Unraveling the Disulfide-Carbonyl n → π* Interactions in a Gas Phase Molecular Complex and Proteins.

The weak contacts between disulfide linkages and carbonyl groups are anticipated to be important in determining the structure and function of enzymes and proteins. However, the characteristics of the disulfide-carbonyl n → π* (nSS → π* C═O) interactions remain unexplored. Herein, we investigated the nSS → π* C═O interactions in the gas phase and in proteins. Rotational spectroscopic investigation of a model complex of allyl methyl disulfide with formaldehyde identified two structures, both of which are stabilized through a dominant nSS → π* C═O interaction. Surveys of the Protein Data Bank revealed the occurrence of 18 675 nSS → π* C═O interactions associated with 15 320 disulfide bonds in 7105 protein structures. Further theoretical analyses characterize the bonding nature of the nSS → π* C═O interactions. This study provides an in-depth understanding of the stabilizing effect of the nSS → π* C═O interactions in small molecular complexes and biomacromolecules.

The inhibitory effects of free and bound phenolics from Phyllanthus emblica Linn. on α-amylase: a comparison study.

BACKGROUND: Phyllanthus emblica Linn. (PE) is rich in polyphenols, which can be categorized into free and bound phenolics (PEFP and PEBP). This study evaluated the inhibitory effect of PEFB and PEBP on α-amylase for the first time. The mechanism of the inhibition effect of PEFP and PEBP on α-amylase was investigated by enzyme inhibition kinetics, multispectral analysis, thermodynamics, and molecular docking. RESULTS: Free and bound phenolics inhibited α-amylase activity effectively in a mixed type of inhibition. Fluorescence quenching and thermodynamic analyses showed that the binding of PEFP and PEBP to α-amylase occurred through a static quenching process (Kq = 6.94 × 10¹² and 5.74 × 10¹² L mol-1 s-1), which was accompanied by a redshift (λem from 343 to 347 nm), leading to a change in the microenvironment. This process was found to be a spontaneous exothermic reaction (ΔG < 0). Circular dichroism (CD) analysis confirms that the secondary structure of α-amylase was altered, in particular a decrease in α-helixes and an increase in random coils. Molecular docking studies showed that PEFP and PEBP interacted with α-amylase through hydrogen bonding and hydrophobic interactions. CONCLUSION: The present study provides valuable insights into the mechanism of action of PEFP and PEBP on α-amylase, which will provide a theoretical basis for their possible use as novel natural α-amylase inhibitors. © 2024 Society of Chemical Industry.

The sEVs miR-487a/Notch2/GATA3 axis promotes osteosarcoma lung metastasis by inducing macrophage polarization toward the M2-subtype.

Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

Inhibitory activities and mechanisms of free and bound phenolics on α-glucosidase in fresh fruits of Phyllanthus emblica Linn. using spectroscopy and molecular docking.

Phyllanthus emblica Linn. (PE) fresh fruits contain high concentrations of polyphenolics, of which free and bound phenolics are rich in biological activities. In this study, the inhibitory activity and mechanism of PEFP and PEBP on α-glucosidase (α-GLU) were investigated using spectroscopic techniques, kinetic analysis, and molecular docking. The results showed that 13 PEFP and 12 PEBP were identified by UPLC-MS/MS analysis, and Bis-HHDP-hexose and castalagin (vesgalagin) were found for the first time in PE fresh fruits. Kinetic analysis of enzyme inhibition showed that a mixture of free and bound phenolics inhibited α-GLU, and the effect of the conformational relationship of PEFP and PEBP with α-GLU on hypoglycemia was further explored by fluorescence quenching, circular dichroism (CD) spectroscopy, and molecular docking analysis. The findings demonstrated the inhibitory activity and mechanism of free and bound phenolics on α-GLU and provided a theoretical basis for PE polyphenolics as α-GLU inhibitors for hypoglycemia.

Cost-Effectiveness Analysis of Fluocinolone Acetonide Intravitreal (FAI) Implant for Chronic Noninfectious Uveitis Affecting the Posterior Segment of the Eye (NIU-PS) in China.

INTRODUCTION: Chronic non-infectious uveitis affecting the posterior segment (NIU-PS), which can be recurrent and persistent for numerous years, mainly affects people of working age and significantly increases the risk of visual impairment. This study aimed to investigate the cost-effectiveness of fluocinolone acetonide intravitreal (FAI) implant in the treatment of patients with chronic NIU-PS from the Chinese healthcare perspective. METHODS: A Markov model with a 2-week cycle was constructed from the perspective of the Chinese healthcare system over a lifetime time horizon. The model consists of four health states: on-treatment, treatment failure, blindness, and death. The outcomes for effectiveness were based on the Chinese real-world study (RWS). Utilities and mortality rates were derived from published literature and standard sources. Costs were determined from the MENET website, prices of medical service items at local providers, published literature, and expert surveys. Outcomes were measured in quality-adjusted life years (QALYs). Sensitivity analyses were performed to account for the impact of uncertainty. RESULTS: It was estimated that in the base case, the FAI implant provided 0.43 incremental QALYs compared with the limited current practice (LCP) at an additional cost of $7503.72 (¥50,575.05), resulting in an incremental cost-effectiveness ratio (ICER) of $17,373.49 (¥117,097.33) per QALY gained. Parameters related to utility emerged as the primary influencers on the outcomes. In probabilistic sensitivity analysis (PSA), considering the willingness-to-pay (WTP) threshold of $19,072 (¥128,547) and $38,145 (¥257,094), the FAI implant had 67.70% and 99.50% probability of being cost-effective, respectively. As demonstrated in the scenario analysis, if the FAI implant aligns its price reduction with the average rate from the 2023 negotiation of the National Reimbursement Drug List (NRDL), it would result in lower costs and represent an absolute advantage. CONCLUSIONS: The FAI implant, which can effectively reduce the recurrence rate and maintain the incremental costs within the WTP limit, is likely to be cost-effective in treating chronic NIU-PS in China.

Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis.

Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.

Feasibility study on identifying the source of cigarette ash based on infrared spectroscopy and chemometrics.

Crime scene investigation is a key step in collecting and identifying physical evidence that may be closely related to the crime. The size of physical evidence can range from macro to micro. Cigarettes are a type of popular consumables, and their burned ashes are valuable resources of physical evidence since they contain important information such as brand preferences. This work explores the feasibility of using attenuated total reflection mid-infrared (ATR-MIR) spectroscopy and chemometrics to achieve cigarette brand recognition from burned ash. A total of 600 cigarette samples from ten brands were collected for experiments, and the samples were divided into a training set and a testing set in a 2:1 ratio. The Relief-F algorithm was used to sort variables and the forward search was used to further optimize variables to obtain the optimal subset of variables. Based on this, a partial least-squares discriminant analysis (PLS-DA) model was established, achieving a total accuracy of 97% on the test set. As a reference, the maximum correlation coefficient method was also used for classification, with an accuracy of only 73%. It seems that using the variable selection and modeling scheme proposed in this article is feasible for identifying cigarette brands from burned ash.

Rotational spectroscopy of hydrogen-bonded binary trifluoro-propanol conformers: conformational diversity, preference and abundances in a jet expansion.

The rich conformational landscape including the associated conformational conversion paths of the hydrogen-bonded binary 3,3,3-trifluoropropanol (TFP) aggregate was explored using chirped pulse Fourier transform microwave spectroscopy and computational chemistry. To appropriately identify the binary TFP conformers responsible for the five sets of candidate rotational transitions assigned, we established a set of important conformational assignment criteria. These include an extensive conformational search, good agreement between the experimental and theoretical rotational constants, relative magnitude of the three dipole moment components, and quartic centrifugal distortion constants, and observation and non-observation of the predicted conformers. Extensive conformational searches were carried out using CREST, a conformational search tool, producing hundreds of structural candidates. The CREST candidates were screened using a multitier approach and subsequently the low energy conformers (<25 kJ mol-1) were optimized at the B3LYP-D3BJ/def2-TZVP level, leading to 62 minima within an energy window of 10 kJ mol-1. Good agreement with the predicted spectroscopic properties mentioned above allowed us to clearly identify five binary TFP conformers as the molecular carriers. Particularly, a combined kinetic and thermodynamic model was developed, which provides a satisfactory explanation for the observation and non-observation of the low energy conformers predicted. The role of the intra- and intermolecular hydrogen bonding interactions in the stability ordering of the binary conformers is discussed.

Identification of microRNAs implicated in modulating resveratrol-induced apoptosis in porcine granulosa cells.

MicroRNAs (miRNAs) are small, noncoding RNAs that play a crucial role in the complex and dynamic network that regulates the apoptosis of porcine ovarian granulosa cells (POGCs). Resveratrol (RSV) is a nonflavonoid polyphenol compound that is involved in follicular development and ovulation. In previous study, we established a model of RSV treatment of POGCs, confirming the regulatory effect of RSV in POGCs. To investigate the miRNA-level effects of RSV on POGCs to reveal differentially expressed miRNAs, a control group (n = 3, 0 µM RSV group), a low RSV group (n = 3, 50 µM RSV group), and a high RSV group (n = 3, 100 µM RSV group) were created for small RNA-seq. In total, 113 differentially expressed miRNAs (DE-miRNAs) were identified, and a RT-qPCR analysis showed a correlation with the sequencing data. Functional annotation analysis revealed that DE-miRNAs in the LOW vs. CON group may be involved in cell development, proliferation, and apoptosis. In the HIGH vs. CON group, RSV functions were associated with metabolic processes and responses to stimuli, while the pathways were related to PI3K24, Akt, Wnt, and apoptosis. In addition, we constructed miRNA-mRNA networks related to Apoptosis and Metabolism. Then, ssc-miR-34a and ssc-miR-143-5p were selected as key miRNAs. In conclusion, this study provided an improved understanding of effects of RSV on POGCs apoptosis through the miRNA modulations. The results suggest that RSV may promote POGCs apoptosis by stimulating the miRNA expressions and provided a better understanding of the role of miRNAs combined with RSV in ovarian granulosa cell development in pigs.

Evaluation of preclinical efficacy of human umbilical cord mesenchymal stem cells in ankylosing spondylitis.

Objective: Umbilical cord mesenchymal stem cells (UCMSCs) have significant regenerative, tissue repair, and immunomodulatory properties that can help reduce inflammatory responses in patients with ankylosing spondylitis (AS). In this study, we used a combination of bovine proteoglycan and dimethyldioctadecylammonium (DDA) to establish a mouse model of proteoglycan-induced spondylitis (PGISp). To evaluate the therapeutic effects of UCMSCs, we treated PGISp mice with different doses of hUCMSCs via tail vein injection. Methods: At week 13, the PGISp mice exhibited thickened, erythematous paws, erythema in the extremities, and lameness. CT scans revealed necrotic lysis of chondrocytes, formation of fissures, visible hemorrhage, connective tissue hyperplasia, and focal infiltration of lymphocytes in the intervertebral discs. At week 14, the PGISp mice were randomly divided into three groups and administered different doses of hUCMSCs (0.25, 0.5, and 1.0×107 cells/kg, iv, QOW×2, n=10). To assess the therapeutic effects of hUCMSCs, we evaluated Th cell subsets in the spleen, spleen and thymus coefficients, peripheral blood inflammatory factors, and pathological and imaging observations of the spines and lumbar spines in the PGISp mice. Results: The results demonstrated that injection of hUCMSCs shifted the balance axis between Th1 and Th2 cells in the spleen towards Th2 cells. Moreover, the spleen coefficient and levels of inflammatory cytokines (TNF-α and CCL-2) in the serum decreased after hUCMSC injection. CT imaging and pathological analysis indicated that hUCMSC treatment inhibited ectopic osteogenesis and maintained clear small joint gaps, which slowed down the progression of structural lesions in the disc, nucleus pulposus, fibrous ring, and cartilage in PGISp mice. Conclusion: Administering hUCMSCs at the 14th week after modeling proved to be an effective treatment for PGISp mice. This experiment offers a valuable reference for the pre-clinical use of hUCMSCs in the treatment of AS.

Indirubin combined with umbilical cord mesenchymal stem cells to relieve psoriasis-like skin lesions in BALB/c mice.

Objective: To investigate the efficacy of indirubin combined with human umbilical cord mesenchymal stem cells (hUC-MSCs) in the treatment of psoriatic lesions in BALB/c mice and to explore the related mechanism of indirubin in the treatment of psoriasis. Methods: A BALB/c mouse psoriasis model induced by imiquimod was established and randomly divided into the control group, model group, indirubin group, hUC-MSCs group, and indirubin combined with hUC-MSCs group. Psoriasis area and severity index (PASI) score was used to observe skin lesion changes in the psoriasis-like mouse model. The epidermal scale, the degree of keratinization, and the infiltration of inflammatory cells were observed by hematoxylin eosin (HE) staining. The concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice were measured using enzyme-linked immunosorbent assay (ELISA). Results: The PASI integral trend chart indicates that hUC-MSCs and indirubin and the combination of drugs could relieve the appearance of skin lesions and accelerate the recovery of skin lesions. The indirubin group had the best effect in improving the scale of skin lesions. HE staining showed that the number of parakeratosis cells in the three treatment groups was significantly reduced, the degree of erythrocyte extravasation dermis hyperplasia and inflammatory cell infiltration was significantly lower than that in the model group, and the skin thickness and spleen index of the combined treatment group exhibited the most noticeable improvement. ELISA showed that the concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice in the hUC-MSCs treatment group, indirubin group, and combined administration group were all decreased compared with those in the model group, and the concentrations of IFN-γ, IL-17A, and IL-23 could be decreased significantly in the indirubin group. Conclusions: Both hUC-MSCs and indirubin can effectively reduce psoriasis-like lesions in BALB/c mice, and the combined administration of these drugs has the best effect.

A biomineralized Prussian blue nanotherapeutic for enhanced cancer photothermal therapy.

Photothermal therapy is a promising tumor ablation technique that converts light into heat energy to kill cancer cells. Prussian blue (PB), a biocompatible photothermal reagent, has been widely explored for cancer treatment. However, the translational potential of PB is severely hampered by its low photothermal conversion efficiency (PCE) and poor stability. To tackle these issues, we adopted the biomineralization modality where PB was integrated with calcium phosphate (CaP) through the binding between calcium ions and PB. The mineralized PB (CaP&PB) demonstrated significantly improved PCE (40.2%), resulting from a calcium-induced bandgap-narrowing effect, and exhibited superior suspension stability. Using a 4T1 orthotopic breast cancer BALB/c mouse model, we observed that mineralized PB showed a significant temperature increase within the tumor, which led to better tumoricidal activity compared with CaP and PB when identical NIR treatment was applied. These achievements demonstrated the success of introducing calcium phosphate into Prussian blue by biomineralization to improve the PCE and stability of photothermal reagents, suggesting an alternative translational strategy for enhanced cancer photothermal therapy.

Development of pyrazolo[3,4-d]pyrimidin-4-one scaffold as novel CDK2 inhibitors: Design, synthesis, and biological evaluation.

A series of pyrazolo[3,4-d]pyrimidin-4-one scaffold were designed and synthesized as novel CDK2 inhibitors. By analyzing the common motifs of various known inhibitors, the designed compounds 1 were virtually screen for their inhibitory activity by docking into the active pocket of CDK2. The influence of different substitutes on the docking results was investigated. A total of 15 pyrazolo[3,4-d]pyrimidin-4-ones 1 were synthesized by Paal-Knorr reaction, pyrimidine ring closure, bromination, Suzuki coupling reaction, amide formation and Knoevenagel condensation. The Cell Counting Kit-8 (CCK-8) was used to evaluate the inhibitory activity of pyrazolo[3,4-d]pyrimidin-4-ones 1 in the breast cancer cell line MCF-7 in vitro using Etoposide as a reference control substance. The screening results demonstrated that the designed compounds have significant antiproliferative activity, and compounds 1e and 1j were the most active compounds with IC50 values of 10.79 µM and 10.88 µM, respectively, being better than that of Etoposide (IC50 = 18.75 µM). The enzyme inhibition assay was carried out against CDK2, the results indicated that the compounds 1e and 1j significantly inhibited CDK2 with IC50 values of 1.71 µM and 1.60 µM.

Manganese Phosphate-Doxorubicin-Based Nanomedicines Using Mimetic Mineralization for Cancer Chemotherapy.

Inorganic nanomaterials showed great potential as drug carriers for chemotherapeutics molecules due to their biocompatible physical and chemical properties. A manganese-based inorganic nanomaterial manganese phosphate (MnP) had become a new drug carrier in cancer therapy. However, the approach for manganese phosphate preparation and drug integration is still confined in complex methods. Inspired by mimetic mineralization, we proposed a "one-step" method for the preparation of manganese phosphate-doxorubicin (DOX) nanomedicines (MnP-DOX) by manganese ion and DOX complexation. The structural characterization results revealed that the prepared MnP-DOX nanocomplexes were homogeneous with controlled sizes and shapes. More importantly, the MnP-DOX nanocomposites could significantly induce cancer inhibition in vitro and in vivo. The results indicated that the drug molecules were integrated into MnP nanocarriers by mimetic mineralization, which not only prevented the premature release of the drug but also reduced excessive modification. Moreover, the designed MnP-DOX complex showed high loading efficacy and pH-dependent degradation leading to drug release, achieving high efficiency for cancer chemotherapy in vitro and in vivo via a facile process. These achievements presented an approach to construct the manganese phosphate-based chemotherapy nanomedicines by mimetic mineralization for cancer therapy.

Pre-clinical efficacy evaluation of human umbilical cord mesenchymal stem cells for ischemic stroke.

Objective: This study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship. Methods: The levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1ß, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment. Results: The hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1ß but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×107/kg treatment showed the best therapeutic effect, followed by the 1×107/kg treatment, and the worst is 0.5×107/kg treatment from the test of balance beam, forelimb muscle strength, limb placement and the infarct area of the rat brain tissues. Conclusion: The hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurological/motor function and reduce the size of cerebral infarction in rats.

Fractional laser-assisted administration of human umbilical cord mesenchymal stem cells to reduce hypertrophic scars in rabbit ears.

BACKGROUND: The formation of hypertrophic scar is due to the abnormal accumulation and remodeling of the extracellular matrix, especially collagen tissue. Our research was designed to investigate the treatment effect of different administrations of human umbilical cord-derived stem cells and to hypertrophic scars on rabbit ears. METHODS: Thirty New Zealand female white rabbits were treated as hypertrophic scar models. PBS was injected into the scars on the right ear of each group as control, while human umbilical cord-derived stem cells or condition medium of human umbilical cord-derived stem cells were administrated into the left ear through subcutaneous injection or fractional laser-assisted administration. Gross examination, scar elevation index (SEI) calculation and sampling were executed 5 weeks after administration. Then H&E and Masson staining analysis and the expression levels detections of α-SMA, Collagen I, TGF-ß1, IL-1ß, and IL-6 were performed. RESULTS: Our results demonstrated that the severity of hyperplasia was lower than the model group after stem cells and conditioned medium treatment. H&E and Masson staining results showed that the inflammation in scars was greatly alleviated and the degree of fibrosis was reduced after treatment. There was no significant difference in the therapeutic effect between subcutaneous injection or fractional laser-assisted administration. Both stem cells and conditioned medium can down-regulate SEI and factors expression levels in all groups. However, compared with the stem cells, the therapeutic effects of the conditioned medium were lower. CONCLUSIONS: The results confirmed that stem cells had an available treatment effect on hypertrophic scars of rabbit ears. In addition to the paracrine pathway, stem cells may have other ways to treat hypertrophic scars. Fractional laser-assisted administration may become a potential administration of stem cell clinical application in the future.

The review of alpha-linolenic acid: Sources, metabolism, and pharmacology.

α-linolenic acid (ALA, 18:3n-3) is a carboxylic acid composed of 18 carbon atoms and three cis double bonds, and is an essential fatty acid indispensable to the human body. This study aims to systematically review related studies on the dietary sources, metabolism, and pharmacological effects of ALA. Information on ALA was collected from the internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library, and Europe PMC using a combination of keywords including "pharmacology," "metabolism," "sources." The following findings are mainly contained. (a) ALA can only be ingested from food and then converted into eicosapentaenoic acid and docosahexaenoic acid in the body. (b) This conversion process is relatively limited and affected by many factors such as dose, gender, and disease. (c) Pharmacological research shows that ALA has the anti-metabolic syndrome, anticancer, antiinflammatory, anti-oxidant, anti-obesity, neuroprotection, and regulation of the intestinal flora properties. (d) There are the most studies that prove ALA has anti-metabolic syndrome effects, including experimental studies and clinical trials. (e) The therapeutic effect of ALA will be affected by the dosage. In short, ALA is expected to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of ALA.

Preclinical evidence of synergism between atovaquone and chemotherapy by AMPK-dependent mitochondrial dysfunction.

Chemoresistance has been associated with increased reliance on mitochondrial functions in many cancers, including lung cancer. Atovaquone is an anti-malaria drug and mitochondrial inhibitor. In this work, we attempted to explore whether atovaquone can be repurposed for lung cancer treatment to overcome chemoresistance. We showed that atovaquone inhibited proliferation, colony formation and survival in non-small cell lung cancer cell (NSCLC) cells. Of note, the effective dose of atovaquone was clinically achievable. Combination index value indicated that atovaquone and carboplatin were synergistic in inhibiting NSCLC. The potent efficacy of atovaquone and its synergism with chemotherapeutic drug were also demonstrated in NSCLC xenograft mice model. Mechanism studies showed that the synergism between atovaquone and carboplatin was due to atovaquone's ability in disrupting mitochondrial functions via specifically inhibiting complex III induced oxygen consumption. Subsequently, atovaquone activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR) signaling. AMPK inhibition reversed the anti-NSCLC activity of atovaquone, suggesting that the action of atovaquone is also dependent on AMPK. Our work suggests that atovaquone is an attractive candidate for NSCLC treatment. Our findings emphasize that inhibition of mitochondrial function is a promising therapeutic strategy to enhance NSCLC chemosensitivity.

Efficacy and safety of Salvia miltiorrhiza (Salvia miltiorrhiza Bunge) and ligustrazine injection in the adjuvant treatment of early-stage diabetic kidney disease: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza and ligustrazine injection is a compound injection composed of the extract from Salvia miltiorrhiza and Ligusticum striatum (Ligusticum striatum DC.), has been frequently used for the adjuvant treatment of early-stage diabetic kidney disease (DKD) in China. Safety and efficacy studies in terms of evidence-based medical practice have become more prevalent in application to Chinese Herbal Medicine. It is necessary to assess the efficacy and safety of Salvia miltiorrhiza and ligustrazine injection in the adjuvant treatment of early-stage diabetic kidney disease by conducting a systematic review and meta-analysis of available clinical data. AIM OF THE STUDY: The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of Salvia miltiorrhiza and ligustrazine injection as an adjunctive therapy to conventional therapies for early-stage DKD. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist was used to structure this study. We searched the English databases PubMed, Cochrane library, and Chinese databases including Chinese journal full text database (CNKI), China Biomedical Documentation Service System (SinoMed), Wanfang digital periodical full text database and Chinese Scientific Journal Database (VIP). Relevant studies were selected based on the inclusion and exclusion criteria. Meta-analysis was performed with RevMan 5.3 software after data extraction and the quality of studies assessment. The quality of the evidence was assessed with the Cochrane risk of bias tool. Sensitivity analysis and Egger's test were performed using Stata 15.0 software. RESULTS: A total of 22 trials were included with 1939 patients. Meta-analysis showed that compared with the control group of conventional western medicine alone, Salvia miltiorrhiza and ligustrazine injection combined with conventional western medicine can achieve better efficacy in the treatment of early-stage DKD, reduce urinary albumin excretion rate (12RCTs, 1181 participants; SMD = -1.82, 95% CI [-2.62, -1.01], P < 0.00001), serum creatinine (13RCTs, 1228 participants; MD = -13.21 µmol/L, 95% CI [-19.58, -6.83], P < 0.0001), ß2-microglobulin (9RCTs, 669 participants; SMD = -1.45, 95% CI [-2.43, -0.48], P = 0.003) and reduce interleukin-6 (4RCTs, 331 participants; MD = -6.38 ng/L, 95% CI [-9.03, -3.78], P < 0.00001), interleukin-18 (2RCTs, 177 participants; MD = -29.78 ng/L, 95% CI [-41.51, -18.05], P < 0.00001), tumor necrosis factor-α (4RCTs, 331 participants; MD = -18.03 ng/L, 95% CI [-22.96, -13.09], P < 0.00001), with statistical differences and alleviate the body inflammatory response effectively. CONCLUSION: Based on the existing evidence, that Salvia miltiorrhiza and ligustrazine injection in the adjuvant treatment of early-stage diabetic kidney disease is safe and effective. However, due to the limitation of the quality of the included studies, the above conclusions need to be further verified by more relevant randomized controlled trials with high-quality large samples.