Major depressive disorder has become a global public health problem of serious concern. Most of the clinical antidepressants are developed under the classic “monoamine hypothesis (strategy)”. These ...drugs generally have such deficiencies including slow onset and limited efficiency, cognitive impairment and suicidal tendency. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABAA) receptors. There are two main trends in the development of fast-onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance modulation. Based to the research conducted by foreign peers and our lab, we propose a hypothesis of “monoamine (5-HT)- Glu/GABA long neural circuit”, which holds the view that both monoaminergic mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoaminergic mechanisms (Glu/GABA neurons located in prefrontal cortex) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long neural circuit mediating the fast synaptogenesis of the brain regions including prefrontal cortex. Based on this, it is proposed that fast launch and activation of this circuit may be an important mechanism for fast-onset of antidepressant, in which Glu/GABA (excitation/ inhibition, E/I) rebalance should be the critical rate-limiting step for the onset speed. Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT1A/1B (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It is hoped that these ideas will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily ...member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.
c-MYB has been reported to be elevated in few cancers, including in ovarian cancer. It influences resistance to cisplatin but the details are not very well understood. The objective of this study was ...to further evaluate role of c-MYB in ovarian cancer's cisplatin resistance. To elucidate the underlying mechanism of cisplatin resistance in ovarian cancer, we focused on the epigenetic regulation by miRNAs. Two cell lines, ES2 and OVCAR3, were used as the model systems. C-MYB expression was either up-regulated or silenced and the resulting effect on cisplatin resistance evaluated, along with the mechanistic role of miR-21, through transfections with pre/anti-miRNAs. An in vivo cisplatin resistance model was also employed to verify findings. High c-MYB correlated with increased miR-21. High c-MYB also resulted in induction of EMT and increased resistance against cisplatin which was attenuated by anti-miR-200s. c-MYB decreased β-catenin phosphorylation and thus activated wnt signaling. Silencing of c-MYB resulted in reduced miR-21 levels, reduced EMT, reduced cisplatin IC-50s and increased β-catenin phosphorylation. In an in vivo mice model of cisplatin resistance, c-MYB overexpressing ES2 xenografts were more aggressive than their control counterparts. These c-MYB overexpressing ES xenografts were significantly more resistant to cisplatin but could be sensitized to cisplatin by anti-miR-21. Our results provide a novel mechanism of cisplatin resistance by c-MYB which involves an essential role of miR-21.
Cancer remains to be a major challenge for public health providers, and is the second leading cause of death worldwide. Therefore, it is imperative to explore the mechanisms underlying cancer ...initiation and development, and design novel diagnostics and therapeutics. Circular RNAs (circRNAs), which exhibit a covalently closed loop structure, are involved in a variety of diseases, including cancer. The aberrant expression of circRNAs contributes to the initiation and development of various cancers by disrupting the interplay of specific signaling pathways, including the Wnt/β-catenin pathway, which controls a plethora of cellular processes that drive cancer development. The interactions between circRNAs (specifically expressed in different cancer tissues) and Wnt/β-catenin signaling pathway presents potential diagnostic biomarkers and novel therapeutic targets. In this review, we have summarized research discoveries on the functions of Wnt/β-catenin pathway-related circRNAs in the modulation of oncogenesis and progression of different types of cancer. We anticipate that our findings will contribute to the improvement or development of circRNAs-based strategies for cancer treatment.
A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors ...affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the
(also known as
or
) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype,
-deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.
SUMMARY
Floral patterns are unique to rice and contribute significantly to its reproductive success. SL1 encodes a C2H2 transcription factor that plays a critical role in flower development in rice, ...but the molecular mechanism regulated by it remains poorly understood. Here, we describe interactions of the SL1 with floral homeotic genes, SPW1, and DL in specifying floral organ identities and floral meristem fate. First, the sl1 spw1 double mutant exhibited a stamen‐to‐pistil transition similar to that of sl1, spw1, suggesting that SL1 and SPW1 may located in the same pathway regulating stamen development. Expression analysis revealed that SL1 is located upstream of SPW1 to maintain its high level of expression and that SPW1, in turn, activates the B‐class genes OsMADS2 and OsMADS4 to suppress DL expression indirectly. Secondly, sl1 dl displayed a severe loss of floral meristem determinacy and produced amorphous tissues in the third/fourth whorl. Expression analysis revealed that the meristem identity gene OSH1 was ectopically expressed in sl1 dl in the fourth whorl, suggesting that SL1 and DL synergistically terminate the floral meristem fate. Another meristem identity gene, FON1, was significantly decreased in expression in sl1 background mutants, suggesting that SL1 may directly activate its expression to regulate floral meristem fate. Finally, molecular evidence supported the direct genomic binding of SL1 to SPW1 and FON1 and the subsequent activation of their expression. In conclusion, we present a model to illustrate the roles of SL1, SPW1, and DL in floral organ specification and regulation of floral meristem fate in rice.
Significance Statement
The morphology of rice flowers is crucial for successful reproduction and grain yield. However, research on floral organ specification gene regulatory network (FOS‐GRN) in rice and other grass species is not as extensive as in Arabidopsis. In this study, we unveil the crucial role of the C2H2 zinc finger transcription factor SL1 in regulating flower organ development and floral meristem fate in rice. Our experimental evidence indicates that SL1 positively regulates the expression of SPW1, which, in turn, activates B‐class genes OsMADS2 and OsMADS4 to indirectly suppress DL expression, influencing the formation of floral organs. Additionally, we identify a cooperative role of SL1 and DL in terminating floral meristem fate.
Objective
Clinical sepsis-associated biomarkers were utilized in a cecal ligation and puncture (CLP) septic mouse model to provide a reference for investigating pathophysiological mechanisms and ...evaluating novel therapeutic interventions for sepsis.
Methods
Sepsis in mice was induced by CLP, and clinical biomarkers were evaluated (survival rate, blood physiological and biochemical indices, cytokines, hepatorenal function parameters, and blood coagulation).
Results
The mortality rate was >70%. The body temperature, blood pressure, and heart rate decreased within 48 h. Low lactic acid was found at 8 h. The CLP mice showed typical inflammatory symptoms with decreased white blood cells and procalcitonin and increased levels of soluble triggering receptor expressed on myeloid cells-1, interleukin (IL)-6, IL-10, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, MIP-1β, and MIP-2. The platelet count and activated partial thromboplastin time significantly decreased, and the prothrombin time and prothrombin time–international normalized ratio markedly increased. Phenotypes of multiple organ dysfunction were found in the CLP model, including increased liver alanine aminotransferase and aspartate transaminase; significantly reduced total protein, globulin, and serum albumin; increased blood urea nitrogen and creatinine; and decreased blood glucose.
Conclusion
The clinical features of the CLP mouse model were similar to those of human patients with sepsis.
Background and Aims
NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG ...is controlled by sterol regulatory element‐binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway.
Approach and Results
Here, we identify a potent SREBP inhibitor, 25‐hydroxylanosterol (25‐HL). 25‐HL binds to insulin‐induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25‐HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25‐HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down‐regulating the expression of lipogenic genes. Furthermore, 25‐HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet‐treated Ldlr−/− mice, and reduces the formation of cholesterol crystals and associated crown‐like structures of Kupffer cells. Notably, 25‐HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25‐HL shows a good safety and pharmacokinetics profile.
Conclusions
This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25‐HL in human NASH and demonstrates the critical role of SREBP‐controlled lipogenesis in the progression of NASH by pharmacological inhibition.
Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and ...norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects.
The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism.
Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells.
Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.
Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cAMP signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as ...memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D) consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial arm maze, water maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similarly as rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP response element-binding protein (pCREB). Furthermore, microinfusion of lentiviral vectors that contained microRNAs (miRNAs) targeting long-form PDE4D isoforms into bilateral dentate gyri of the mouse hippocampus downregulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D deficiency shortened α2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knock-down in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4D, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, or at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease.
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