Therapeutic Potential of Fingolimod in Diabetes Mellitus and Its Chronic Complications.

Diabetes mellitus is a metabolic disease characterized by elevated blood glucose due to a deficiency of insulin secretion and/or action. Long-term poor blood glucose control may lead to chronic damage and dysfunction of the heart, kidneys, eyes, and other organs. Therefore, it is important to develop treatments for diabetes and its chronic complications. Fingolimod is a structural sphingosine analogue and sphingosine-1-phosphate receptor modulator currently used for the treatment of relapsing-remitting multiple sclerosis. Several studies have shown that it has beneficial effects on the improvement of diabetes and its chronic complications. This paper reviews the therapeutic potential of Fingolimod in diabetes and its chronic complications, aiming to further guide future treatment strategies.

Strontium ranelate retards disc degradation and improves endplate and bone micro-architecture in ovariectomized rats with lumbar fusion induced - Adjacent segment disc degeneration.

Objectives: Adjacent segment disc degeneration (ASDD) is one of the long-term sequelae of spinal fusion, which is more susceptible with osteoporosis. As an anti-osteoporosis drug, strontium ranelate (SR) has been reported to not only regulate bone metabolism but also cartilage matrix formation. However, it is not yet clear whether SR has a reversal or delaying effect on fusion-induced ASDD in a model of osteoporosis. Materials and methods: Fifth three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery. Animals were administered vehicle (V) or SR (900 mg/kg/d) orally for 12 weeks post-PLF as follows: Sham+V, OVX + V, PLF + V, OVX + PLF + V, and OVX + PLF + SR. Manual palpation and X-ray were used to evaluate the state of lumbar fusion. Adjacent-segment disc was assessed by histological (VG staining and Scoring), histomorphometry (Disc Height, MVD, Calcification rate and Vascular Bud rate), immunohistochemical (Col-II, Aggrecan, MMP-13, ADAMTS-4 and Caspase-3), and mRNA analysis (Col-I, Col-II, Aggrecan, MMP-13 and ADAMTS-4). Adjacent L6 vertebrae microstructures were evaluated by microcomputed tomography. Results: Manual palpation and radiographs showed clear evidence of the fused segment's immobility. After 12 weeks of PLF surgery, a fusion-induced ASDD model was established. Low bone mass caused by ovariectomy can significantly exacerbate ASDD progression. SR exerted a protective effect on adjacent segment intervertebral disc with the underlying mechanism possibly being associated with preserving bone mass to prevent spinal instability, maintaining the functional integrity of endplate vascular microstructure, and regulating matrix metabolism in the nucleus pulposus and annulus fibrosus. Discussion: Anti-osteoporosis medication SR treatments not only maintain bone mass and prevent fractures, but early intervention could also potentially delay degenerative conditions linked to osteoporosis. Taken together, our results suggested that SR might be a promising approach for the intervention of fusion-induced ASDD with osteoporosis.

Hotspots and frontier trends of diabetic associated cognitive decline research based on rat and mouse models from 2012 to 2021: A bibliometric study.

Background: The establishment of rodent models, such as rat and mouse models, plays a critical role in the study of diabetic associated cognitive decline. With the continuous growth of relevant literature information, it is difficult for researchers to accurately and timely capture the topics in this field. Therefore, this study aims to explore the current status and frontier trends of diabetic associated cognitive decline research based on rat and mouse models through a bibliometric analysis. Methods: We collected 701 original articles on this subject from the Science Citation Index Expanded of the Web of Science Core Collection from 2012 to 2021. Then we utilized CiteSpace and VOSviewer for plotting knowledge maps and evaluating hotpots and trends. Results: During this decade, except for a slight decline in 2020, the number of annual outputs on diabetes associated cognitive decline research using rat and mouse models increased every year. China (country), China Pharmaceutical University (institution), Gao, Hongchang (the author from the School of Pharmacy of Wenzhou Medical University, China), and Metabolic Brain Disease (journal) published the most papers in this research field. The analysis results of co-cited references and co-occurrence keywords indicated that "mechanisms and prevention and treatment methods", especially "oxidative stress", "potential association with Alzheimer's disease" and "spatial memory" are research focuses in this subject area. The bursts detection of references and keywords implied that "cognitive impairment of type 1 diabetes" and "autophagy and diabetes associated cognitive decline" will be potential directions for future research in this subject area. Conclusion: This study systematically assessed general information, current status and emerging trends of diabetic associated cognitive decline research using rat and mouse models in the past decade based on a bibliometric analysis. The number of publications was annually increasing although a slight decline was observed in 2020. Contributions from different countries/regions, institutions, authors, co-cited authors, journals and co-cited journals were evaluated, which may also be used to guide future research. Through the analysis of references and keywords, we predicted the future research hotspots and trends in this field.

Forsythoside B ameliorates diabetic cognitive dysfunction by inhibiting hippocampal neuroinflammation and reducing synaptic dysfunction in ovariectomized mice.

Background: Diabetes-associated cognitive impairment (DACI) is a common complication of diabetes, and studies have shown that DACI is more severe in postmenopausal patients with diabetes. Forsythoside B (FTS⋅B) can inhibit inflammation and reduce synaptic dysfunction, which can improve cognitive function. However, it has not been confirmed whether FTS⋅B has a reversing or retarding effect on postmenopausal diabetic encephalopathy. Methods: Seven days after bilateral ovariectomy (OVX) or sham surgery, adult female C57 mice (n = 15/group) received intraperitoneal injection of streptozotocin (60 mg/kg/day/L) and citrate buffer for 5 consecutive days to induce diabetes mellitus (DM). Fourteen days later, ovariectomized diabetic mice were given intraperitoneal injection of FTS⋅B (100, 150 mg/kg/day/L) and subcutaneous injection of 17ß-estradiol (1 mg/kg) for 8 weeks [OVX + DM + low-FTS⋅B group (L-F), OVX + DM + high-FTS⋅B group (H-F), and OVX + DM + 17ß-estradiol (ER)]. In addition, the following control groups were defined: Sham, OVX, DM, and OVX + DM (O + D). Fasting plasma glucose, body weight and blood insulin levels were determined in each group of mice. Next, their cognitive function was tested through behavioral experiments. Hematoxylin & eosin (H&E) and Nissl staining were used to detect the morphological changes in the hippocampus. The aggregation of amyloid beta (Aß) and the hyperaggregation of p-tau were assessed by immunohistochemistry. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), post-synaptic density-95 (PSD-95), synaptophysin, and synapsin-1 expression in the hippocampus was detected by real-time polymerase chain reaction (RT-PCR) and western blot analysis. Results: FTS⋅B can decrease fasting glucose and blood insulin level. Behavioral results showed that cognitive decline was the most severe in the O + D group, and the ER, L-F, and H-F groups revised the cognitive decline. Compared to the O + D group, more normal morphology, which has obvious nucleoli and clear nuclear membrane, was observed by H&E and Nissl staining in the ER, L-F, and H-F groups. FTS⋅B alleviated DACI by reducing the aggregation of Aß and the hyperaggregation of p-tau in the hippocampus. Moreover, the protein and mRNA expression showed that FTS⋅B not only inhibited inflammation by decreasing IL-1ß, IL-6, and TNF-α but also modulated synaptic plasticity by increasing BDNF, PSD-95, synaptophysin, and synapsin-1. Conclusion: These results suggest that FTS⋅B may be a novel therapeutic target for postmenopausal diabetic encephalopathy treatment.

Raloxifene retards the progression of adjacent segmental intervertebral disc degeneration by inhibiting apoptosis of nucleus pulposus in ovariectomized rats.

BACKGROUND: Adjacent segmental intervertebral disk degeneration (ASDD) is a major complication secondary to lumbar fusion. Although ASSD pathogenesis remains unclear, the primary cause of intervertebral disk degeneration (IVDD) development is apoptosis of nucleus pulposus (NP). Raloxifene (RAL) could delay ASDD by inhibiting NP apoptosis. METHODS: An ASDD rat model was established by ovariectomy (OVX) and posterolateral spinal fusion (PLF) on levels 4-5 of the lumbar vertebrae. Rats in the treatment groups were administered 1 mg/kg/d RAL by gavage for 12 weeks, following which, all animals were euthanized. Lumbar fusion, apoptosis, ASDD, and vertebrae micro-architecture were evaluated. RESULTS: RAL maintained intervertebral disk height (DHI), delayed vertebral osteoporosis, reduced histological score, and inhibited apoptosis. The OVX+PLF+RAL group revealed upregulated expression of aggrecan and B-cell lymphoma-2 (bcl2), as well as significantly downregulated expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), metalloproteinase-13 (MMP-13), caspase-3, BCL2-associated X (bax), and transferase dUTP nick end labeling (TUNEL) staining. Micro-computed tomography (Micro-CT) analysis revealed higher bone volume fraction (BV/TV), bone mineral density (BMD), and trabecular number (Tb.N), and lower trabecular separation (Tb.Sp) in OVX+PLF+RAL group than in the OVX+PLF group. CONCLUSIONS: RAL can postpone ASDD development in OVX rats through inhibiting extracellular matrix metabolic imbalance, NP cell apoptosis, and vertebral osteoporosis. These findings showed RAL as a potential therapeutic target for ASDD.

Complete Local and Abscopal Responses from a Combination of Radiation and Nivolumab in Refractory Hodgkin's Lymphoma.

Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report in our case series that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.

Immunotherapeutic Approaches to the Management of Head and Neck Cancer.

The two programmed death 1 checkpoint inhibitors nivolumab and pembrolizumab are approved by the US Food and Drug Administration as second-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Based on the existing data, the effectiveness of these two drugs is similar in this setting. When choosing between them, the decision should be individualized and can be determined by patient and provider preferences, as well as scheduling. Testing for tumor programmed death ligand 1 (PD-L1) and human papillomavirus status is not required for use of these checkpoint inhibitors in the second-line setting, but the level of tumor PD-L1 expression can be useful for decision making in special situations. There are many ongoing trials that are studying immunotherapy as frontline treatment for recurrent or metastatic HNSCC, as well as trials combining immunotherapy with definitive chemoradiation in locally advanced disease. Based on the updated results of the KEYNOTE-048 trial, checkpoint inhibitors will likely be a part of first-line therapy in the near future.

Leukapheresis reduces 4-week mortality in acute myeloid leukemia patients with hyperleukocytosis - a retrospective study from a tertiary center.

Hyperleukocytosis in patients with acute myeloid leukemia (AML) can lead to leukostasis, which if left untreated, has a high mortality. While prompt cytoreductive chemotherapy is essential, treatment with leukapheresis is controversial. This study investigated the outcomes of patients with hyperleukocytosis who received leukapheresis. From 5596 encounters of patients with leukemia seen at Houston Methodist Hospital, we identified 26 patients who had newly diagnosed AML, WBC >50,000/µL, and received leukapheresis. We matched 26 patients who had similar baseline characteristics but did not receive leukapheresis. The primary endpoint was to compare the 28-day mortality rates between the treatment and the control groups. Secondary endpoints were 6-month, 1-year, and 2-year mortality rates. Using multivariate logistic regression analysis, leukapheresis was associated with significantly lower 28-day mortality rate (30.8% vs. 57.7%, p = .022). There was, however, no difference in long-term mortality rate. Our study demonstrates the short-term mortality benefit of using leukapheresis in AML patients presenting with hyperleukocytosis.

Primary thyroid lymphoma presenting as dermatomyositis: a first case and review of the literature.

A 55-year-old woman presented with a 3-week history of weakness. On examination, she had a heliotrope rash, V-neck and shawl signs. There was symmetric proximal muscle weakness, and 2/5 strength in upper and lower extremities. Laboratory values showed CK 5836, CRP 14.9, erythrocyte sedimentation rate 49, lactate dehydrogenase 633, negative antinuclear antibodies and anti-Jo1 antibodies. Muscle biopsy and immunohistochemistry findings were consistent with dermatomyositis. Treatment with high-dose steroids, cyclophosphamide and intravenous immunoglobulin (IVIG) was started, without improvement of symptoms. She was found to have cold agglutinins with a cold screen titre of 1:256,256. Work up for malignancy ensued. Positron emission tomography-computed tomography (PET-CT) showed increased uptake in the thyroid. Fine-needle thyroid biopsy with flow cytometry studies revealed atypical lymphocytes consistent with diffuse large B-cell lymphoma. The patient underwent R-CHOP therapy, with remarkable improvement of her symptoms. Dermatomyositis associated with primary thyroid lymphoma has not been previously reported. This case reinforces the importance of cancer screening in dermatomyositis patients.

Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex.

BACKGROUND: Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region. METHODS: Seven-day-old littermates (n = 36) were randomly assigned to a 6-hour exposure to either 1.5% isoflurane or fasting in room air. Animals were euthanized immediately after exposure and brain sections were double-stained for activated caspase 3 and one of the following cellular markers: Neuronal Nuclei (NeuN) for neurons, glutamic acid decarboxylase (GAD)65 and GAD67 for GABAergic cells, as well as GFAP (glial fibrillary acidic protein) and S100ß for astrocytes. RESULTS: In 7-day-old mice, isoflurane exposure led to widespread increases in apoptotic cell death relative to controls, as measured by activated caspase 3 immunolabeling. Confocal analyses of caspase 3-labeled cells in cortical layers II and III revealed that the overwhelming majority of cells were postmitotic neurons, but some were astrocytes. We then quantified isoflurane-induced neuronal apoptosis in visual cortex, an area of substantial injury. In unanesthetized control animals, 0.08% ± 0.001% of NeuN-positive layer II/III cortical neurons were immunoreactive for caspase 3. By contrast, the rate of apoptotic NeuN-positive neurons increased at least 11-fold (lower end of the 95% confidence interval [CI]) to 2.0% ± 0.004% of neurons immediately after isoflurane exposure (P = 0.0017 isoflurane versus control). In isoflurane-treated animals, 2.9% ± 0.02% of all caspase 3-positive neurons in superficial cortex also coexpressed GAD67, indicating that inhibitory neurons may also be affected. Analysis of GABAergic neurons, however, proved unexpectedly complex. In addition to inducing apoptosis among some GAD67-immunoreactive neurons, anesthesia also coincided with a dramatic decrease in both GAD67 (0.98 vs 1.84 ng/mg protein, P < 0.00001, anesthesia versus control) and GAD65 (2.25 ± 0.74 vs 23.03 ± 8.47 ng/mg protein, P = 0.0008, anesthesia versus control) protein levels. CONCLUSIONS: Prolonged exposure to isoflurane increased neuronal apoptotic cell death in 7-day-old mice, eliminating approximately 2% of cortical neurons, of which some were identified as GABAergic interneurons. Moreover, isoflurane exposure interfered with the inhibitory nervous system by downregulating the central enzymes GAD65 and GAD67. Conversely, at this age, only a minority of degenerating cells were identified as astrocytes. The clinical relevance of these findings in animals remains to be determined.

Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice.

BACKGROUND: Volatile anesthetics facilitate surgical procedures and imaging studies in millions of children every year. Neuronal cell death after prolonged exposure to isoflurane in developing animals has raised serious concerns regarding its safe use in children. Although sevoflurane and desflurane are becoming more popular for pediatric anesthesia, their cytotoxic effects have not been compared with those of isoflurane. Accordingly, using newborn mice, the current study established the respective potencies of desflurane, isoflurane, and sevoflurane and then compared equipotent doses of these anesthetics regarding their effects on cortical neuroapoptosis. METHODS: Minimum alveolar concentrations were determined in littermates (aged 7-8 days, n = 42) using tail-clamp stimulation in a bracketing study design. By using equipotent doses of approximately 0.6 minimum alveolar concentration, another group of littermates was randomly assigned to receive desflurane, isoflurane, or sevoflurane or to fast in room air for 6 h. After exposure, animals (n = 47) were euthanized, neocortical apoptotic neuronal cell death was quantified, and caspase 3 activity was compared between the four groups. RESULTS: The minimum alveolar concentration was determined to be 12.2% for desflurane, 2.7% for isoflurane, and 5.4% for sevoflurane. After a 6-h exposure to approximately 0.6 minimum alveolar concentration of desflurane, isoflurane, or sevoflurane, neuronal cell death and apoptotic activity were significantly increased, irrespective of the specific anesthetic used. CONCLUSIONS: In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.