Clinical characteristics of cognitive deficits in major depressive disorder: a 6-month prospective study

Background: Previous studies have shown that major depressive disorder (MDD) is associated with a variety of cognitive deficits, which can persist even in remitted states. Nevertheless, the relationship between the cognitive and affective symptoms in depression remains obscure. The aim of the present study was to explore the clinical characteristics and correlates of the cognitive deficits in patients with MDD. Methods: Clinical and neuropsychological assessments were conducted at baseline and 6-month follow-ups. The severity of the disease and the effect of treatment were assessed with the Hamilton Depression Scale-17. Neuropsychological tests, including the digital symbol substitution test and digit span test, were administered to 67 depressed patients and 56 healthy participants. Results: MDD patients showed impairments in memory, attention, and executive function at baseline. After the 6-month treatment phase, patients in remission showed significant alleviation of these cognitive deficits, although impairments in attention and executive function were still present when compared to controls. Discussion: Significant cognitive deficits are present in MDD. The speed of remission of cognitive functions seems to be slower than and inconsistent with emotional symptoms, which provides new support for the argument that cognitive deficits are independent factors from the emotional symptoms in MDD

Reconstitution of Kidney Side Population Cells after Ischemia-Reperfusion Injury by Self-Proliferation and Bone Marrow-Derived Cell Homing

The aim of this study was to examine the contribution of side population (SP) cells from kidney and bone marrow for reconstitution of kidney SP pools after ischemia-reperfusion injury (IRI). The SP and non-SP cells in kidneys following IRI were isolated and serially assessed by fluorescence-activated cell sorting. The apoptosis, proliferation, phenotype, and paracrine actions of SP cells were evaluated in vitro and in vivo. Results indicated that the SP cells from ischemic kidney were acutely depleted within one day following renal IRI and were progressively restored to baseline within 7 days after IRI, through both proliferation of remaining kidney SP cells and homing of bone marrow-derived cells to ischemic kidney. Either hypoxia or serum deprivation alone increased apoptosis of SP cells, and a combination of both further aggravated it. Furthermore, hypoxia in vivo and in vitro induced the increase in the secretion of vascular endothelial growth factor, insulin-like growth factor 1, hepatocyte growth factor, and stromal cell-derived factor-1α in kidney SP but not non-SP cells. In summary, these results suggest that following renal IRI, kidney SP cells are acutely depleted and then progressively restored to baseline levels by both self-proliferation and extrarenal source, that is, bone marrow-derived cell homing

Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys

Background and Purpose: Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. Experimental Approach: MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2−/− mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. Key Results: Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. Conclusions and Implications: Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy

Xin-Li-Fang efficacy and safety for patients with chronic heart failure: A study protocol for a randomized, double-blind, and placebo-controlled trial

IntroductionXin-Li-Fang (XLF), a representative Chinese patent medicine, was derived from years of clinical experience by academician Chen Keji, and is widely used to treat chronic heart failure (CHF). However, there remains a lack of high-quality evidence to support clinical decision-making. Therefore, we designed a randomized controlled trial (RCT) to evaluate the efficacy and safety of XLF for CHF.Methods and designThis multicenter, double-blinded RCT will be conducted in China. 300 eligible participants will be randomly assigned to either an XLF group or a control group at a 1:1 ratio. Participants in the XLF group will receive XLF granules plus routine care, while those in the control group will receive placebo granules plus routine care. The study period is 26 weeks, including a 2-week run-in period, a 12-week treatment period, and a 12-week follow-up. The primary outcome is the proportion of patients whose serum NT-proBNP decreased by more than 30%. The secondary outcomes include quality of life, the NYHA classification evaluation, 6-min walking test, TCM symptom evaluations, echocardiography parameters, and clinical events (including hospitalization for worsening heart failure, all-cause death, and other major cardiovascular events).DiscussionThe results of the study are expected to provide evidence of high methodological and reporting quality on the efficacy and safety of XLF for CHF.Clinical trial registrationChinese Clinical Trial Registration Center (www.chictr.org.cn). The trial was registered on 13 April 2022 (ChiCTR2200058649)

Topical TWEAK Accelerates Healing of Experimental Burn Wounds in Mice

The interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) participates in inflammatory responses, fibrosis, and tissue remodeling, which are central in the repair processes of wounds. Fn14 is expressed in main skin cells including dermal fibroblasts. This study was designed to explore the therapeutic effect of TWEAK on experimental burn wounds and the relevant mechanism underlying such function. Third-degree burns were introduced in two BALB/c mouse strains. Recombinant TWEAK was administrated topically, followed by the evaluation of wound areas and histologic changes. Accordingly, the downstream cytokines, inflammatory cell infiltration, and extracellular matrix synthesis were examined in lesional tissue. Moreover, the differentiation markers were analyzed in cultured human dermal fibroblasts upon TWEAK stimulation. The results showed that topical TWEAK accelerated the healing of burn wounds in wild-type mice but not in Fn14-deficient mice. TWEAK strengthened inflammatory cell infiltration, and exaggerated the production of growth factor and extracellular matrix components in wound areas of wild-type mice. Moreover, TWEAK/Fn14 activation elevated the expression of myofibroblastic differentiation markers, including alpha-smooth muscle actin and palladin, in cultured dermal fibroblasts. Therefore, topical TWEAK exhibits therapeutic effect on experimental burn wounds through favoring regional inflammation, cytokine production, and extracellular matrix synthesis. TWEAK/Fn14 activation induces the myofibroblastic differentiation of dermal fibroblasts, partially contributing to the healing of burn wounds

Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance

Cellular therapies with polyclonal regulatory T-cells (Tregs) in transplantation and autoimmune diseases have been carried out in both animal models and clinical trials. However, The use of large numbers of polyclonal Tregs with unknown antigen specificities has led to unwanted effects, such as systemic immunosuppression, which can be avoided via utilization of antigen-specific Tregs. Antigen-specific Tregs are also more potent in suppression than polyclonal ones. Although antigen-specific Tregs can be induced in vitro, these iTregs are usually contaminated with effector T cells during in vitro expansion. Fortunately, Tregs can be efficiently engineered with a predetermined antigen-specificity via transfection of viral vectors encoding specific T cell receptors (TCRs) or chimeric antigen receptors (CARs). Compared to Tregs engineered with TCRs (TCR-Tregs), CAR-modified Tregs (CAR-Tregs) engineered in a non-MHC restricted manner have the advantage of widespread applications, especially in transplantation and autoimmunity. CAR-Tregs also are less dependent on IL-2 than are TCR-Tregs. CAR-Tregs are promising given that they maintain stable phenotypes and functions, preferentially migrate to target sites, and exert more potent and specific immunosuppression than do polyclonal Tregs. However, there are some major hurdles that must be overcome before CAR-Tregs can be used in clinic. It is known that treatments with anti-tumor CAR-T cells cause side effects due to cytokine “storm” and neuronal cytotoxicity. It is unclear whether CAR-Tregs would also induce these adverse reactions. Moreover, antibodies specific for self- or allo-antigens must be characterized to construct antigen-specific CAR-Tregs. Selection of antigens targeted by CARs and development of specific antibodies are difficult in some disease models. Finally, CAR-Treg exhaustion may limit their efficacy in immunosuppression. Recently, innovative CAR-Treg therapies in animal models of transplantation and autoimmune diseases have been reported. In this mini-review, we have summarized recent progress of CAR-Tregs and discussed their potential applications for induction of immunological tolerance

Clinical and imaging markers for the prognosis of acute ischemic stroke

Background and purposeSignificant differences in the outcomes observed in patients with acute ischemic stroke (AIS) have led to research investigations for identifying the predictors. In this retrospective study, we aimed to investigate the relationship of different clinical and imaging factors with the prognosis of AIS.Materials and methodsAll clinical and imaging metrics were compared between the good and poor prognosis groups according to the modified Rankin Scale (mRS) score at 90 days after discharge. Clinical factors included gender, age, NIHSS scores at admission, and other medical history risk factors. Imaging markers included the lesion’s size and location, diffusion, and perfusion metrics of infarction core and peripheral regions, and the state of collateral circulation. Spearman’s correlations were analyzed for age and imaging markers between the different groups. The Chi-square test and Cramer’s V coefficient analysis were performed for gender, collateral circulation status, NIHSS score, and other stroke risk factors.ResultsA total of 89 patients with AIS were divided into the good (mRS score ≤ 2) and poor prognosis groups (mRS score ≥ 3). There were differences in NIHSS score at the admission; relative MK (rMK), relative MD (rMD), relative CBF (rCBF) of the infarction core; relative mean transit time (rMTT), relative time to peak (rTTP), and relative CBF (rCBF) of peripheral regions; and collateral circulation status between the two groups (p < 0.05). Among them, the rMK of infarction lesions had the strongest correlation with the mRS score at 90 days after discharge (r = 0.545, p < 0.001).ConclusionPerfusion and diffusion metrics could reflect the microstructure and blood flow characteristics of the lesion, which were the key factors for the salvage ability and prognosis of the infarction tissue. The characteristics of the infarction core and peripheral regions have different effects on the outcomes. Diffusion of infarction core has strong relations with the prognosis, whereas the time metrics (MTT, TTP) were more important for peripheral regions. MK had a more significant association with prognosis than MD. These factors were the primary markers influencing the prognosis of cerebral infarction patients

Mangiferin Attenuates Murine Lupus Nephritis by Inducing CD4+Foxp3+ Regulatory T Cells via Suppression of mTOR Signaling

Background/Aims: Lupus nephritis (LN) is an autoimmune glomerulonephritis that frequently develops secondary to systemic lupus erythematosus. Patients with LN require extensive treatments with global immunosuppressive agents. However, long-term treatment with conventional immunosuppressants may cause various side effects. Therefore, it’s important to seek alternative drugs for treating LN. Here we aimed to investigate the immunoregulatory effects of mangiferin (MG), an ingredient that was originally extracted from natural herbs, including Mangifera Indica Linn. and Rhizoma Anemarrhenae. Methods: FasL-deficient B6/ gld mice were used as a spontaneous LN model. The serum anti-dsDNA Ab and creatinine levels were analyzed via ELISA. Renal histology and immunopathology were determined using H&E and PAS staining, immunofluorescence (IgG and C3), and IHC staining (CD3 and a-SMA). Cytokine gene expression was measured by RT-PCR assays while effector T cells and Tregs were enumerated by flow analysis. Finally, the proliferation and apoptosis of T cells were measured by CFSE staining and flow analysis while their mTOR signaling was detected through Western blotting. Results: We found that administration of MG ameliorated LN in lupus-prone B6/gld mice by reducing the urinary protein and serum creatinine levels, diminishing T cell infiltration in kidneys and improving renal immunopathology. MG also significantly lowered the percentages of CD44highCD62Llow effector T cells in B6/gld mice. Importantly, treatments with MG augmented CD4+FoxP3+ Treg frequencies in spleens, lymph nodes and kidneys of B6/gld mice. It also induced CD4+FoxP3+ Tregs from CD3+ T cells in vitro and promoted Treg proliferation. Furthermore, it inhibited CD3+ T cell proliferation in vitro and suppressed their phosphorylation of mTOR and its downstream P70S6K. However, MG did not promote T cell apoptosis, implying that it is not cytotoxic. Depletion of CD4+CD25+FoxP3+ Tregs in B6/gld mice abrogated its therapeutic effects on LN. Conclusion: MG exerts a novel therapeutic effect on murine LN via upregulating CD4+FoxP3+ Tregs, downregulating mTOR/p70S6K pathway and improving renal immunopathology. It may be useful for treating LN in clinic