AI-based Virtual Screening of Traditional Chinese Medicine and the Discovery of Novel Inhibitors of TCTP.

BACKGROUND: Translationally controlled tumour protein (TCTP) is associated with tumor diseases, such as breast cancer, and its inhibitor can reduce the growth of tumor cells. Unfortunately, there is currently no effective medication available for treating TCTP-related breast cancer. OBJECTIVE: The objective of this study was to explore the inhibitor candidates among natural compounds for the treatment of breast cancer related to TCTP protein. METHODS: To explore the potential inhibitors of TCTP, we first screened out four potential inhibitors in the Traditional Chinese Medicine (TCM) for cancer based on AI virtual screening using the docking method, and then revealed the interaction mechanism of TCTP and four candidate inhibitors from TCM with molecular docking and molecular dynamics (MD) methods. RESULTS: Based on the conformational characteristics and the MD properties of the four leading compounds, we designed the new skeleton molecules with the AI method using MolAICal software. Our MD simulations have revealed that different small molecules bind to different sites of TCTP, but the flexible regions and the signaling pathways are almost the same, and the VDW and hydrophobic interactions are crucial in the interactions between TCTP and ligands. CONCLUSION: We have proposed the candidate inhibitor of TCTP. Our study has provided a potential new method for exploring inhibitors from Traditional Chinese Medicine (TCM).

Danggui Buxue decoction ameliorates mitochondrial biogenesis and cognitive deficits through upregulating histone H4 lysine 12 acetylation in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.

A tumor-targetable NIR probe with photoaffinity crosslinking characteristics for enhanced imaging-guided cancer phototherapy.

Spatiotemporally manipulating the in situ immobilization of theranostic agents within cancer cells to improve their bioavailability is highly significant yet challenging in tumor diagnosis and treatment. Herein, as a proof-of concept, we for the first time report a tumor-targetable near-infrared (NIR) probe DACF with photoaffinity crosslinking characteristics for enhanced tumor imaging and therapeutic applications. This probe possesses great tumor-targeting capability, intensive NIR/photoacoustic (PA) signals, and a predominant photothermal effect, allowing for sensitive imaging and effective photothermal therapy (PTT) of tumors. Most notably, upon 405 nm laser illumination, DACF could be covalently immobilized within tumor cells through a photocrosslinking reaction between photolabile diazirine groups and surrounding biomolecules resulting in enhanced tumor accumulation and prolonged retention simultaneously, which significantly facilitates the imaging and PTT efficacy of tumor in vivo. We therefore believe that our current approach would provide a new insight for achieving precise cancer theranostics.

Acoustic-Based Theranostic Probes Activated by Tumor Microenvironment for Accurate Tumor Diagnosis and Assisted Tumor Therapy.

Acoustic-based imaging techniques, including ultrasonography and photoacoustic imaging, are powerful noninvasive approaches for tumor imaging owing to sound transmission facilitation, deep tissue penetration, and high spatiotemporal resolution. Usually, imaging modes were classified into "always-on" mode and "activatable" mode. Conventional "always-on" acoustic-based probes often have difficulty distinguishing lesion regions of interest from surrounding healthy tissues due to poor target-to-background signal ratios. As compared, activatable probes have attracted attention with improved sensitivity, which can boost or amplify imaging signals only in response to specific biomolecular recognition or interactions. The tumor microenvironment (TME) exhibits abnormal physiological conditions that can be used to identify tumor sections from normal tissues. Various types of organic dyes and biomaterials can react with TME, leading to obvious changes in their optical properties. The TME also affects the self-assembly or aggregation state of nanoparticles, which can be used to design activatable imaging probes. Moreover, acoustic-based imaging probes and therapeutic agents can be coencapsulated into one nanocarrier to develop nanotheranostic probes, achieving tumor imaging and cooperative therapy. Satisfactorily, ultrasound waves not only accelerate the release of encapsulated therapeutic agents but also activate therapeutic agents to exert or enhance their therapeutic performance. Meanwhile, various photoacoustic probes can convert photon energy into heat under irradiation, achieving photoacoustic imaging and cooperative photothermal therapy. In this review, we focus on the recently developed TME-triggered ultrasound and photoacoustic theranostic probes for precise tumor imaging and targeted tumor therapy.

Dual-spectrum online monitoring of puerarin and total flavonoids contents during the extraction process of Pueraria lobata.

In the extraction process of traditional Chinese medicine (TCM), the rapid detection of the active components of TCM plays a vital role. We pioneered the choice of dual-spectrum technology based on near-infrared (NIR) and ultraviolet-visible (UV-Vis) spectra and applied it to the quantitative monitoring of online extraction of puerarin and total flavonoids from Pueraria lobata. An online monitoring system was constructed to fulfill the dual-spectrum online monitoring. The extraction solution flows from a flask into a pipeline under the control of a peristaltic pump, removing the solid residues contained in the solution with filters. When the extraction solution flows into the cuvette, it will be measured with NIR and UV-Vis portable spectrometers. After finishing the spectra collection, the peristaltic pump will reverse to push the extraction solution back to the flask. The partial least squares (PLS) models were established to quantitatively analyze puerarin and total flavonoids by NIR, UV-Vis, and dual-spectrum data. As for NIR, UV-Vis and dual-spectrum, the RMSEP (mg/mL) of the puerarin models were 0.0803, 0.0500, and 0.0351, and those of the total flavonoids models were 0.4373, 0.2402, and 0.1795, respectively. The results show that the dual-spectrum online monitoring system is simple, stable and fast (a few seconds) in operation, and accurate in prediction. Compared with individual NIR or UV-Vis spectra, the dual-spectra contains more comprehensive information, and the prediction ability is stronger. This method is expected to become a promising tool for the quantitative analysis of other traditional Chinese medicines.

Carbon Dots in Biomedicine: A Review.

Despite the rapid development of science and technology, the effective treatment of cancer still threatens human life and health. However, the success of cancer treatment is closely related to early diagnosis, identification, and effective treatment. In recent years, with the strengthening of the development and research of nanomaterials for cancer diagnosis and treatment, researchers have found that carbon dots (CDs) have the advantages of wide absorption, excellent biocompatibility, diverse imaging characteristics, and photostability and are widely used in various fields, such as sensing, imaging, and drug/gene transportation. Recently, researchers also discovered that CDs could be used as an effective photosensitizer to generate active oxygen or convert light energy into heat under the stimulation of the external lasers, making them have the effects of photothermal and photodynamic therapy for cancer. In this review, we first outline the single-modal and multimodal imaging analysis of CDs in cancer cells. After introducing diversified imaging functions, we focused on the design and the latest research progress of CDs in phototherapy and introduced in detail the strategies of CDs in phototherapy treatment and the challenges faced by clinical applications. We hope that this overview can provide important insights for researchers and accelerate the pace of research on CDs in imaging-guided phototherapy treatment.

Protective effect and mechanism of loganin and morroniside on acute lung injury and pulmonary fibrosis.

BACKGROUND: Loganin and morroniside are two iridoid glycosides with anti-inflammatory, antioxidant and anti-tumor effects. Whether they have effect on acute lung injury and pulmonary fibrosis are still unknown. PURPOSE: To explore the potential effects of loganin and morroniside against acute lung cancer and pulmonary fibrosis, and the underlying molecular mechanism. STUDY DESIGN AND METHODS: Cell and animal models of acute lung injury were established by the induction of LPS. After intervention with loganin and morroniside, the pathological symptom of lung tissue was assessed, pro-inflammatory factors in cells and lung tissues were detected, NF- κB/STAT3 signaling pathway related proteins were detected by western blotting. Mice pulmonary fibrosis model was induced by bleomycin, pathological symptom was assessed by HE and Masson staining. Fibrosis related indicators were detected by qPCR or western blot. CD4+/CD8+ was detected by flow cytometry. RESULTS: Loganin and morroniside relieved the pathological symptom of lung tissue in acute lung injury, pro-inflammatory factors such as IL-6, IL-1ß, TNF-α mRNA were inhibited. Expression of p-p65 and STAT3 in lung tissues were also downregulated. In addition, loganin and morroniside downregulated the expression of collagen fiber, hydroxyproline and TGF-ß1, collagen I and α-SMA mRNA in lung tissues of pulmonary fibrosis model. This study proved that loganin and morroniside have protective effect on acute lung injury and pulmonary fibrosis, and may provide theoretical basis for the development of new clinical drugs.

The underlying mechanisms of anti-hepatitis B effects of formula Le-Cao-Shi and its single herbs by network pharmacology and gut microbiota analysis.

Formula Le-Cao-Shi (LCS), a traditional Chinese medicine (TCM), has been used as folk remedy for treating hepatitis B for a long time. In our previous study, the anti-hepatitis B effects of LCS have been verified. In the present study, the anti-hepatitis B activities of LCS and its three single herbs were investigated in vitro by HepG2.2.15 cellular model, and the mechanisms against hepatitis B were deciphered via network pharmacology and gut microbiota analysis. By network pharmacology method, twelve key compounds that played a vital role in LCS were filtered from 213 ingredients. The targets RORA, CDK2, RELA, AKT1, IKBKG, PRKCß and CASP3 were directly related to hepatitis B pathway, which indicated that LCS could exert anti-hepatitis B effect by co-regulating cell cycle and inflammatory pathways. The interactions between candidate compounds and target proteins that were directly involved in hepatitis B pathway were validated by molecular docking simulation and RT-PCR. By gut microbiota analysis, it was revealed that LCS could alter the disordered microbial composition in the infected ducks towards normal, especially the restoration of three key strains, namely Streptococcus alactolyticus, Enterococcus cecorum and Bacteroides fragilis. The above findings could provide a scientific basis for further development and utilization of LCS against hepatitis B.

Polymer-Assisted Metallization of Mammalian Cells.

Developing biotemplating techniques to translate microorganisms and cultured mammalian cells into metallic biocomposites is of great interest for biosensors, electronics, and energy. The metallization of viruses and microbial cells is successfully demonstrated via a genetic engineering strategy or electroless deposition. However, it is difficult to transform mammalian cells into metallic biocomposites because of the complicated genes and the delicate morphological features. Herein, "polymer-assisted cell metallization" (PACM) is reported as a general method for the transformation of mammalian cells into metallic biocomposites. PACM includes a first step of in situ polymerization of functional polymer on the surface and in the interior of the mammalian cells, and a subsequent electroless deposition of metal to convert the polymer-functionalized cells into metallic biocomposites, which retain the micro- and nanostructures of the mammalian cells. This new biotemplating method is compatible with different cell types and metals to yield a wide variety of metallic biocomposites with controlled structures and properties.

Periodically hydrologic alterations decouple the relationships between physicochemical variables and chlorophyll-a in a dam-induced urban lake.

Periodically hydrologic alterations driven by seasonal change and water storage capacity management strongly modify physicochemical properties and chlorophyll-a (Chl-a) and their interactions in dam-induced lakes. However, the extent and magnitude of these changes still remain unclear. This study aimed to determine the effects of periodically hydrologic alterations on physicochemical variables and Chl-a in the dam-induced urban Hanfeng Lake, upstream of Three Gorges Reservoir. Shifts in Chl-a and 13 physicochemical variables were recorded monthly in the lake from January 2013 to December 2014. Chl-a was neither seasonal nor inter-annual differences while a few physical variables such as flow velocity (V) exhibited significantly seasonal variabilities, and chemical variables like total nitrogen (TN), nitrate-nitrogen (NO3-N), total phosphorus (TP), dissolved silica (DSi) were markedly inter-annual differences. Higher TN:TP (40:1) and lower NO3-N:DSi (0.8:1) relative to balanced stoichiometric ratios suggested changes in composition of phytoplankton communities and potentially increased proportion of diatom in Hanfeng Lake. Chl-a was predicable by combination of dissolved oxygen (DO), TN and DSi in dry season, and by V alone in wet season. During the whole study period, Chl-a was solely negatively correlated with TN:TP, indicating decline in N concentration and increase in P could therefore increase Chl-a. Our results highlight pronounced decoupling of linkages between Chl-a and physicochemical variables affected by periodically hydrologic alterations in dam-induced aquatic systems.

[TCMATCOV--a bioinformatics platform to predict efficacy of TCM against COVID-19].

There is urgent need to discover effective traditional Chinese medicine(TCM) for treating coronavirus disease 2019(COVID-19). The development of a bioinformatic tool is beneficial to predict the efficacy of TCM against COVID-19. Here we deve-loped a prediction platform TCMATCOV to predict the efficacy of the anti-coronavirus pneumonia effect of TCM, based on the interaction network imitating the disease network of COVID-19. This COVID-19 network model was constructed by protein-protein interactions of differentially expressed genes in mouse pneumonia caused by SARS-CoV and cytokines specifically up-regulated by COVID-19. TCMATCOV adopted quantitative evaluation algorithm of disease network disturbance after multi-target drug attack to predict potential drug effects. Based on the TCMATCOV platform, 106 TCM were calculated and predicted. Among them, the TCM with a high disturbance score account for a high proportion of the classic anti-COVID-19 prescriptions used by clinicians, suggesting that TCMATCOV has a good prediction ability to discover the effective TCM. The five flavors of Chinese medicine with a disturbance score greater than 1 are mainly spicy and bitter. The main meridian of these TCM is lung, heart, spleen, liver, and stomach meridian. The TCM related with QI and warm TCM have higher disturbance score. As a prediction tool for anti-COVID-19 TCM prescription, TCMATCOV platform possesses the potential to discovery possible effective TCM against COVID-19.

Default Mode Network as a Neural Substrate of Acupuncture: Evidence, Challenges and Strategy.

Acupuncture is widely applied all over the world. Although the neurobiological underpinnings of acupuncture still remain unclear, accumulating evidence indicates significant alteration of brain activities in response to acupuncture. In particular, activities of brain regions in the default mode network (DMN) are modulated by acupuncture. DMN is crucial for maintaining physiological homeostasis and its functional architecture becomes disrupted in various disorders. But how acupuncture modulates brain functions and whether such modulation constitutes core mechanisms of acupuncture treatment are far from clear. This Perspective integrates recent literature on interactions between acupuncture and functional networks including the DMN, and proposes a back-translational research strategy to elucidate brain mechanisms of acupuncture treatment.

Mass-Manufactural Lanthanide-Based Ultraviolet B Microlasers.

Lanthanide (Ln3+ )-based ultraviolet B (UVB) microlasers are highly desirable for diagnostics and phototherapy. Despite their progress, the potential applications of UVB microlasers are strongly hindered by their low optical gain, weak light confinements, and poor device repeatability. Herein, a novel all-in-one approach to solve the above limitations and realize mass-manufactural UVB microlasers is reported. The gain coefficient at 289 nm is improved from two aspects, i.e., the enhanced absorption via LiYbF4 :Tm(1mol%)@LiYbF4 @LiLuF4 core-shell-shell nanocrystals and the suppression of competitive ultraviolet emissions. Consequently, by spin-coating the solution onto a patterned SiO2 substrate, high-quality Ln3+ -based microdisks are formed by self-assembly on each SiO2 pillar and UVB whispering-gallery-mode lasers are realized. The resulted lasing threshold is an order of magnitude smaller than the shortest deep-ultraviolet emission at 310.5 nm. Importantly, the lasing wavelengths and mode numbers of UVB lasers are highly controllable and repeatable, making them suitable for mass production for the first time.

Gastrodin protects against chronic inflammatory pain by inhibiting spinal synaptic potentiation.

Tissue injury is known to produce inflammation and pain. Synaptic potentiation between peripheral nociceptors and spinal lamina I neurons has been proposed to serve as a trigger for chronic inflammatory pain. Gastrodin is a main bioactive constituent of the traditional Chinese herbal medicine Gastrodia elata Blume, which has been widely used as an analgesic since ancient times. However, its underlying cellular mechanisms have remained elusive. The present study demonstrated for the first time that gastrodin exhibits an analgesic effect at the spinal level on spontaneous pain, mechanical and thermal pain hypersensitivity induced by peripheral inflammation, which is not dependent on opioid receptors and without tolerance. This analgesia by gastrodin is at least in part mediated by depressing spinal synaptic potentiation via blockade of acid-sensing ion channels. Further studies with miniature EPSCs and paired-pulse ratio analysis revealed the presynaptic origin of the action of gastrodin, which involves a decrease in transmitter release probability. In contrast, neither basal nociception nor basal synaptic transmission was altered. This study revealed a dramatic analgesic action of gastrodin on inflammatory pain and uncovered a novel spinal mechanism that could underlie the analgesia by gastrodin, pointing the way to a new analgesic for treating chronic inflammatory pain.

The germinomas arising from the basal ganglia and thalamus.

OBJECTIVE: To introduce the features of germinomas arising from the basal ganglia (BG) and thalamus. METHOD: Retrospective analysis was done with the clinical cases of germinomas in BG and thalamus from 1996 to 2000. The data included the symptoms, signs, neuroimaging findings, treatment, and outcomes. RESULT: Fourteen cases were included, only one female was included. The main symptoms are disorder of numbness and weakness in limbs. Neuroimaging showed no or mild peritumor high signal in T2 weighted imaging of magnetic resonance, accompanied with cyst, calcification or bleeding. Total gross resection was obtained in nine cases, subtotal resection in four. Follow-up data were available in 11 cases with average of 56 months. Eight cases underwent only postoperative radiotherapy, one underwent only chemotherapy, and two underwent both. One case died of complication 6 months after chemotherapy, the rest lived good life. CONCLUSION: Germinoma in BG and thalamus predominate in a boy. The neuroimaging features are very informative for diagnosis. Surgical resection should not be the first choice although it is has lesser complications. The long-term outcome is favorable.

[Transcallosal interforniceal approach for removing the medial type of thalamic gliomas].

OBJECTIVE: To report an approach for removing the medial type of thalamic gliomas. METHODS: Eight cases of medial type of thalamic gliomas, 4 males and 4 females, aged 22 (14 approximately 53), underwent resection of the tumor by transcallosal interforniceal approach: right frontal craniotomy, along the cerebral midline natural cleft to reach the third ventricle. RESULTS: By using microsurgical skill, subtotal removal of the tumors was achieved in 5 cases and partial removal was achieved in 3 cases with satisfactory postoperative effects. CONCLUSIONS: Keeping the fornix, thalamus, midbrain, and internal cerebral vein intact with few complication and good outcome, transcallosal interforniceal approach is an ideal way to resect the medial type of thalamic gliomas.

Microsurgical treatment for hypothalamic hamartoma in children with precocious puberty.

BACKGROUND: We review the surgical treatment of hypothalamic hamartoma causing precocious puberty. METHODS: Six children (three girls and three boys) with precocious puberty secondary to hypothalamic hamartoma were recruited for our study. The mean age of the patients was 30 months old (range 13 months to 5 years), and the mean age of the onset of puberty was 7.3 months. All patients were treated by microsurgery. RESULTS: All patients had higher then normal stature, body weight, bone growth, and serum levels of sexual hormones. The boys presented with mature external genitalia, pubic hair, frequent erection, and acne, while the girls presented with growth of breasts and menarche. Magnetic resonance image (MRI) revealed an isointense mass below the tuber cinereum extending into the supersellar and interpeduncular cistern, ranging from 4 to 12 mm in diameter, consistent with pedunculate hamartoma. The hamartoma was removed completely via a right pterional approach. The symptoms and signs of precocious puberty resolved completely, and sexual hormone levels decreased to the pre-pubertal range in all six patients without any postoperative complications. CONCLUSION: We report a series of six children with hypothalamic hamartoma-induced precocious puberty who underwent microsurgical treatment. All of them recovered completely to their age-appropriate state. Microsurgery is a good choice of treatment for pedunculate hypothalamic hamartoma.

Pediatric craniopharyngiomas: clinicomorphological study of 189 cases.

OBJECTIVE: To understand the pathological changes in pediatric craniopharyngiomas in order to determine the diagnosis and operative strategy and to prevent damage to the hypothalamus. METHODS: A total of 189 cases of pediatric craniopharyngiomas from 1990 to 1998 were reviewed and analyzed based on computerized tomography scans, magnetic resonance imaging and operations. RESULTS: Of the 189 cases, 187 (98.9%) were cystic tumors and calcification could be seen in 176 cases (93.1%). Two cases were solid tumors (1.1%), and calcification occurred in only 1 of these. There was a gliosis layer between the wall of the tumor and the hypothalamus. CONCLUSION: Cystic changes and calcification are the pathological features of pediatric craniopharyngiomas. There are some special relationships between the tumors and stalk. This is the basis for the total removal of pediatric craniopharyngiomas.