Withanolides from the active extract of Physalis angulate and their anti-hepatic fibrosis effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L., a traditional Chinese medicine called "Kuzhi" in China, was used traditionally to treat liver diseases (eg. icterus, hepatitis) as well as malaria, asthma, and rheumatism. AIM OF THE STUDY: Our study aimed to investigate the withanolides with anti-hepatic fibrosis effect from P. angulate. MATERIALS AND METHODS: Withanolides were obtained from the EtOH extract of P. angulate by bioassay-molecular networking analysis-guided isolation using column chromatography and normal/reversed-phase semipreparative HPLC. The structures of new withanolides were elucidated by combinations of spectroscopic techniques with NMR and ECD calculations. MTT cell viability assay, AO/EB staining method, cell wound healing assay, ELISA and Western blot experiments were employed to evaluate the anti-hepatic fibrosis activity and to uncover related mechanism. Molecular docking analysis and cellular thermal shift assay were used to evaluate and verify the interaction between the active withanolides and their potential targets. RESULTS: Eight unreported withanolides, withagulides A-H (1-8), along with twenty-eight known ones were obtained from P. angulate. Withanolides 6, 9, 10, 24, 27, and 29-32 showed marked anti-hepatic fibrosis effect with COL1A1 expression inhibition above 50 %. Physalin F (9), the main component in the active fraction, significantly decreased the TGF ß1-stimulated expressions of collagen I and α-SMA in LX-2 cells. Mechanism study revealed that physalin F exerted its anti-hepatic fibrosis effect via the PI3K/AKT/mTOR signaling pathway. CONCLUSION: This study suggested that withanolides were an important class of natural products with marked anti-hepatic fibrosis effect. The main withanolide physalin F might be a promising candidate for hepatic fibrosis treatment. The work provided experimental foundation for the use of P. angulate to treat hepatic fibrosis.

Platforms of graphene/MXene heterostructure for electrochemical monitoring of rutin in drug and Tartary buckwheat tea.

The use of two-dimensional heterostructure composite as electrode modification material has become a new strategy to improve the electrocatalytic activity and electroactive sites of electrochemical sensor. Herein, a soluble heterostructure, namely rGO-PSS@MXene, was designed and synthesized by integrating poly (sodium p-styrenesulfonate)-functionalized reduced graphene oxide into MXene nanosheets via ultrasonic method. The interactive heterostructure can effectively alleviate the self-stacking of MXene and rGO, endowing them with superior electron transfer capacity and large specific surface area, thereby producing prominent synergistic electrocatalytic effect towards rutin. In addition, the excellent enrichment effect of rGO-PSS@MXene for rutin also plays an important role through the electrostatic and π-π stacking interactions. The electrochemical characteristics of rutin on the sensor were examined in detail and a sensitive sensing method was proposed. Under optimized conditions, the method showed satisfactory linear relationship for rutin in the concentration range of 0.005-10.0 µM, with limit of detection of 1.8 nM (S/N = 3). The quantitative validation results in herbal medicine and commercial Tartary buckwheat tea were highly consistent with the labeled quantity and the results of HPLC determination, respectively, suggesting the sensor possessed excellent selectivity and accuracy. This proposed strategy for rutin determination is expected to expand the application of MXene heterostructure in electrochemical sensors, and is envisioned as a promising candidate for quality monitoring of drugs and foods.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor.

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

An injectable hydrogel based on Bi2Se3 nanosheets and hyaluronic acid for chemo-photothermal synergistic therapy.

To resolve poor accumulation caused by systemic administration, injectable and responsive hydrogels are the prospective drug delivery systems for localized tumor treatment, owning to negligible invasiveness and accurate administration. Herein, an injectable hydrogel, based on dopamine (DA) crosslinked hyaluronic acid and Bi2Se3 nanosheets (NSs) loading with doxorubicin (DOX) coated with polydopamine (Bi2Se3-DOX@PDA), was developed for synergistic chem-photothermal cancer therapy. The ultrathin functional Bi2Se3-DOX@PDA NSs could be responsive to the weak acidic condition and photothermal effect under NIR laser irradiation, achieving controlled release of DOX. Moreover, nanocomposite hydrogel based on hyaluronic acid matrix could be precisely administrated through intratumoral injection since its injectability and self-healing capacity, remaining at injected sites for at least 12 days. Furthermore, the excellent therapeutics effect of Bi2Se3-DOX@PDA nanocomposite hydrogel was demonstrated on 4 T1 xenograft tumor with outstanding injectability and negligible systemic side-effect. In short, the construction of Bi2Se3-DOX@PDA nanocomposite hydrogel paves a prospective path for local treatment of cancers.

Butylphthalide protects against ischemia-reperfusion injury in rats via reducing neuron ferroptosis and oxidative stress.

Local ischemia in the cerebra leads to vascular injury and necrosis. Ferroptosis is involved in the pathophysiological process of many diseases and widely exists when ischemia-reperfusion injury occurs in many organs. The aim of this study was to evaluate the effect of Butylphthalide (NBP) on middle cerebral artery occlusion (MCAO) rats model-caused neuron injury. Sprague Dawley Rats were randomly allocated to receive sham and MCAO operation. NBP low-dose (40 mg/kg b.w), and high-dose (80 mg/kg b.w) were administrated in MACO rats. Results showed NBP improves infarct volume, attenuates neuronal apoptosis in the brain tissue of MCAO rats. The tumor necrosis factor (TNF-α), IL-6, and malondialdehyde (MDA) levels decreased after NBP administration, while the activity of superoxide dismutase (SOD) and the ratio of GSH/GSSG in MACO rats increased. MACO caused non-heme iron accumulation in the brain tissue and Perl's staining confirmed NBP attenuates ferroptosis in MACO rats. The protein expressions of SCL7A11 and glutathione peroxidase 4 (GPX4) decreased following MCAO, and NBP treatment subsequently increased the expression of SCL7A11 and GPX4. In vitro analysis in cortical neuron cells indicated that the GPX4 inhibitor reverses the inhibition of ferroptosis by NBP, which suggested that the SCL7A11/GPX4 pathway majorly contributed to the NBP ferroptosis protection effect.

Losartan attenuates acetic acid enema-induced visceral hypersensitivity by inhibiting the ACE1/Ang II/AT1 receptor axis in enteric glial cells.

Enteric glial cells (EGCs) play an important role in visceral hypersensitivity associated with irritable bowel syndrome (IBS). Losartan (Los) is known to reduce pain; however, its function in IBS is unclear. The present study aimed to investigate Los's therapeutic effect on visceral hypersensitivity in IBS rats. Thirty rats were randomly divided into control, acetic acid enema (AA), AA + Los low, medium and high dose groups in vivo. EGCs were treated with lipopolysaccharide (LPS) and Los in vitro. The molecular mechanisms were explored by assessing the expression of EGC activation markers, pain mediators, inflammatory factors and angiotensin-converting enzyme 1(ACE1)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis molecules in colon tissue and EGCs. The results showed that the rats in the AA group showed significantly higher visceral hypersensitivity than the control rats, which was alleviated by different doses of Los. The expression of GFAP, S100ß, substance P (SP), calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid 1 (TRPV1), tumor necrosis factor (TNF), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) was considerably increased in colonic tissues of AA group rats and LPS-treated EGCs compared with control rats and EGCs, and reduced by Los. In addition, Los reversed ACE1/Ang II/AT1 receptor axis upregulation in AA colon tissues and LPS-treated EGCs. These results show that Los inhibits ACE1/Ang II/AT1 receptor axis upregulation by suppressing EGC activation, resulting in reduced expression of pain mediators and inflammatory factors, thereby alleviating visceral hypersensitivity.

[Hepatotoxicity and mechanism of Rhododendri Mollis Flos based on zebrafish model].

This study used the zebrafish model to explore the hepatotoxicity of Rhododendri Mollis Flos(RMF). The mortality was calculated according to the number of the survival of zebrafish larvae 4 days after fertilization under different concentration of RMF, and the dose-toxicity curve was fitted to preliminarily evaluate the toxicity of RMF. The liver phenotypes under the sublethal concentration of RMF in the treatment group and the blank control group were observed by hematoxylin-eosin(HE) staining and acridine orange(AO) staining. Meanwhile, the activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were determined to confirm the hepatotoxicity of RMF. Real-time quantitative polymerase chain reaction(real-time PCR) and Western blot were used to determine the expressions of genes and proteins in zebrafish larvae. Gas chromatography time-of-flight mass spectrometry(GC-TOF-MS) was used to conduct untargeted metabolomics testing to explore the mechanism. The results showed that the toxicity of RMF to zebrafish larvae was dose-dependent, with 1 100 µg·mL~(-1) of the absolute lethal concentration and 448 µg·mL~(-1) of sublethal concentration. The hepatocyte apoptosis and degeneration appeared in the zebrafish larvae under the sublethal concentration of RMF. The content of ALT and AST in zebrafish larvae at the end of the experiment was significantly increased in a dose-dependent manner. Under the sublethal concentration, the expressions of genes and proteins related to apoptosis in zebrafish larvae were significantly increased as compared with the blank control group. The results of untargeted metabolomics showed that the important metabolites related to the he-patotoxicity of RMF were mainly enriched in alanine, aspartic acid, glutamic acid, and other pathways. In conclusion, it is inferred that RMF has certain hepatotoxicity to zebrafish larvae, and its mechanism may be related to apoptosis.

Quality analysis of Rosae Radix et Rhizoma / 中国中药杂志

Rosae Radix et Rhizoma is a herbal medicine in a variety of famous Chinese patent medicines, while the quality standard for this medicine remains to be developed due to the insufficient research on the quality of Rosae Radix et Rhizoma from different sources. Therefore, this study comprehensively analyzed the components in Rosae Radix et Rhizoma of different sources from the aspects of extract, component category content, identification based on thin-lay chromatography, active component content determination, and fingerprint, so as to improve the quality control. The results showed that the content of chemical components varied in the samples of different sources, while there was little difference in the chemical composition among the samples. The content of components in the roots of Rosa laevigata was higher than that in the other two species, and the content of components in the roots was higher than that in the stems. The fingerprints of triterpenoids and non-triterpenoids were established, and the content of five main triterpenoids including multiflorin, rosamultin, myrianthic acid, rosolic acid, and tormentic acid in Rosae Radix et Rhizoma was determined. The results were consistent with those of major component categories. In conclusion, the quality of Rosae Radix et Rhizoma is associated with the plant species, producing area, and medicinal parts. The method established in this study lays a foundation for improving the quality standard of Rosae Radix et Rhizoma and provides data support for the rational use of the stem.

Self-assembled nano-photosensitizer for targeted, activatable, and biosafe cancer phototheranostics.

Cancer treatment currently still faces crucial challenges in therapeutic effectiveness, precision, and complexity. Photodynamic therapy (PDT) as a non-invasive tactic has earned widespread popularity for its excellent therapeutic output, flexibility, and restrained toxicity. Nonetheless, drawbacks, including low efficiency, poor cancer specificity, and limited therapeutic depth, remain considerable during the cancer treatment. Although great effort has been made to improve the performance, the overall efficiency and biosafety are still ambiguous and unable to meet urgent clinical needs. Herein, this study integrates merits from previous PDT strategies and develops a cancer-targeting, activatable, biosafe photosensitizer. Owing to excellent self-assembly ability, this photosensitizer can be conveniently prepared as multifunctional nano-photosensitizers, namely MBNPs, and applied to in vivo cancer phototheranostics in "all-in-one" mode. This study successfully verifies the mechanism of MBNPs, then deploys them to cell-based and in vivo cancer PDT. Based on the unique cancer microenvironment, MBNPs achieve precise distribution, accumulation, and activation towards the tumor, releasing methylene blue as a potent photosensitizer for phototherapy. The PDT outcome demonstrates MBNPs' superior cancer specificity, remarkable PDT efficacy, and negligible toxicity. Meanwhile, in vivo NIR fluorescence and photoacoustic imaging have been utilized to guide the PDT treatment synergistically. Additionally, the biosafety of the MBNPs-based PDT treatment is ensured, thus providing potential for future clinical studies.

Targeted Wolfram-Doped Polypyrrole for Photonic Hyperthermia-Synergized Radiotherapy.

Single ionizing radiation at a tolerable dose is ineffectual in eliminating malignancies but readily generates harmful effects on surrounding normal tissues. Herein, we intelligently fabricated novel wolfram-doped polypyrrole (WPPy) through a simple oxidative polymerization method with WCl6 as an oxidizing catalyst, which possessed good biocompatibility, high photothermal conversion, and intensive radiosensitivity capacities to concurrently serve as a photothermal reagent and a radiosensitizer for hyperthermia-synergized radiotherapy (RT) against a malignant tumor. In comparison with traditional polypyrrole without noble metal doping, the innovative introduction of WCl6 not only successfully launched the polymerization of a pyrrole monomer but also endowed WPPy with additional radiosensitization. More importantly, after further decoration with an active targeted component (SP94 polypeptide), the obtained WPPy@SP94 significantly increased tumor internalization and accumulation in vitro and in vivo and induced obvious DNA damage as well as robust ROS generation under X-ray irradiation, which meanwhile synergized with strong photonic hyperthermia to effectively inhibit tumor growth by single drug injection. Moreover, such biocompatible WPPy@SP94 showed negligible adverse effects on normal cells and tissues. WPPy@SP94 developed in this study not only expands the category of polypyrrole chemical syntheses but also sheds light on WPPy@SP94-based radiosensitizers for cancer RT.

Ban-xia-xie-xin-tang ameliorates hepatic steatosis by regulating Cidea and Cidec expression in HFD-fed mice.

BACKGROUND: Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown. PURPOSE: To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice. METHODS: After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy. RESULTS: First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs ß-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT. CONCLUSION: BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.

[Anti-tumor and analgesic activity evaluation and mechanism of Compound Kushen Injection].

This study aims to evaluate the anti-tumor and analgesic activities of Compound Kushen Injection(CKI) based on zebrafish model in vivo and investigate the anti-tumor mechanism. To be specific, zebrafish tumor xenotransplantation model was established by microinjection of murine LPC H12 cells into yolk sac. Then the high-dose CKI(H-CKI), medium-dose CKI(M-CKI), low-dose CKI(L-CKI) groups, and the model group were set. The anti-tumor activity of CKI was evaluated with the tumor area growth fold and integral absorbance(IA) growth fold 72 h after administration. The peripheral pain and central pain in zebrafish were respectively induced with acetic acid(AA) and phorbol myristate acetate(PMA). Zebralab ViewPoint system was employed to monitor behavioral trajectory of zebrafish, and movement times, movement time, movement distance, and movement velocity were used to evaluate the analgesic activity of CKI. Finally, real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) was performed to detect the expression levels of apoptosis-related B lymphocyte tumor-2(Bcl-2) and phosphatidylinositol-3-kinase(PI3 K)/protein kinase B(Akt or PKB) pathway-related genes, for the verification of the anti-tumor mechanism. Compared with the model group, M-CKI and H-CKI significantly reduced the growth folds of tumor area and IA, relief the peripheral pain and central pain. The mechanism was that CKI can up-regulate the expression of cysteine aspartic acid specific protease-3(caspase-3, Casp3) and caspase-9(Casp9), down-regulate the expression of phosphoinositide 3-kinase(PI3 K) and Akt, and significantly reduce the expression of Bcl-2, hypoxia-inducible factor-1α(HIF-1α), and vascular endothelial growth factor(VEGF). In conclusion, CKI has significant inhibitory effect on tumor growth and pain, which is related to the PI3 K/Akt signaling pathway. The pathway mediates cell apoptosis, suppresses tumor growth, and alleviates tumor pain.

Polypyrrole Nanoenzymes as Tumor Microenvironment Modulators to Reprogram Macrophage and Potentiate Immunotherapy.

Nanozyme-based tumor catalytic therapy has attracted widespread attention in recent years, but its therapeutic outcome is drastically diminished by species of nanozyme, concentration of substrate, pH value, and reaction temperature, etc. Herein, a novel Cu-doped polypyrrole nanozyme (CuP) with trienzyme-like activities, including catalase (CAT), glutathione peroxidase (GPx), and peroxidase (POD), is first proposed by a straightforward one-step procedure, which can specifically promote O2 and ·OH elevation but glutathione (GSH) reduction in tumor microenvironment (TME), causing irreversible oxidative stress damage to tumor cells and reversing the redox balance. The PEGylated CuP nanozyme (CuPP) has been demonstrated to efficiently reverse immunosuppressive TME by overcoming tumor hypoxia and re-educating macrophage from pro-tumoral M2 to anti-tumoral M1 phenotype. More importantly, CuPP exhibits hyperthermia-enhanced enzyme-mimic catalytic and immunoregulatory activities, which results in intense immune responses and almost complete tumor inhibition by further combining with αPD-L1. This work opens intriguing perspectives not only in enzyme-catalytic nanomedicine but also in macrophage-based tumor immunotherapy.

Mussel-Inspired Ligand Clicking and Ion Coordination on 2D Black Phosphorus for Cancer Multimodal Imaging and Therapy.

As a promising 2D nanocarrier, the biggest challenge of bare black phosphorus nanosheets (BP NSs) lies in the inherent instability, while it can be improved by surface modification strategies to a great extent. Considering the existing infirm BP NSs surface modification strategies, A mussels-inspired strong adhesive biomimetic peptide with azide groups for surface modification to increase the stability of BP NSs is synthesized. The azide groups on the peptide can quickly and precisely bind to the targeting ligand through click chemistry, solving the problem of nonspecificity of secondary modification of other mussel-mimicking materials. Besides, a catechol-Gd3+ coordination network is further constructed for magnetic resonance imaging (MRI) and inducing intracellular endo/lysosome escape. The fabricated BP-DOX@Gd/(DOPA)4 -PEG-TL nanoplatform exhibits enhanced antitumor abilities through synergetic chemo/photothermal effects both in vitro and in vivo.

A Platelet Intelligent Vehicle with Navigation for Cancer Photothermal-Chemotherapy.

Controllable and visible delivery of therapeutic agents is critical for tumor precise therapy. Tumor targeting and deep penetration of therapeutic agents are still challenging issues for controllable delivery. Visible drug delivery with imaging navigation can optimize the treatment window for personalized medicine. Herein, a biomimetic platelet intelligent vehicle with navigation (IRDNP-PLT) was developed to achieve controllable and visible delivery with a navigation system, a driving system, and a loading system. The platelets acted as engines and drug repositories to exert the target driving and delivery functions. The fluorescent photothermal agent IR-820 was introduced in the platform to offer an imaging navigation for the intelligent platelet vehicle in addition to photothermal therapy. The nanodrug-loaded platelets enabled efficient drug loading and controlled release of the therapeutic payload by encapsulating photothermal-/pH-sensitive chemotherapeutic nanoparticles (PDA@Dox NPs). In in vivo experiments on 4T1 tumor-bearing mice models, IRDNP-PLT performed well in tumor targeting and showed excellent therapeutic efficacy and tumor recurrence prevention ability. The intelligent platelet vehicle achieved the functions of tumor targeting and deep penetration, fluorescence imaging guidance, photocontrolled drug release, and chemo-photothermal combination therapy, suggesting the advancement for tumor precise delivery and efficient therapy.

Construction of iron-mineralized black phosphorene nanosheet to combinate chemodynamic therapy and photothermal therapy.

Chemodynamic therapy (CDT) by triggering Fenton reaction or Fenton-like reaction to generate hazardous hydroxyl radical (•OH), is a promising strategy to selectively inhibit tumors with higher H2O2 levels and relatively acidic microenvironment. Current Fe-based Fenton nanocatalysts mostly depend on slowly releasing iron ions from Fe or Fe oxide-based nanoparticles, which leads to a limited rate of Fenton reaction. Herein, we employed black phosphorene nanosheets (BPNS), a biocompatible and biodegradable photothermal material, to develop iron-mineralized black phosphorene nanosheet (BPFe) by in situ deposition method for chemodynamic and photothermal combination cancer therapy. This study demonstrated that the BPFe could selectively increase cytotoxic ·OH in tumor cells whereas having no influence on normal cells. The IC50 of BPFe for tested tumor cells was about 3-6 µg/mL, which was at least one order of magnitude lower than previous Fe-based Fenton nanocatalysts. The low H2O2 level in normal mammalian cells guaranteed the rare cytotoxicity of BPFe. Moreover, the combination of photothermal therapy (PTT) with CDT based on BPFe was proved to kill tumors more potently with spatiotemporal accuracy, which exhibited excellent anti-tumor effects in xenografted MCF-7 tumor mice models.

Effect of electroacupuncture on motor function and gait in patients with post-stroke spasticity in lower limbs / 中国针灸

OBJECTIVE@#To observe the effect on motor function, spasticity degree, muscle strength and the relevant parameters of three-dimensional gait analysis in the patients with post-stroke spasticity in the lower limbs treated with the combined therapy of electroacupuncture (EA) and muscle electricity biofeedback or the simple muscle electricity biofeedback therapy on the base of rehabilitation medicine.@*METHODS@#A total of 60 patients with post-stroke spasticity in the lower limbs were randomized into an EA + biofeedback group, a biofeedback group and a rehabilitation group, 20 cases in each one. In the rehabilitation group, the basic rehabilitation training was provided, 45 min each time. In the biofeedback group, on the base of the treatment as the rehabilitation group, the biofeedback therapy was added, 30 min each time. In the EA + biofeedback group, besides the treatment as the biofeedback group, acupuncture was supplemented at Futu (ST 32), Liangqiu (ST 34), Zusanli (ST 36) and Fenglong (ST 40), etc, and EA was applid at Zusanli (ST 36) and Taichong (LR 3) with continuous wave and 5 Hz in frequency. In each group, the treatment was given once daily, 5 times a week, for 6 weeks totally. Separately, before and after treatment, the score of Fugle-Meyer assessment (FMA), the score of clinical spasticity index (CSI) in the lower limbs and the strength of the anterior tibial muscle on the affected side were assessed, and the spatial-temporal parameters (step frequency and steep speed) in the three-dimensional gait analysis and the kinematic parameters (maximum dorsal flexion and maximum plantar flexion of ankle joint on the affected side) were measured in the patients of three groups.@*RESULTS@#After treatment, FMA score was increased as compared with that before treatment in all of three groups (P<0.05). FMA score in the EA + biofeedback group and the biofeedback group was higher than the rehabilitation group respectively (P<0.05). CSI score in the EA + biofeedback group and the biofeedback group was lower than that before treatment respectively (P<0.05), and lower than the rehabilitation group (P<0.05). After treatment, the step frequency and speed were all improved and the angles of maximum dorsal flexion and maximum plantar flexion of ankle joint on the affected side were all increased as compared with those before treatment in the patients of three groups separately (P<0.05). The step frequency and speed, as well as the angles of maximum dorsal flexion and maximum plantar flexion of ankle joint on the affected side in either the EA + biofeedback group or the biofeedback group were all higher than the rehabilitation group (P<0.05), and the step speed in the EA + biofeedback group was higher than the biofeedback group (P<0.05). After treatment, the strength of the anterior tibial muscle on the affected side was increased as compared with that before treatment in the patients of each group (P<0.05); and the strength of the anterior tibial muscle in the EA + biofeedback group and the biofeedback group was larger than the rehabilitation group (P<0.05).@*CONCLUSION@#On the base of rehabilitation treatment, the combined regimen of EA and muscle electricity biofeedback therapy and the simple muscle electricity biofeedback therapy all effectively strengthen the motor functions and reduce spasticity as well as improve step frequency, step speed and the range of motion of ankle joint in the patients with post-stroke spasticity in the lower limbs. Regarding the gait improvement, the combined regimen of EA and muscle electricity biofeedback is better than the simple muscle electricity biofeedback.

Charge-reversal biodegradable MSNs for tumor synergetic chemo/photothermal and visualized therapy.

Given the difficulties of biodegradation of mesoporous silica nanoparticles (NPs), enrichment and penetration of tumor sites, and real-time monitoring of the treatment process, we developed a kind of mannose-doping doxorubicin-loading mesoporous silica nanoparticle (MSN-Man-DOX) and coated by polydopamine-Gd3+ (PDAGd) metal-phenolic networks, as well as modified by poly (2-Ethyl-2-Oxazoline) (PEOz), constructing a novel nanomedicine MSN-Man-DOX@PDA-Gd-PEOz. Its pH-responsive charge reversal, photothermal, biodegradation, drug release, and magnetic resonance imaging (MRI) properties were evaluated in vitro. Cellular uptake, tumor penetration, lysosomal escape properties, as well as cell safety and toxicity of the nanoplatform were investigated through cell experiments. Finally, the MRI, organ distribution, photothermal condition, and comprehensive anti-tumor therapy in vivo were evaluated comprehensively through animal experiments. Research results showed that MSN-Man-DOX@PDA-Gd-PEOz had outstanding tumor enrichment and penetration abilities, which can produce excellent treatment effects through the synergistic effect of chemotherapy and photothermal therapy (PTT) with the function of magnetic resonance imaging contrast agent for disease monitoring. Besides, after finishing the therapeutic effect MSN-Man-DOX@PDA-Gd-PEOz can be biodegraded, so it had a good prospect of clinical application.

The effect of estrogen therapy on spermatogenesis in transgender women.

OBJECTIVE: To describe the histopathologic parameters of orchiectomy specimens obtained after gender-affirming surgery from transgender women who used gender-affirming hormone therapy (GAHT), which included estrogen and spironolactone. Our hypothesis was that an increasing duration of GAHT affects testicular health. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: All transgender women (individuals assigned male at birth who identified as female) who underwent orchiectomy with or without vaginoplasty between December 2015 and March 2020. INTERVENTIONS: GAHT (estrogen and spironolactone) in the setting of patients with orchiectomy with or without vaginoplasty. MAIN OUTCOME MEASURES: Demographic and perioperative data and pathology records were reviewed. The following pathology parameters were recorded: testicular volume, testicular weight, presence of spermatogenesis (active vs. reduced), maturation arrest, testicular atrophy, hyalinization, scarring/fibrosis, and Sertoli cell and Leydig cell phenotypes. The patients were grouped into one of three categories describing the duration of GAHT use: 0-36 months, 37-60 months, and >60 months years. Descriptive statistics were performed and comparisons between outcomes (demographic data and pathology parameters) were made among the GAHT groups. RESULTS: Eighty-five (N = 85) patients underwent orchiectomy during the study period with 85.9% (n = 73) undergoing concurrent vaginoplasty. The mean (SD) age and body mass index of the cohort were 39 ±16 years and 28.4 ± 5.4 kg/m2, respectively. In addition, although this was not statistically significant, patients in the 37-60 and >60-month groups were more likely to smoke marijuana than those in the 0-36-month group (26.3% and 21.2% vs. 4.2%, respectively). Mean testicular weight and volume across the cohort were 60.1 ± 24.9 grams and 65.5 ± 41.1 cm3, respectively. Spermatogenesis was present in 28.2% (n = 24) of specimens with active spermatogenesis noted in 8.2% (n = 7). Hyalinization, scarring/fibrosis, and atrophy were present in 28.2% (n = 24), 20.0% (n = 17), and 25.9% (n = 22) of specimens, respectively. There were no differences in pathology parameters across the GAHT groups. Testicular weight and volume were not associated with any differences in pathology parameters. Additionally, age was not associated with testicular weight, volume, or pathology parameters with the exception of the following: when patients were categorized as either ≤40 years of age (n = 48) vs. > 40 years of age (n = 37), patients who were older were more likely to have hyalinization (43.2% vs. 16.7%) as well as atrophy (40.5% vs. 14.6%). CONCLUSIONS: The duration of GAHT use was not associated with any differences in orchiectomy pathology parameters in patients undergoing gender-affirming surgery, and some patients may still have some spermatogenesis based on the parameters observed in this study.

Early 1,25-Dihydroxyvitamin D3 Supplementation Effectively Lowers the Incidence of Type 2 Diabetes Mellitus via Ameliorating Inflammation In KK-Ay Mice.

Few studies have been performed to investigate the effect of vitamin D supplementation and T2DM in type 2 diabetic animal models. The present study aimed to explore the relationship between early 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the incidence of T2DM and determine whether early 1,25(OH)2D3 supplementation was associated with inflammation in KK-Ay mice. The KK-Ay mice were divided into 4 vitamin D treatment groups, the low-dose vitamin D supplementation group (VDS-L, 1.5 µg/kg 1,25(OH)2D3), moderate-dose vitamin D supplementation group (VDS-M, 3.0 µg/kg 1,25(OH)2D3), high-dose vitamin D supplementation group (VDS-H, 6.0 µg/kg 1,25(OH)2D3) and the model control group (MC). C57BL/6J mice were used as the controls. The treatment period lasted for 9 wk. During this treatment period, fasting blood glucose (FBG) level of the mice was measured on a weekly basis. The levels of lipid profile, insulin and inflammation biomarkers were determined after 9 wk of 1,25(OH)2D3 intragastric gavage. After 9 wk of 1,25(OH)2D3 intragastric gavage, FBG level was significantly decreased in the vitamin D treatment groups compared with the MC group. The number of T2DM incidence in the VDS-L group (n=7), VDS-M group (n=5) and VDS-H group (n=3) was lower than those in the MC group (n=10) on week 9. Moreover, serum C-reactive protein (CRP) and interleukin-6 (IL-6) in the vitamin D treatment groups were significantly suppressed by 1,25(OH)2D3 administration compared with the MC group. Early 1,25(OH)2D3 supplementation could effectively lower the incidence of T2DM via ameliorating inflammation in KK-Ay mice.