(III) intermediate subsequently undergoes an intramolecular oxidative addition into the O-N bond to form a Rh(V) nitrenoid species that is protonated and further directed toward electrophilic addition to the second ortho position of the phenyl ring. This work might provide a new direction for unsymmetrical C-H difunctionalization reactions in an efficient manner.

Mass Spectrometry and Theoretical Investigation of VN n+ ( n = 8, 9, and 10) Clusters.

VN n+ clusters were generated by laser ablation and analyzed by mass spectrometry. The results showed that VN8+, VN9+, and VN10+ clusters were formed, and the mass peak of VN8+ is dominant in the spectrum. The VN8+ cluster was further investigated by a photodissociation experiment with 266 nm photons. Density functional theory calculations were conducted at the M06-2X/6-311+G(d,p) level to search for stable structures of VN n+ ( n = 8, 9, and 10) and their neutral counterparts. The theoretical calculations revealed that the most stable structure of VN8+ is in the form of V(N2)4+ with D 4h symmetry. The binding energy from the calculation is in good agreement with that obtained from the photodissociation experiments. The global minimum structures of VN8, VN9+/0, and VN10+/0 contain a similar substructure of the N4 ring and exhibit energy properties. The most stable structure of VN9+ is in the form of (η2-N4)V+N(N2)2 with C1 symmetry, while that of VN10+ is in the form of (η4-N4)V+(N2)3 with C s symmetry. For neutral VN8, VN9, and VN10, (η4-N4)V(N2)2, (η4-N4)V(N3)(N2), and (η4-N4)V(N2)3 are their ground-state structures, with decomposition into one V atom, and corresponding quantities of N2 can release energies of about 50.20, 96.28, and 57.76 kcal/mol, respectively.

Eutypenoids A-C: Novel Pimarane Diterpenoids from the Arctic Fungus Eutypella sp. D-1.

Eutypenoids A-C (1-3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A-C (1-3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities.

Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel.

Clopidogrel, a thienopyridine antiplatelet prodrug, is metabolized by oxidation to 2-oxo-clopidogrel, followed by conversion to its pharmacologically active thiol metabolite. After oral administration of clopidogrel to humans, two thiol isomers (H3 and H4) are observed in plasma, with similar concentrations, and only H4 is active in humans. In this work, the mechanism of stereoselectivity in the formation and S-methylation of H3 and H4 was investigated in vitro. The two diastereomers of 2-oxo-clopidogrel were epimerized rapidly at physiologic pH. The intrinsic clearance (CLint) for H3 formation from 2-oxo-clopidogrel in human liver microsomes (HLMs) was 3.1-fold higher than that for H4 formation, indicating stereoselective metabolism. Kinetic studies using expressed enzymes demonstrated that the contributions of CYP2B6, CYP2C19, and CYP3A4 to the formation of H4 from 2-oxo-clopidogrel were 18.5%, 26.1%, and 53.5%, respectively. The CLint ratios of H3 formation to H4 formation from 2-oxo-clopidogrel by CYP2B6, CYP2C19, and CYP3A4 were 2.2, 1.0, and 1.7, respectively. In HLMs, H3 and H4 were further S-methylated, and the S-methylation was inhibited by 2,3-dichloromethyl benzylamine, indicating the involvement of thiol S-methyltransferase. The CLint value for the S-methylation of H3 in HLMs was 98.1-fold higher than that for H4. The stereoselective formation of H3 from 2-oxo-clopidogrel and the stereoselective S-methylation of H3 may lead to the similar exposure levels of H3 and H4 previously reported in humans. The epimerization of 2-oxo-clopidogrel and the variations of thiol S-methyltransferase may affect the exposure to H4 in humans.

Redox-neutral rhodium-catalyzed C-H functionalization of arylamine N-oxides with diazo compounds: primary C(sp(3))-H/C(sp(2))-H activation and oxygen-atom transfer.

An unprecedented rhodium(III)-catalyzed regioselective redox-neutral annulation reaction of 1-naphthylamine N-oxides with diazo compounds was developed to afford various biologically important 1H-benzo[g]indolines. This coupling reaction proceeds under mild reaction conditions and does not require external oxidants. The only by-products are dinitrogen and water. More significantly, this reaction represents the first example of dual functiaonalization of unactivated a primary C(sp(3) )H bond and C(sp(2) )H bond with diazocarbonyl compounds. DFT calculations revealed that an intermediate iminium is most likely involved in the catalytic cycle. Moreover, a rhodium(III)-catalyzed coupling of readily available tertiary aniline N-oxides with α-diazomalonates was also developed under external oxidant-free conditions to access various aminomandelic acid derivatives by an O-atom-transfer reaction.

Effect of interface layer on the enhancement of thermal conductivity of SiC-Water nanofluids: Molecular dynamics simulation.

To investigate the impact of interfacial layer effects on the thermal conductivity of nanofluids and the microscopic mechanisms of enhanced thermal conductivity, this study employed non-equilibrium molecular dynamics to compute the thermal conductivity, number density, radial distribution function, and mean square displacement distribution of SiC nanofluids. The impact of nanoparticle volume fraction and particle size parameters on the thermal conductivity of nanofluids and the structure of interfacial adsorption layers was discussed. The simulation calculation results show that the coefficient of thermal conductivity of nanofluid is positively related to the volume fraction of nanoparticles, increasing from 0.6529 W/(m·K) to 0.8159 W/(m·K), and the enhancement of thermal conductivity by the volume fraction can be up to 33.97 %. The thermal conductivity is inversely correlated with the change in particle size, and the maximum improvement in thermal conductivity by particle size can reach up to 12.05 %. The simulated results of the thermal conductivity of nanofluid are almost consistent with the predicted results of the Yu&Choi model, and the error is controlled within 5 %. Simultaneously, the thickness of the interfacial adsorption layer decreases with an increase in particle size. This reduction arises due to larger particles having a smaller specific surface area, resulting in fewer particle surfaces covered by the interface layer. Moreover, the impact of particle size on the arrangement and affinity of molecules within the interface layer contributes to this decrease. Overall, interface layer effects exhibit a dual impact on the thermal conduction of nanofluids. The structured formation and high-density distribution of the adsorption layer contribute to enhanced heat transfer, while thermal resistance between nanoparticle surfaces and the fluid restricts heat transmission.

Panax ginseng against myocardial ischemia/reperfusion injury: A review of preclinical evidence and potential mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer (P. ginseng) is effective in the prevention and treatment of myocardial ischemia-reperfusion (I/R) injury. The mechanism by which P. ginseng exerts cardioprotective effects is complex. P. ginseng contains many pharmacologically active ingredients, such as molecular glycosides, polyphenols, and polysaccharides. P. ginseng and each of its active components can potentially act against myocardial I/R injury. Myocardial I/R was originally a treatment for myocardial ischemia, but it also induced irreversible damage, including oxygen-containing free radicals, calcium overload, energy metabolism disorder, mitochondrial dysfunction, inflammation, microvascular injury, autophagy, and apoptosis. AIM OF THE STUDY: This study aimed to clarify the protective effects of P. ginseng and its active ingredients against myocardial I/R injury, so as to provide experimental evidence and new insights for the research and application of P. ginseng in the field of myocardial I/R injury. MATERIALS AND METHODS: This review was based on a search of PubMed, NCBI, Embase, and Web of Science databases from their inception to February 21, 2022, using terms such as "ginseng," "ginsenosides," and "myocardial reperfusion injury." In this review, we first summarized the active ingredients of P. ginseng, including ginsenosides, ginseng polysaccharides, and phytosterols, as well as the pathophysiological mechanisms of myocardial I/R injury. Importantly, preclinical models with myocardial I/R injury and potential mechanisms of these active ingredients of P. ginseng for the prevention and treatment of myocardial disorders were generally summarized. RESULTS: P. ginseng and its active components can regulate oxidative stress related proteins, inflammatory cytokines, and apoptosis factors, while protecting the myocardium and preventing myocardial I/R injury. Therefore, P. ginseng can play a role in the prevention and treatment of myocardial I/R injury. CONCLUSIONS: P. ginseng has a certain curative effect on myocardial I/R injury. It can prevent and treat myocardial I/R injury in several ways. When ginseng exerts its effects, should be based on the theory of traditional Chinese medicine and with the help of modern medicine; the clinical efficacy of P. ginseng in preventing and treating myocardial I/R injury can be improved.

MC design and FIB preparation of a YSZ biochemical material microstructure.

Aiming at the difficulty of traditional machining of Y2O3-ZrO2 (YSZ) inert ceramic materials, a different method using focused ion beam to selectively create nanoscale microscale structures on the surface of materials was proposed. The sputtering yield, surface damage, and the energy loss of YSZ materials was investigated using the SRIM software using the Monte Carlo method. It is shown that the sputtering yield increases with ion energy in the range 0-30 keV, reaching a maximum of 9.4 atoms/ion at 30 keV. At an ion beam voltage of 30 keV, the most severe damage to the material is 8 mm on the surface. At the same time, the main forms of energy loss in the treatment are phonon energy loss and ionization energy loss, of which phonon energy loss due to the recoil atoms is the largest. In addition, we continue to perform focused ion beam processing experiments on YSZ materials, combining previous MC modeling to optimize different operating conditions such as ion beam, voltage and processing mode. The optimized processing parameters are 30 keV and 2.5 nA. It is shown that the quality of the deep grooves gradually improves with decreasing ion beam current at the same ion beam voltage. However, an excessively small ion beam current leads to an excessively large depth of the deep grooves and lengthy processing times.

Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms.

BACKGROUND: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases. METHODS: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews. RESULTS: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-ß/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases. CONCLUSION: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases.

Ginsenoside compound K protects against cerebral ischemia/reperfusion injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Background: Ginsenoside compound K (CK), the main active metabolite in Panax ginseng, has shown good safety and bioavailability in clinical trials and exerts neuroprotective effects in cerebral ischemic stroke. However, its potential role in the prevention of cerebral ischemia/reperfusion (I/R) injury remains unclear. Our study aimed to investigate the molecular mechanism of ginsenoside CK against cerebral I/R injury. Methods: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion induced PC12 cell model and middle cerebral artery occlusion/reperfusion induced rat model, to mimic I/R injury. Intracellular oxygen consumption and extracellular acidification rate were analyzed by Seahorse multifunctional energy metabolism system; ATP production was detected by luciferase method. The number and size of mitochondria were analyzed by transmission electron microscopy and MitoTracker probe combined with confocal laser microscopy. The potential mechanisms of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by RNA interference, pharmacological antagonism combined with co-immunoprecipitation analysis and phenotypic analysis. Results: Ginsenoside CK pretreatment could attenuate mitochondrial translocation of DRP1, mitophagy, mitochondrial apoptosis, and neuronal bioenergy imbalance against cerebral I/R injury in both in vitro and in vivo models. Our data also confirmed that ginsenoside CK administration could reduce the binding affinity of Mul1 and Mfn2 to inhibit the ubiquitination and degradation of Mfn2, thereby elevating the protein level of Mfn2 in cerebral I/R injury. Conclusion: These data provide evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Gut Microbiota: Therapeutic Targets of Ginseng Against Multiple Disorders and Ginsenoside Transformation.

Panax ginseng, as the king of Chinese herb, has significant therapeutic effects on obesity, type 2 diabetes mellitus, fatty liver disease, colitis, diarrhea, and many other diseases. This review systematically summarized recent findings, which show that ginseng plays its role by regulating gut microbiota diversity, and gut microbiota could also regulate the transformation of ginsenosides. We conclude the characteristics of ginseng in regulating gut microbiota, as the potential targets to prevent and treat metabolic diseases, colitis, neurological diseases, cancer, and other diseases. Ginseng treatment can increase some probiotics such as Bifidobacterium, Bacteroides, Verrucomicrobia, Akkermansia, and reduce pathogenic bacteria such as Deferribacters, Lactobacillus, Helicobacter against various diseases. Meanwhile, Bacteroides, Eubacterium, and Bifidobacterium were found to be the key bacteria for ginsenoside transformation in vivo. Overall, ginseng can regulate gut microbiome diversity, further affect the synthesis of secondary metabolites, as well as promote the transformation of ginsenosides for improving the absorptivity of ginsenosides. This review can provide better insight into the interaction of ginseng with gut microbiota in multiple disorders and ginsenoside transformation.