Metabolomics reveals the implication of acetoacetate and ketogenic diet therapy in radioiodine-refractory differentiated thyroid carcinoma.

OBJECTIVE: Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC. METHODS: The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry. RESULTS: The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression. CONCLUSION: Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC.

PET imaging of neural activity, ß-amyloid, and tau in normal brain aging.

Normal brain aging is commonly associated with neural activity alteration, ß-amyloid (Aß) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aß, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aß PET imaging uncovers the pathophysiological association of Aß deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aß as indicated by tau and Aß PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.

Hollow Prussian Blue Nanozymes Drive Neuroprotection against Ischemic Stroke via Attenuating Oxidative Stress, Counteracting Inflammation, and Suppressing Cell Apoptosis.

Ischemic stroke is a devastating disease and one of the leading causes of mortality worldwide. Overproduction of reactive oxygen and nitrogen species (RONS) following ischemic insult is known as a key factor in exacerbating brain damage. Thus, RONS scavengers that can block excessive production of RONS have great therapeutic potential. Herein, we propose an efficient treatment strategy in which an artificial nanozyme with multienzyme activity drives neuroprotection against ischemic stroke primarily by scavenging RONS. Specifically, through a facile, Bi3+-assisted, template-free synthetic strategy, we developed hollow Prussian blue nanozymes (HPBZs) with multienzyme activity to scavenge RONS in a rat model of ischemic stroke. The comprehensive characteristics of HPBZs against RONS were explored. Apart from attenuating oxidative stress, HPBZs also suppressed apoptosis and counteracted inflammation both in vitro and in vivo, thereby contributing to increased brain tolerance of ischemic injury with minimal side effects. This study provides a proof of concept for a novel class of neuroprotective nanoagents that might be beneficial for treatment of ischemic stroke and other RONS-related disorders.

[PET/CT imaging manifestations of different pathological subtypes of liposarcoma].

OBJECTIVE: To analyze PET/CT imaging manifestations of different pathological subtypes of liposarcoma. METHODS: The 18F-fluorodeoxyglucose(FDG) PET/CT features of 13 patients pathologically confirmed as liposarcoma were retrospectively reviewed. The metabolism degree and distribution of different subtypes of liposarcoma were compared. RESULTS: The well-differentiated liposarcoma showed fat density mass with septa and irregular strip with mild FDG uptake. The myxoid liposarcoma showed cystic or cystic solid mass, single or multiple with mild-moderate FDG uptake heterogeneously or homogeneously. The dedifferentiated liposarcoma showed mixed soft tissue mass with high FDG uptake heterogeneously, larger lesion with necrosis centrally. The mixed type contained well differentiated type and dedifferentiated type, and showed multiple lesion with combined imaging manifestations. There were local invasions in 12 cases, no lymph node matastasis, and the recurrence of dedifferentiated liposarcoma with lung metastasis in 1 case. The maximum standard values (SUVmax) of FNCCLE grade G1, G2 and G3 liposarcoma were 3.00, 5.67 and 10.33, respectively; there was significant difference between G1 and G3 groups, G2 and G3 groups (all P<0.05). CONCLUSIONS: PET/CT manifestations of liposarcoma of various pathological subtypes are different. Preoperative PET/CT examination can clarify the pathological types, scope of tumor invasion and metastasis of liposarcoma, which provides more information for clinical decision-making and is helpful for the preparation of surgical plan.

Time-specific microRNA changes during spinal motoneuron degeneration in adult rats following unilateral brachial plexus root avulsion: ipsilateral vs. contralateral changes.

BACKGROUND: Spinal root avulsion induces multiple pathophysiological events consisting of altered levels of specific genes and proteins related to inflammation, apoptosis, and oxidative stress, which collectively result in the death of the affected motoneurons. Recent studies have demonstrated that the gene changes involved in spinal cord injury can be regulated by microRNAs, which are a class of short non-coding RNA molecules that repress target mRNAs post-transcriptionally. With consideration for the time course of the avulsion-induced gene expression patterns within dying motoneurons, we employed microarray analysis to determine whether and how microRNAs are involved in the changes of gene expression induced by pathophysiological events in spinal cord motoneurons. RESULTS: The expression of a total of 3,361 miRNAs in the spinal cord of adult rats was identified. Unilateral root-avulsion resulted in significant alterations in miRNA expression. In the ipsilateral half compared to the contralateral half of the spinal cord, on the 3rd day after the injury, 55 miRNAs were upregulated, and 24 were downregulated, and on the 14th day after the injury, 36 miRNAs were upregulated, and 23 were downregulated. The upregulation of miR-146b-5p and miR-31a-3p and the downregulation of miR-324-3p and miR-484 were observed. Eleven of the miRNAs, including miR-21-5p, demonstrated a sustained increase; however, only miR-466c-3p presented a sustained decrease 3 and 14 days after the injury. More interestingly, 4 of the miRNAs, including miR-18a, were upregulated on the 3rd day but were downregulated on the 14th day after injury.Some of these miRNAs target inflammatory-response genes in the early stage of injury, and others target neurotransmitter transport genes in the intermediate stages of injury. The altered miRNA expression pattern suggests that the MAPK and calcium signaling pathways are consistently involved in the injury response. CONCLUSIONS: This analysis may facilitate the understanding of the time-specific altered expression of a large set of microRNAs in the spinal cord after brachial root avulsion.

Lithium enhances survival and regrowth of spinal motoneurons after ventral root avulsion.

BACKGROUND: During the clinical treatment of the brachial plexus root avulsion (BPRA), reimplantation surgery can not completely repair the motor function of the hand because the axonal growth velocity of the spinal motoneurons (MNs) is too slow to re-innervate the intrinsic hand muscles before muscle atrophy. Here, we investigated whether lithium can enhance the regenerative capacity of the spinal MNs in a rat model of BPRA. RESULTS: The avulsion and immediate reimplantation of the C7 and C8 ventral roots were performed and followed with daily intraperitoneal administration of a therapeutic concentrationof LiCl. After a 20 week long-term rehabilitation, the motor function recovery of the injured forepaw was studied by a grasping test. The survival and regeneration of MNs were checked by choline acetyltransferase (ChAT) immunofluorescence and by Fluoro-Gold (FG) retrograde labeling through the median and ulnar nerves of the ventral horn MNs. The number and diameter of the nerve fibers in the median nerve were assessed by toluidine blue staining. Our results showed that lithium plus reimplantation therapy resulted in a significantly higher grasping strength of the digits of the injured forepaw. Lithium plus reimplantation allowed 45.1% ± 8.11% of ChAT-positive MNs to survive the injury and increased the number and diameter of nerve fibers in the median nerve. The number of FG-labeled regenerative MNs was significantly elevated in all of the reimplantation animals. Our present data proved that lithium can enhance the regenerative capacity of spinal MNs. CONCLUSIONS: These results suggest that immediate administration of lithium could be used to assist reimplantation surgery in repairing BPRA injuries in clinical treatment.

18F-FDG PET/CT metabolism multi-parameter prediction of chemotherapy efficacy in locally progressive gastric cancer.

PURPOSE: This study aimed to use an 18F-FDG PET/CT multiparametric quantitative analysis to determine the efficacy of neoadjuvant chemotherapy in patients with locally progressive gastric cancer. MATERIALS AND METHODS: We conducted a retrospective analysis of 34 patients with pathologically identified gastric cancer who received neoadjuvant chemotherapy and surgery. Chemotherapy regimens were followed and 18F-FDG PET/CT was conducted. We ascertained multiparamaters of the target lesions pre- and post-treatment and determined the ideal cutoff values for the percentage change in biomarkers. Independent factors were evaluated using binary logistic regression. A response classification system was used to explore the association between metabolic and anatomical responses and the degree of pathological remission. RESULTS: Binary logistic regression analysis showed that Lauren bowel type and change in total lesion glycolysis >45.2% were risk predictors for the efficacy of neoadjuvant chemotherapy; total lesion glycolysis demonstrated the best predictive efficacy. The categorical variable system of the two-module response (metabolic and anatomical response) group had a higher predictive accuracy than that of the single-module response (metabolic or anatomical response) group. CONCLUSIONS: Using 18F-FDG PET/CT multiparametric quantitative analysis, Lauren bowel type and change in total lesion glycolysis >45.2% were independent predictors of the efficacy of neoadjuvant chemotherapy in patients with gastric adenocarcinoma. Additionally, the dual-module assessment demonstrated high predictive efficacy.

Incorporating Network Pharmacology and Experimental Validation to Identify Bioactive Compounds and Potential Mechanisms of Digitalis in Treating Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal malignant tumors for which there is no effective treatment. There are an increasing number of studies on herbal medicine for treating malignant tumors, and the classic botanical medicine Digitalis and its active ingredients for treating heart failure and arrhythmias have been revealed to have significant antitumor efficacy against a wide range of malignant tumors. However, the main components of Digitalis and the molecular mechanisms of its anti-ATC effects have not been extensively studied. Here, we screened the main components and core targets of Digitalis and verified the relationship between the active components and targets through network pharmacology, molecular docking, and experimental validation. These experiments showed that the active ingredients of Digitalis inhibit ATC cell activity and lead to ATC cell death through the apoptotic pathway.

Development and Verification of Diagnosis Model for Papillary Thyroid Cancer Based on Pyroptosis-Related Genes: A Bioinformatic and in vitro Investigation.

Background: The incidence of papillary thyroid cancer (PTC) has been increasing annually; however, early diagnosis can improve patient outcomes. Pyroptosis is a programmed cell death modality that has received considerable attention recently. However, no studies have reported using pyroptosis-related genes in PTC diagnosis. Methods: Analyzed 33 pyroptosis-related genes in PTC transcriptome data from the Gene Expression Omnibus database. Subsequently, used the Least Absolute Shrinkage and Selection Operator (LASSO) model to construct a PTC molecular diagnostic model. Furthermore, confirmed differences in the expression of five genes between PTC and non-tumor tissues using immunohistochemistry. Collected 338 PTC and control samples to construct a five-gene PTC diagnostic model, which was then validated using a training set and underwent correlation analysis with immune cell infiltration. Additionally, validated the biological functions of the core gene NOD1 in vitro. Results: The five-gene PTC diagnostic model demonstrated good diagnostic value for PTC. Moreover, identified three reliable subtypes of pyroptosis and found that NOD1 is involved in tumor-suppressive microenvironment formation. Notably, patients with high NOD1 expression had lower Progression-Free Survival (PFS). Additionally, NOD1 expression was positively correlated with immune markers such as CD47, CD68, CD3, and CD8. Lastly, inhibiting NOD1 showed significant anti-PTC activity in vitro. Conclusion: Our results suggest that pyroptosis-related genes can be used for PTC diagnosis, and NOD1 could be a promising therapeutic target.

Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission.

Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.

Prosapogenin A induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase activation-mediated lysosomal over-acidification.

Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.

Effects of sevoflurane and propofol on cultured bone-marrow mesenchymal stem cells of rats.

OBJECTIVE: Bone marrow mesenchymal stem cell (BMSC) is a potentially effective vehicle for the cell and gene therapy in clinical disease treatment. We studied whether the most commonly used anesthetic drugs have negative effects on rat BMSCs in vitro. MATERIALS AND METHODS: The cultured BMSCs were treated with sevoflurane (in 1.7%, 2.3%, and 3%); propofol (5 µg/ml, 10 µg/ml and 20 µg/ml); or 2.3% sevoflurane plus 10 µg/ml propofol. After 4-hour treatment, the cultured BMSCs were prepared for MTT reduction assays and cell morphology observation. RESULTS: Compared to the controls, the 4-hour sevoflurane exposure resulted in decreased cell viability of BMSCs in a concentration-dependent manner; however, 1.7% sevoflurane did not reduce the cell viability. The 4-hour propofol treatment did not affect the cell viability; but combined usage of 2.3% sevoflurane and 10 µg/ml propofol decreased cell viability. In BMSCs treated with higher concentration of sevoflurane (1.7% and 2.3%) and combined usage of the two anesthetics, the cell became raritas with wizened cytoplasm and had fewer connections to each other of BMSCs. More than 2.3%, or 2.3% sevoflurane plus 10 µg/ ml propofol caused cytotoxicity to BMSCs. However, propofol up to 20 µg/ml did not harm the BMSCs. CONCLUSIONS: The study indicates that it is necessary to choose the right anesthesia during the BMSCs transplantation therapy.

Prediction of hemorrhagic transformation via pre-treatment CT radiomics in acute ischemic stroke patients receiving endovascular therapy.

OBJECTIVE: This study aimed to extract radiomics features (RFs) from pre-treatment CT scans in patients with acute ischemic stroke (AIS), and to establish a radiomics model to predict hemorrhagic transformation (HT) after endovascular therapy (EVT). METHODS: A total of 105 patients who were diagnosed with AIS [with occlusion of the M1 segment of the middle cerebral artery (MCA) and/or internal carotid artery] and received EVT were enrolled. They were randomly divided into the development cohort (n = 73) and the validation cohort (n = 32). The clinicoradiological data of all patients, including pre-treatment cranial CT without contrast enhancement, CT perfusion, and CT angiography, were obtained. The MCA territory on pre-treatment CT images was segmented to extract RFs associated with HT after EVT. Then, a CT radiomics model based on the selected RFs was constructed to predict HT after EVT. RESULTS: The sensitivity, specificity, and area under the curve of the CT radiomics model for predicting HT after EVT based on pre-treatment CT RFs was 0.806, 0.649, and 0.781 (95% confidence interval (CI): 0.675-0.886), respectively, in the development cohort. The sensitivity, specificity, and area under the curve in the validation cohort was 0.625, 0.875, and 0.797 (95% CI: 0.642-0.951), respectively. CONCLUSION: CT radiomics analysis is a valuable tool for predicting HT in AIS patients receiving EVT. It may guide the selection of patients in practice and improve procedural safety and effectiveness. ADVANCES IN KNOWLEDGE: Identification of the importance of pre-treatment CT radiomics in the prediction of HT in AIS patients after EVT.

TESC promotes differentiated thyroid cancer development by activating ERK and weakening NIS and radioiodine uptake.

PURPOSE: Most differentiated thyroid cancer (DTC) patients have a good prognosis after surgery, but radioiodine refractory differentiated thyroid cancer (RAIR-DTC) patients have a significantly reduced 5-year survival rate (<60%) and a significantly increased recurrence rate (>30%). This study aimed to clarify the tescalcin (TESC) role in promoting the malignant PTC progression and providing a potential target for RAIR-DTC treatment. METHODS: We analyzed TESC expression and clinicopathological characteristics using the Cancer Genome Atlas (TCGA) and performed qRT-PCR on tissue samples. TPC-1 and IHH-4 proliferation, migration, and invasion were detected after transfection with TESC-RNAi. Using Western blot (WB), several EMT-related indicators were detected. Moreover, iodine uptake of TPC-1 and IHH-4 after transfection with TESC-RNAi was detected. Finally, NIS, ERK1/2, and p-ERK1/2 levels were determined by WB. RESULTS: TESC was significantly upregulated in DTC tissues and positively correlated with BRAF V600E mutation based on data analysis from TCGA and our center. Reduced expression of TESC in both IHH-4 (BRAF V600E mutation) and TPC-1 (BRAF V600E wild type) cells significantly inhibited cell proliferation, migration, and invasion. It downregulated the EMT pathway markers Vimentin and N-cadherin, and increased E- cadherin. Moreover, TESC knockdown significantly inhibited ERK1/2 phosphorylation and decreased NIS expression in DTC cells, with a remarkably increased iodine uptake rate. CONCLUSIONS: TESC was highly expressed in DTC tissues and may have promoted metastasis through EMT and induced iodine resistance by downregulating NIS in DTC cells.

Alantolactone induces concurrent apoptosis and GSDME-dependent pyroptosis of anaplastic thyroid cancer through ROS mitochondria-dependent caspase pathway.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the fatal cancers and has not effective treatments. Alantolactone (ATL), a terpenoid extracted from traditional Chinese medicinal herb Inula helenium L., confers significant anti-inflammatory, antibacterial and antitumor activity. However, the activity and mechanisms of ATL in ATC remain unclear. PURPOSE: To investigate the potential anti-ATC effects in vitro and in vivo and the mechanisms involved. METHODS: The anti-proliferative activity of Alantolactone (ATL) against ATC cells was analyzed through CCK-8 and colony formation assays. Flow cytometry assay was performed to assess the cell cycle, cell apoptosis, ROS, and mitochondrial membrane potential (ΔΨm), whereas the cellular localization of cytochrome c and calreticulin were determined using cellular immunofluorescence assays. The lactate dehydrogenase (LDH) enzyme activity in the cell culture medium was measured using a commercial LDH kit, whereas ELISA was conducted to assess the secretory function of IL-1ß. Western blot assays were conducted to determine the expression or regulation of proteins associated with apoptosis and pyroptosis. Subcutaneous tumor model of nude mice was established to evaluate the anticancer activity of ATL in vivo. The expression of Ki67, cyclin B1, cleaved-PARP, cleaved-caspase 3, and IL-1ß in the animal tumor tissues was profiled using immunohistochemistry analyses. RESULTS: Our data showed that ATL significantly inhibited the proliferation and colony formation activity of ATC cells. ATL induced ATC cell cycle arrest at G2/M phase, and downregulated the expression of cyclin B1 and CDC2. Furthermore, ATL induced concurrent apoptosis and pyroptosis in the ATC cells, and the cleavage of PARP and GSDME. It also significantly increased the release of LDH and IL-1ß. Mechanically, ATL-mediated increase in ROS suppressed the Bcl-2/Bax ratio, downregulated the mitochondrial membrane potential and increased the release of cytochrome c, leading to caspase 9 and caspase 3 cleavage. We also found that ATL induced the translocation of an immunogenic cell death marker (calreticulin) to the cell membrane. In addition, it inhibited the growth of the ATC subcutaneous xenograft model, and activated proteins associated with apoptosis and pyroptosis, with a high safety profile. CONCLUSION: Taken together, these results firstly demonstrated that ATL exerted an anti-ATC activity by inducing concurrent apoptosis and GSDME-dependent pyroptosis through ROS-mediated mitochondria-dependent caspase activation. Meanwhile, these cell deaths exhibited obvious characteristics of immunogenic cell death, which may synergistically increase the potential of cancer immunotherapy in ATC. Further studies are needed to explore deeper mechanisms for the anti- ATC activity of ATL.

Activation of phospholipase-Cγ and protein kinase C signal pathways helps the survival of spinal motoneurons injured by root avulsion.

The signaling transduction processes involved in avulsion-induced motoneuron (MN) death have not been elucidated. Using the brachial plexus root avulsion rat model, we showed that avulsion-activated phosphorylation of phospholipase-Cγ (PLCγ) and protein kinase C (PKC) occurred in injured spinal MNs within 72 h of injury. Moreover, some MNs positive for PLCγ and PKC are also positive for avulsion-induced neuronal nitric oxide synthase (nNOS). Inhibition of PLCγ/PKC signal pathway, either with PLCγ inhibitor, 1-[6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione, or with PLCγ siRNA augmented avulsion-induced MN death. 1-[6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione also inhibited PKC phosphorylation and exacerbated avulsion-induced reductions in the nNOS protein level in injured spinal segments. Moreover, activation of PLCγ/PKC signal pathway with PKC activator, phorbol-12-myristate-13-acetate, decreased avulsion-induced MN death. The temporal profile of PLCγ/PKC signaling appears to be crucial for the survival of spinal MNs after root avulsion. Our data suggest that PLCγ mediates, while PKC and nNOS are associated with, the avulsion-induced MN death in brachial plexus root avulsion.

A Comparative Study of Total Knee Arthroplasty and Unicondylar Knee Arthroplasty in the Treatment of Knee Osteoarthritis.

Objective: To compare the clinical efficacy of total knee arthroplasty (TKA) and unicondylar knee arthroplasty (UKA) in the treatment of knee osteoarthritis (KOA). Methods: A retrospective analysis was conducted on 30 patients admitted to the Department of Orthopaedics of Yijishan Hospital from 2020 to 2021. The patients were divided into UKA group (n = 15) and TKA group (control, n = 15). The intraoperative situation and postoperative clinical indicators of patients in the two groups were collected and compared, such as operation time, intraoperative blood loss, length of hospital stay, postoperative complications, and postoperative functional recovery. Postoperative functional recovery was investigated by the visual analogue pain scale (VAS), knee score scale (HSS), and knee range of motion (ROM) scores 5 days after surgery. Results: Perioperative indexes in the UKA group were significantly lower than those in the TKA group, including operation time, intraoperative blood loss, first time going to the ground, and length of hospital stay. VAS, HSS, and ROM scores in the two groups were significantly improved after surgery compared with those before surgery. However, ROM scores in the UKA group were significantly better than in the TKA group. In terms of early postoperative complications, there was one case of venous thrombosis of lower limbs in the UKA group, while in the TKA group there was one case of delayed wound healing due to diabetes, and one case of deep infection. Conclusion: Both UKA and TKA are very successful options for the treatment of KOA, but the use of UKA can promote the recovery of postoperative knee function, reduce postoperative complications, and achieve more satisfactory than expected results.

Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke.

The local microenvironment is essential to stem cell-based therapy for ischemic stroke, and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeutic mechanisms. However, relevant studies on microenvironmental changes were mainly confined in the acute phase of stroke, and long-term changes remain unclear. This study aimed to investigate the microenvironmental changes in the subacute and chronic phases of ischemic stroke after stem cell transplantation. Herein, induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) were transplanted into the ischemic brain established by middle cerebral artery occlusion surgery. Positron emission tomography imaging and neurological tests were applied to evaluate the metabolic and neurofunctional alterations of rats transplanted with stem cells. Quantitative proteomics was employed to investigate the protein expression profiles in iPSCs-transplanted brain in the subacute and chronic phases of stroke. Compared with NSCs-transplanted rats, significantly increased glucose metabolism and neurofunctional scores were observed in iPSCs-transplanted rats. Subsequent proteomic data of iPSCs-transplanted rats identified a total of 39 differentially expressed proteins in the subacute and chronic phases, which are involved in various ischemic stroke-related biological processes, including neuronal survival, axonal remodeling, antioxidative stress, and mitochondrial function restoration. Taken together, our study indicated that iPSCs have a positive therapeutic effect in ischemic stroke and emphasized the wide-ranging microenvironmental changes in the subacute and chronic phases.

Resveratrol promotes the survival and neuronal differentiation of hypoxia-conditioned neuronal progenitor cells in rats with cerebral ischemia.

Hypoxia conditioning could increase the survival of transplanted neuronal progenitor cells (NPCs) in rats with cerebral ischemia but could also hinder neuronal differentiation partly by suppressing mitochondrial metabolism. In this work, the mitochondrial metabolism of hypoxia-conditioned NPCs (hcNPCs) was upregulated via the additional administration of resveratrol, an herbal compound, to resolve the limitation of hypoxia conditioning on neuronal differentiation. Resveratrol was first applied during the in vitro neuronal differentiation of hcNPCs and concurrently promoted the differentiation, synaptogenesis, and functional development of neurons derived from hcNPCs and restored the mitochondrial metabolism. Furthermore, this herbal compound was used as an adjuvant during hcNPC transplantation in a photothrombotic stroke rat model. Resveratrol promoted neuronal differentiation and increased the long-term survival of transplanted hcNPCs. 18-fluorine fluorodeoxyglucose positron emission tomography and rotarod test showed that resveratrol and hcNPC transplantation synergistically improved the neurological and metabolic recovery of stroke rats. In conclusion, resveratrol promoted the neuronal differentiation and therapeutic efficiency of hcNPCs in stroke rats via restoring mitochondrial metabolism. This work suggested a novel approach to promote the clinical translation of NPC transplantation therapy.