Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors.

Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 µM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 µM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma.

Ultra-weak photon emission in healthy subjects and patients with type 2 diabetes: evidence for a non-invasive diagnostic tool.

BACKGROUND: Spontaneous ultra-weak photon emission (UPE) is a common phenomenon in biological systems and has been linked to pathological states. Researchers have always considered ultra-weak photon emission a potential non-invasive diagnostic tool, but its application in the medical field is stagnant due to the lack of relevant data for pathological states. METHODS: Ultra-weak photon signals from five body sites (forehead, neck, heart, stomach, and navel) in fifty patients with type 2 diabetes and sixty age-matched healthy subjects were measured using a moveable whole-body biophoton detection system. Photon signal is measured for 10 min and detected in bins of 50 ms by a photomultiplier with a range of 290-630 nm. Each signal is a time series of 12 000 elements. Various parameters including photon intensity, Q value, squeezed state parameters (|α|, θ, ø, r) and SSI were analyzed. RESULTS AND CONCLUSION: we found significant differences in the abovementioned parameters between groups, and all subjects could be clustered into two groups according to the results obtained by principal component analysis. Methods and results from this study could be useful for constructing a UPE database for a range of diseases, which would promote the application of UPE in clinical diagnosis in the future.

Correlation between the different therapeutic properties of Chinese medicinal herbs and delayed luminescence.

In the practice and principle of Chinese medicine, herbal materials are classified according to their therapeutic properties. 'Cold' and 'heat' are the most important classes of Chinese medicinal herbs according to the theory of traditional Chinese medicine (TCM). In this work, delayed luminescence (DL) was measured for different samples of Chinese medicinal herbs using a sensitive photon multiplier detection system. A comparison of DL parameters, including mean intensity and statistic entropy, was undertaken to discriminate between the 'cold' and 'heat' properties of Chinese medicinal herbs. The results suggest that there are significant differences in mean intensity and statistic entropy and using this method combined with statistical analysis may provide novel parameters for the characterization of Chinese medicinal herbs in relation to their energetic properties.

Classification of Chinese herbs based on the cluster analysis of delayed luminescence.

Traditional Chinese material medica are an important component of the Chinese pharmacopeia. According to the traditional Chinese medicinal concept, Chinese herbal medicines are classified into different categories based on their therapeutic effects, however, the bioactive principles cannot be solely explained by chemical analysis. The aim of this study is to classify different Chinese herbs based on their therapeutic effects by using delayed luminescence (DL). The DL of 56 Chinese herbs was measured using an ultra-sensitive luminescence detection system. The different DL parameters were used to classify Chinese herbs according to a hierarchical cluster analysis. The samples were divided into two groups based on their DL kinetic parameters. Interestingly, the DL classification results were quite consistent with classification according to the Chinese medicinal concepts of 'cold' and 'heat' properties. In this paper, we show for the first time that by using DL technology, it is possible to classify Chinese herbs according to the Chinese medicinal concept and it may even be possible to predict their therapeutic properties.

The integrative and conjugative element ICECiPOL15 mediates horizontal transfer of ß-lactam resistance gene in Chryseobacterium indoltheticum POL15.

OBJECTIVES: The dissemination of antibiotic resistance genes (ARGs) from the environment, including agricultural sources, is of increasing concern. In this study, we examined the antibiotic resistance profile and genomic sequence of a strain of Chryseobacterium indoltheticum obtained from an agricultural location. METHODS: The multidrug-resistant bacterial strain POL15 was isolated from the wastewater of a livestock farm in China. Whole-genome sequencing was performed followed by bioinformatics analyses to identify integrative and conjugative elements (ICEs) and ARGs. Mating assays were performed to analyse ICE transferability. RESULTS: Whole-genome sequencing and annotation showed that the genome of POL15 encodes ARGs. Additionally, an ICE named ICECiPOL15, which carries a class C ß-lactamase-encoding gene blaAQU, was identified in the POL15 genome. Genes encoding an integrase, an excisionase, a relaxase, a type IV coupling protein and conjugative transposon proteins involved in a type IV secretion system were also identified in ICECiPOL15. Sequence alignment revealed that ICECiPOL15 might have evolved from other Chryseobacterium species. The horizontal transferability of ICECiPOL15 was demonstrated by mating experiments between C. indoltheticum POL15 and Escherichia coli DL21. CONCLUSIONS: This study represents the first characterization of a mobilizable antibiotic resistance ICE in a species of C. indoltheticum and provides evidence that C. indoltheticum strains could be important reservoirs and vehicles for ARGs on livestock farms.

Corrigendum: A biophoton method for identifying the quality states of fresh Chinese herbs.

[This corrects the article DOI: 10.3389/fphar.2023.1140117.].

A biophoton method for identifying the quality states of fresh Chinese herbs.

Introduction: The quality of Chinese herbs is the basis for ensuring their safety and efficacy. However, the quality evaluation system is imperfect. In particular, there is a lack of quality evaluation methods for fresh Chinese herbs during growth. The biophoton is a common phenomenon and provides complete information about the interior of the living system, which is consistent with the holistic concept of traditional Chinese medicine. Therefore, we aim to correlate the biophoton characteristics with the quality states to find the biophoton parameters that can characterize the quality states of fresh Chinese herbs. Methods: The biophoton characteristics of motherwort and safflower were measured and characterized by the counts per second (CPS) in the steady state and the initial intensity (I0) and coherent time (T) of delayed luminescence. The active ingredient content was measured by ultra-high-performance liquid chromatography (UPLC). The pigment content of motherwort leaves was measured by UV spectrophotometry. The t-test and correlation analysis were performed on the experimental results. Results: The CPS and I0 of motherwort and I0 of safflower showed a significant downward trend during the growth process, and their active ingredient content showed a trend that increased and then decreased. The CPS, I0, and the content of active ingredients and pigments in a healthy state were significantly higher than those in a poor state, while T showed the opposite results. The CPS and I0 were all significantly and positively correlated with the content of active ingredients and pigments, while the T of motherwort showed the opposite results. Conclusion: It is feasible to identify the quality states of fresh Chinese herbs by using their biophoton characteristics. Both CPS and I0 have better correlations with the quality states and can be considered characteristic parameters of the quality of fresh Chinese herbs.

K Value: An Indicator that can Characterize the Cold and Hot Properties of Traditional Chinese Medicines.

Aims: The cold and hot properties of Chinese medicines are an important concept to represent the function of drugs, and are also a unique classification method of traditional Chinese medicine (TCM). The method reflects an herb's therapeutic properties and guides reasonable clinical prescription. However, the present key problem is the lack of an objective and quantitative evaluation index for the cold and hot properties of Chinese herbs. Delayed luminescence (DL) is the long-term afterglow of biological systems after illumination with light, which can reflect differences in herbal materials prepared under different conditions. We aim to use S. obliquus as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. Methods: Scenedesmus obliquus (S. obliquus) was used as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. The decoction solution of different properties of Chinese herbs was added to S. obliquus culture medium; then, the delayed luminescence (DL) of S. obliquus after the addition of decoctions of different properties of Chinese herbs was measured to obtain information on the effect of different properties of Chinese herbs on S. obliquus. Many DL parameters were calculated, and ROC curve analysis was applied with the aim of finding a suitable parameter that can characterize the differences in cold and hot properties of Chinese herbs. Results: Our results show that the K value is a sensitive parameter that can reflect the differences of cold and hot properties of Chinese herbs, thus providing new insights into the cold and hot properties of Chinese herbs. Conclusions: DL measurement of S. obliquus after addition of different properties of Chinese herbs could be a novel and promising method to study the cold and hot properties of Chinese herbs.

Integrating Ultra-Weak Photon Emission Analysis in Mitochondrial Research.

Once regarded solely as the energy source of the cell, nowadays mitochondria are recognized to perform multiple essential functions in addition to energy production. Since the discovery of pathogenic mitochondrial DNA defects in the 1980s, research advances have revealed an increasing number of common human diseases, which share an underlying pathogenesis involving mitochondrial dysfunction. A major factor in this dysfunction is reactive oxygen species (ROS), which influence the mitochondrial-nuclear crosstalk and the link with the epigenome, an influence that provides explanations for pathogenic mechanisms. Regarding these mechanisms, we should take into account that mitochondria produce the majority of ultra-weak photon emission (UPE), an aspect that is often ignored - this type of emission may serve as assay for ROS, thus providing new opportunities for a non-invasive diagnosis of mitochondrial dysfunction. In this article, we overviewed three relevant areas of mitochondria-related research over the period 1960-2020: (a) respiration and energy production, (b) respiration-related production of free radicals and other ROS species, and (c) ultra-weak photon emission in relation to ROS and stress. First, we have outlined how these research areas initially developed independently of each other - following that, our review aims to show their stepwise integration during later stages of development. It is suggested that a further stimulation of research on UPE may have the potential to enhance the progress of modern mitochondrial research and its integration in medicine.

Characterization of the hot and cold medicinal properties of traditional Chinese herbs by spontaneous photon emission ratio of mice.

ETHNOPHARMACOLOGICAL RELEVANCE: One important therapeutic characteristic of traditional Chinese medicine (TCM) for its properly-guided clinical prescription is considering the cold and hot medicinal properties of traditional Chinese herbs. According to the TCM theory, the hot and cold medicinal properties are defined by the general responses of a human body to a given herbal medicine. This definition is subjective and ambiguous which attenuates the modernization of TCM. Biological spontaneous photon emission (SE) is a normal phenomenon reflecting the transition of the quantum state of molecules inside an organism. The alteration of its level can indicate the changes of many aspects of the organism including metabolism. Thus, we can exploit this feature to develop a novel and scientific approach to quantitively and objectively characterize the hot and cold medicinal properties of traditional Chinese herbs. OBJECTIVE: To determine whether SE can be used to characterize the hot and cold medicinal properties of traditional Chinese herbs, this study took advantage of the ultra-weak luminescence detection technology to examine the effects of traditional Chinese herbs with hot or cold medicinal property to the level of SE in mice. MATERIALS AND METHODS: Mice were intragastrically administered with twenty traditional Chinese herbs harboring cold or hot property for ten consecutive days respectively. During the course of treatment, SE intensity of the abdomen and the back of each individual mouse were measured and recorded. At the end of the treatment, the total antioxidant capacity, superoxide dismutase activity, Na+-K+-ATPase activity and Ca2+-Mg2+-ATPase activity in the liver of all mice were examined. RESULTS: Ratio between the SE intensity of the abdomen and back of mice (defined as SE ratio) was able to distinguish the cold and hot medicinal properties of traditional Chinese herbs. Mice treated with hot herbs and cold herbs have higher and lower SE ratios respectively compared with control mice. Furthermore, levels of selected biochemical indexes in the liver were correlated with most of the SE ratio changes induced by herbal treatment. CONCLUSIONS: We have developed a novel and promising approach to quantitatively investigate herbal properties and we propose that SE ratio defined in this study can serve as a sensitive parameter to characterize the cold and hot medicinal properties of traditional Chinese herbs.

ERα and Wnt/ß­catenin signaling pathways are involved in angelicin­dependent promotion of osteogenesis.

Reports of the ameliorative effect of angelicin on sex hormone deficiency­induced osteoporosis have highlighted this compound as a candidate for the treatment of osteoporosis. However, the molecular mechanisms of action of angelicin on osteoblast differentiation have not been thoroughly researched. The aim of the present study was to evaluate the effect of angelicin on the proliferation, differentiation and mineralization of rat calvarial osteoblasts using a Cell Counting Kit­8, alkaline phosphatase activity and the expression of osteogenic genes and proteins. Treatment with angelicin promoted the proliferation, matrix mineralization and upregulation of osteogenic marker genes including collagen type I α 1 and bone γ­carboxyglutamate in fetal rat calvarial osteoblasts. Furthermore, angelicin promoted the expression of ß­catenin and runt related transcription factor 2, which serve a vital role in the Wnt/ß­catenin signaling pathway. Consistently, the osteogenic effect of angelicin was attenuated by the use of a Wnt inhibitor. Moreover, angelicin increased the expression of estrogen receptor α (ERα), which also serves a key role in osteoblast differentiation. Taken together, these results demonstrated that angelicin may promote osteoblast differentiation through activation of ERα and the Wnt/ß­catenin signaling pathway.

A "weak acid and weak base" type fluorescent probe for sensing pH: mechanism and application in living cells.

A simple pH fluorescent probe, N-(6-morpholino-1, 3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl) isonicotinamide (NDI), based on naphthalimide as the fluorophore and isonicotinic acid hydrazide as the reaction site was synthesized and characterized. It is useful for monitoring acidic and alkaline pH. The results of pH titration indicated that NDI exhibits obvious emission enhancement with a pK a of 4.50 and linear response to small pH fluctuations within the acidic range of 3.00-6.50. Interestingly, NDI also displayed strong pH-dependent characteristics with pK a 9.34 and linearly responded to an alkaline range of 8.30-10.50. The sensing response mechanism was confirmed by 1H NMR and ESI-MS spectroscopy. The mechanism of the optical responses of NDI toward pH was also determined by density functional theory (DFT) calculations. In addition, NDI displayed a highly selective and sensitive response to hydrogen ions and hydroxyl ions. The probe was successfully applied to image acidic and alkaline pH value fluctuations in HeLa cells and has lysosomal targeting ability.

A Bridge of Light: Toward Chinese and Western Medicine Perspectives Through Ultraweak Photon Emissions.

The gap between Western medicine and traditional Chinese medicine (CM) is closely related to the diversity in culture, philosophy, and scientific developments. Although numerous studies have evaluated the efficacy of acupuncture, the gap in explanatory disease models has not been bridged so far. Developments in research of ultraweak photon emission (UPE) and organized dynamics of metabolism and its relationship with technological advances in metabolomics have created the conditions to bring the basics of the medicines of the West and East together which might open the avenue for a scientific dialogue. The paper discusses (1) the UPE in relation to Qi energy, meridians and acupuncture points in CM, (2) the biochemical explanation of photon emission of living systems in Western biomedicine, and (3) the progress in research on the large-scale organization and dynamics of the metabolic network including photon metabolism.

Spontaneous photon emission: A promising non-invasive diagnostic tool for breast cancer.

Ultra-weak photon emission (UPE) has attracted significant scientific attention for its potential to monitor the physiological and pathological characteristics of living systems. In this study, we investigated the strength of spontaneous photon emission (SPE) from the right (R) and left (L) side of body surface of human breast cancer-bearing nude mice models, considering the entire breast cancer growth process, and healthy controls using a photon detector. And then we calculated the ratio of the average SPE strength (ratio (R/L)) between the right and left side of each mouse. Cluster analysis was used to evaluate the accuracy rates of strength-R, strength-L, ratio (R/L) and their combination to identify tumor mice from the controls. Our results revealed that the discriminating powers of different parameters were different in different growth stages of tumor: in tumor incubation period, the accuracy rates of strength-R, strength-L, ratio (R/L) and their combination to identify tumor mice from control mice were 63.6%, 40.9%, 81.8% and 86.4%, respectively; For nude mice with tumor diameter <0.5cm, the accuracies were 72.7%, 45.5%, 86.4% and 90.9%; and for nude mice with tumor diameters larger than 1.5cm, the accuracies were 86.4%, 77.3%, 95.5% and 100%, respectively. These results indicated that the SPE from the body surface of the lesion site could significantly distinguish tumor mice from the controls when tumors were obvious or when there were no obvious morphological changes, although the accuracy was relatively low. The results suggest that SPE, as a sensitive and promising optical method, may contribute to the preliminary screening of breast cancer, especially for early diagnosis, and it may play a critical role in curtailing the effects of breast cancer and improving the survival of patients in the future.

Application of Spontaneous Photon Emission in the Growth Ages and Varieties Screening of Fresh Chinese Herbal Medicines.

Ultraweak photon emission emitted by all living organisms has been confirmed to be a noninvasive indicator for their physiological and pathological characteristics. In this study, we investigated the characteristics of spontaneous photon emission (SPE) and the contents of specific active compounds of roots and flowers buds of several fresh Chinese herbal medicines (natural medicines) with different growth ages and varieties. The results revealed that the contents of specific active compounds from same species herbs with different growth ages and varieties were significantly different, and this difference could be reflected by their SPE. Because the contents of specific bioactive constituents in Chinese herbs are closely related to their quality and curative effect, the SPE measurement technique may contribute to the quality control of Chinese herbal medicine in the future.

Spectrum of spontaneous photon emission as a promising biophysical indicator for breast cancer research.

In this study, we investigated the spectral characteristics of Spontaneous Photon Emission (SPE) from the body surface of a human breast cancer-bearing nude mice model during the overall growth process of breast cancers. By comparing and analyzing the data, we found that there was a striking difference between tumor mice and healthy controls in the spectral distribution of SPE from the body surface of lesion site, even when the morphological changes at the lesion site were not obvious. The spectral distribution of SPE from the healthy site of the tumor mice also differed from that of the healthy controls as the breast cancer developed to a certain stage. In addition, the difference in spectrum was related with different growth states of tumors. Interestingly, there was a positive correlation between the spectral ratio (610-630/395-455 nm) and the logarithm of the tumor volume for both the lesion site (R2 = 0.947; p < 0.001) and the normal site (R2 = 0.892; p < 0.001) of the tumor mice. The results suggested that the spectrum of SPE was sensitive to changes in the tumor status.

Association Between Dentin Matrix Protein 1 (rs10019009) Polymorphism and Ankylosing Spondylitis in a Chinese Han Population from Shandong Province.

BACKGROUND: Ankylosing spondylitis (AS) is the most common rheumatic condition that is slowly progressive and predominantly affects adolescents. Pathological bone formation associated with AS is an important cause of disability. The aim of the study was to investigate the possible involvement of the genes related to endochondral ossification and ectopia ossification in genetic susceptibility to AS in a Chinese Han population. METHODS: Sixty-eight single nucleotide polymorphisms (SNPs) from 13 genes were genotyped in discovery cohorts including 300 AS patients and 180 healthy controls. The rs10019009 in dentin matrix protein 1 (DMP1) gene shown as association with AS after multiple testing corrections in discovery cohorts was replicated in a validation independent cohort of 620 AS patients and 683 healthy controls. The rs10019009 was assessed with bioinformatics including phylogenetic context, F-SNP and FastSNP functional predictions, secondary structure prediction, and molecular modeling. We performed a functional analysis of rs10019009 via reverse transcription-polymerase chain reaction, alkaline phosphatase (ALP) activity in human osteosarcoma U 2 OS cells. RESULTS: Interestingly, the SNP rs10019009 was associated with AS in both the discovery cohort (P = 0.0012) and validation cohort (P = 0.0349), as well as overall (P = 0.0004) in genetic case-control association analysis. After a multivariate logistic regression analysis, the effect of this genetic variant was observed to be independent of linkage disequilibrium. Via bioinformatics analysis, it was found that the amino acid change of the rs10019009 led to changes of SNP function, secondary structure, tertiary conformation, and splice mode. Finally, functional analysis of rs10019009 in U 2 OS cells demonstrated that the risk T allele of the rs10019009 increased enzymatic activity of ALP, compared to that of the nonrisk allele (P = 0.0080). CONCLUSIONS: These results suggested that the DMP1 gene seems to be involved in genetic predisposition to AS, which may contribute to the ectopic mineralization or ossification in AS. In addition, DMP1 gene may be a promising intervention target for AS in the future.

Spectral Analysis of Chinese Medicinal Herbs Based on Delayed Luminescence.

Traditional Chinese medicine (TCM) plays a critical role in healthcare; however, it lacks scientific evidence to support the multidimensional therapeutic effects. These effects are based on experience, and, to date, there is no advanced tool to evaluate these experience based effects. In the current study, Chinese herbal materials classified with different cold and heat therapeutic properties, based on Chinese medicine principles, were investigated using spectral distribution, as well as the decay probability distribution based on delayed luminescence (DL). A detection system based on ultraweak biophoton emission was developed to determine the DL decay kinetics of the cold and heat properties of Chinese herbal materials. We constructed a mathematical model to fit the experimental data and characterize the properties of Chinese medicinal herbs with different parameters. The results demonstrated that this method has good reproducibility. Moreover, there is a significant difference (p < 0.05) in the spectral distribution and the decay probability distribution of Chinese herbal materials with cold and heat properties. This approach takes advantage of the comprehensive nature of DL compared with more reductionist approaches and is more consistent with TCM principles, in which the core comprises holistic views.

The Quantitative Ideas and Methods in Assessment of Four Properties of Chinese Medicinal Herbs.

The purpose of this review is to summarize and reflect on the current status and problems of the research on the properties of Chinese medicinal herbs. Hot, warm, cold, and cool are the four properties/natures of Chinese medicinal herbs. They are defined based on the interaction between the herbs with human body. How to quantitatively assess the therapeutic effect of Chinese medicinal herbs based on the theoretical system of Traditional Chinese medicine (TCM) remains to be a challenge. Previous studies on the topic from several perspectives have been presented. Results and problems were discussed. New ideas based on the technology of biophoton radiation detection are proposed. With the development of biophoton detection technology, detection and characterization of human biophoton emission has led to its potential applications in TCM. The possibility of using the biophoton analysis system to study the interaction of Chinese medicinal herbs with human body and to quantitatively determine the effect of the Chinese medicinal herbal is entirely consistent with the holistic concept of TCM theory. The statistical entropy of electromagnetic radiations from the biological systems can characterize the four properties of Chinese medicinal herbs, and the spectrum can characterize the meridian tropism of it. Therefore, we hypothesize that by the use of biophoton analysis system, the four properties and meridian tropism of Chinese medicinal herbs can be quantitatively expressed.

Study and analysis of the state of rare disease research in Shandong Province, China.

As the world's most populous country, China has the world's largest number of rare disease groups in terms of prevalence. However, the country has no system of registering cases of most rare diseases, so there is very little documented information on the epidemiology of those diseases. The purpose of this study was to study the state of rare disease research and survey doctors in Shandong Province regarding their level of awareness of rare diseases. Types of rare diseases and numbers of cases were tallied and their geographical distribution over the decades was analyzed. Eight hundred and twenty-four doctors in tertiary hospitals and maternity and child care hospitals were surveyed by questionnaire. Data were descriptively analyzed and a map of disease distribution was created. Articles about rare diseases were retrieved from the Chinese Biomedical Literature Database to provide pertinent data. This study yielded 5,749 cases of 323 different types of rare diseases. The survey found that doctors lack awareness of research on rare diseases. An authoritative and information-rich platform for rare disease research is urgently needed. Key steps are to study epidemiological and statistical techniques and then obtain available data to provide a basis for the definition and regulation of rare diseases in China.