Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors.

Recently, some inhibitors of soluble epoxide hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC50 of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC50: 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-α and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors.

Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.

Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience.

Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

Hepatic soluble epoxide hydrolase activity regulates cerebral Aß metabolism and the pathogenesis of Alzheimer's disease in mice.

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-ß (Aß) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aß metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aß is essential for preventing Aß deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.

A thalamic-primary auditory cortex circuit mediates resilience to stress.

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

[Treatment of acetabular fracture involving quadrilateral body by external rectus abdominis incision combined with calcaneal profiled plate internal fixation].

OBJECTIVE: To investigate the therapeutic effect of lateral rectus abdominis incision combined with winged calcaneal plate on pelvic and acetabular fractures involving quadrilateral body. METHODS: From January 2017 to April 2021, 21 cases of pelvic and acetabular fractures involving quadrilateral bodies were retrospectively analyzed, including 12 males and 9 females. The age ranged from 21 to 73 years with an average of (43.23±6.45) years. All patients were treated by lateral incision of rectus abdominis combined with open reduction and internal fixation with aerofoil plate, including 12 cases of pelvis with anterior and posterior column fractures, 7 cases of acetabular fractures with quadrilateral involvement, and 2 cases of acetabular fractures with central dislocation. RESULTS: All 21 patients were followed up for 12 to 36 months with an average of (18.60±6.45) months. All fractures healed. According to Matta's image reduction evaluation after operation, 11 cases of pelvic anterior and posterior column fractures were all anatomic reduction, 1 case was satisfactory reduction, 7 cases of acetabular fractures involving quadrilateral were anatomic reduction, 1 case with central dislocation was anatomic reduction, and 1 case was satisfactory reduction. The modified Merle D'Aubigne Postel hip joint score was 13 to 17 points. CONCLUSION: Lateral incision approach of rectus abdominis combined with wing-shaped steel plate can obtain good radiological and clinical results in the treatment of complex pelvic and acetabular fractures involving quadrilateral bodies, and has advantages in the treatment of complex pelvic fractures and acetabular quadrilateral fractures.

Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission.

Schizophrenia is a polygenetic disease, the heterogeneity of which is likely complicated by epigenetic modifications yet to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for schizophrenia and identified a schizophrenia-associated down-regulated microRNA, miR-501-3p. We showed that the loss of miR-501-3p in germline knockout (KO) male mice resulted in dendritic structure defects, glutamatergic transmission enhancement, and sociability, memory, and sensorimotor gating disruptions, which were attenuated when miR-501 expression was conditionally restored in the nervous system. Combining the results of proteomic analyses with the known genes linked to schizophrenia revealed that metabotropic glutamate receptor 5 (mGluR5) was one of the miR-501-3p targets and was elevated in vivo upon loss of miR-501. Treatment with the mGluR5 negative allosteric modulator 3-2((-methyl-4-thiazolyl) ethynyl) pyridine or the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid ameliorated the deficits observed in Mir501-KO mice. The epigenetic and pathophysiological mechanism that links miR-501-3p to the modulation of glutamatergic transmission provides etiological implications for schizophrenia.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity.

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex-entorhinal cortex-hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

Decreasing hyaluronic acid combined with drug-loaded nanoprobes improve the delivery and efficacy of chemotherapeutic drugs for pancreatic cancer.

Pancreatic cancer is one of the common malignant tumors of the digestive system, and its clinical treatment is still very challenging. Most of the pancreatic cancer chemotherapeutic drugs have poor plasma stability, low cell uptake efficiency, and are prone to developing drug resistance and toxic side effects. Besides, pancreatic cancer often has a dense extracellular matrix, which consists of collagens, hyaluronic acid, and other proteoglycans. Among them, hyaluronic acid is a key component of the dense matrix, which results in vascular compression and insufficient perfusion, and hinders the delivery of chemotherapeutic drugs. In this study, we explore using hyaluronidase in tumor-bearing mice to eliminate the hyaluronic acid barrier, to reduce blood vessel compression and reshape the tumor microenvironment. In addition, we evaluate using doxorubicin-loaded nanoprobes to improve the stability and local tumor-killing effect of the drug. The nanoprobes have the characteristics of near-infrared optical imaging, which are used to monitor the tumor size in real-time during the treatment process, and dynamically observe the tumor inhibitory effect. The results show that elimination of the hyaluronic acid barrier combined with the doxorubicin-loaded nanoprobes can greatly increase drug penetration into tumor tissue and improve the effectiveness of chemotherapy drugs. This study provides a novel strategy for the treatment of pancreatic cancer.

The Ghrelin/Growth Hormone Secretagogue Receptor System Is Involved in the Rapid and Sustained Antidepressant-Like Effect of Paeoniflorin.

Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the Ghsr gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of Ghsr attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.

LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.

Acute EPA-induced learning and memory impairment in mice is prevented by DHA.

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.

[Bridging system for severe comminuted femoral fracture].

OBJECTIVE: To explore the clinical effect of bridging system in the treatment of severe comminuted femoral fracture. METHODS: From March 2016 to October 2018, 50 patients with severe comminuted femoral fracture including 35 males and 15 females, aged 48 to 72(54.6±8.7) years, were admitted. All cases were comminuted fractures of the femoral shaft, 16 with proximal femur fractures and 7 with distal femur fractures. All cases were all unilateral fractures, 23 on the left and 27 on the right. The time from injury to operation was 5 to 60 (26.7±13.3) hours. The cause of injury was traffic accident, 12 cases with high fall, 35 cases fell and 3 cases fell accidentally. The patients were treated with bridge combined internal fixation system, and the operative effect and fracture healing were analyzed. RESULTS: The operation was successful in all patients. There was no change to other fixed operation. The operation time was (75.8±12.3) min, the amount of bleeding was(356.4±64.8) ml, and there was no serious postoperative complications such as infection, internal fixation displacement, re fracture and nonunion. After 6 to 36 months follow-up, the fracture healing was evaluated by Warden's score. With the extension of observation time, Warden's score gradually increased, and the time of bone healing was(5.5±0.9) months. Harris score and HSS score were used to evaluate the function of hip and knee joint respectively. With the extension of time, Harris score and HSS score increased gradually. Six months after operation, Harris score was 83.5±11.2, HSS score was 79.7±10.5. During the follow-up period, there were no serious complications such as internal fixation displacement, re-fracture, nonunion of fracture and deep vein thrombosis of lower extremity. CONCLUSION: The bridge combined internalfixation system has better safety and effectiveness in the treatment of severe comminuted femoral fracture. As long as the requirements of local anatomy and biomechanics are strictly mastered and the operation risks are fully evaluated in combination with imaging, the better fixation effect can be achieved. The operation has less trauma, fewer complications and simple operation, which is believed to have a wider application potential. Due to the limited sample size and follow-up time, no clinical control was set up, the results of the study still need to be further verified by prospective trials.

Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress.

Major depression is a serious global health concern; however, the pathophysiology underlying this condition remains unclear. While numerous studies have focused on brain-specific mechanisms, few have evaluated the role of peripheral organs in depression. Here, we show that the liver activates an intrinsic metabolic pathway that can modulate depressive-like behavior. We find that chronic stress specifically increases the protein levels of monomeric and oligomeric soluble epoxide hydrolase (sEH), a key enzyme in epoxyeicosatrienoic acid (EET) signaling, in the liver. Hepatic deletion of Ephx2 (which encodes sEH) results in antidepressant-like effects, while the hepatic overexpression of sEH induces depressive phenotypes. The activity of sEH in hepatocytes modulates the plasma levels of 14,15-EET, which then interacts with astrocytes in the medial prefrontal cortex to mediate the effects of hepatic Ephx2 deletion. These results suggest that targeting mechanisms underlying the hepatic response to stress would increase our therapeutic options for the treatment of depression.

Axonal iron transport in the brain modulates anxiety-related behaviors.

Iron is essential for a broad range of biochemical processes in the brain, but the mechanisms of iron metabolism in the brain remain elusive. Here we show that iron functionally translocates among brain regions along specific axonal projections. We identified two pathways for iron transport in the brain: a pathway from ventral hippocampus (vHip) to medial prefrontal cortex (mPFC) to substantia nigra; and a pathway from thalamus (Tha) to amygdala (AMG) to mPFC. While vHip-mPFC transport modulates anxiety-related behaviors, impairment of Tha-AMG-mPFC transport did not. Moreover, vHip-mPFC iron transport is necessary for the behavioral effects of diazepam, a well-known anxiolytic drug. By contrast, genetic or pharmacological promotion of vHip-mPFC transport produced anxiolytic-like effects and restored anxiety-like behaviors induced by repeated restraint stress. Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments.

Targeting carbon nanotubes based on IGF-1R for photothermal therapy of orthotopic pancreatic cancer guided by optical imaging.

Pancreatic cancer is one of the most lethal malignancies worldwide. The existing therapeutic regimen in the clinic for advanced inoperable carcinomas are far from satisfactory, thus it is urgent to seek more effective anticancer strategies. In the pursuit of novel, more effective interventions, photothermal therapy (PTT) based on nanomaterials has attracted increased attention. Recent advances in related fields have catalyzed the generation of novel nanoprobes, such as organic dyes, metal nanoparticles. However, organic dyes are poorly stable and easy to quench while metal nanoparticles with potential metal toxicity are difficult to degrade, both of which have low light-to-heat conversion efficiency, broad spectrum of anti-tumor effects, and lack of tumor targeting specificity. Single-walled carbon nanotubes (SWNTs) can remedy the above inadequacies. Herein, we report our water-soluble, bio-stable and low-toxicity SWNTs with excellent photothermal conversion efficiency. Specific modifications can enable visualization of the aggregate characteristics of SWNTs at the macroscopic or microscopic level in tumors. The dye-conjugated SWNTs bound with targeting antibodies that can induce them specifically targeting to pancreatic tumors for purposes of performing dyes imaging-guided cytotoxic PTT. PTT using this method achieves precise and excellent curative effects with minimal adverse effects, thus providing a promising strategy for anticancer therapy.

Vitamin D Status and Patient Outcomes after Knee or Hip Surgery: A Meta-Analysis.

BACKGROUND: This study evaluates the effect of vitamin D status in patient outcomes after hip or knee joint surgery. METHOD: Literature search was carried out in electronic databases, and study selection followed predetermined eligibility criteria. Data were extracted from relevant studies and meta-analyses of standardized mean differences between hypovitaminosis D (vitamin D deficiency or insufficiency) and euvitaminosis D in assessment scores of patient-reported outcomes were performed. RESULTS: A total of 12 studies (2,593 patients; age 69.89 years [95% CI 68.07-71.70]; 35.95% [29.43-42.46] males) were included in the meta-analysis. The prevalence of hypovitaminosis D (vitamin D deficiency or insufficiency) was 33.18% [25.10-41.26], but the combined prevalence of deficiency and insufficiency was 46.99 [34.02-59.96]. Hospital stay was 1.09 days [-0.39 to 2.56] longer in the hypovitaminosis D group compared to the euvitaminosis D group. Preoperatively, Harris Hip Score (HHS) and Knee Society Score were significantly lower (p = 0.001 and p = 0.00001, respectively) in the hypovitaminosis D group than in the euvitaminosis D group. Postoperatively, HHS (p = 0.004) score was significantly lower in the hypovitaminosis D group than in the euvitaminosis D group. CONCLUSION: The prevalence of hypovitaminosis D is high in osteoarthritis patients undergoing knee or hip surgery. Vitamin D deficiency may affect the outcomes of orthopedic joint surgery. However, randomized trial/s will be required to confirm these findings.

An improved Ultra-High Performance Liquid chromatography-tandem mass spectrometry method for simultaneous quantitation of cytochrome P450 metabolites of arachidonic acid in human plasma.

This study aims to develop a straightforward, sensitive UHPLC-MS/MS method to quantify 15 eicosanoids derived from arachidonic acid in human plasma. Tert-Butyl methyl ether was used on the liquid-liquid extraction method and significantly reduced the expense and time. The method showed excellent linearity for all analytes, with regression coefficients higher than 0.99 over a wide range of concentrations from 0.01 ng mL-1 to 100 ng mL-1. The recovery rates were over 65.00%, and the matrix effects ranged from 8.42% to 40.00%. The limits of detection ranged from 6 pg mL-1 to 10 pg mL-1, and all of the limits of quantification were 20 - 33 pg mL-1. For the broad concentration range, the RE% for accuracy and precision were less than ±â€¯15%. Moreover, trans-4-{4-[3-(4-Trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB) pretreatment extended the window of detection for as much as 30 days. Eicosanoid signaling is altered in various neurological diseases, including pain, Alzheimer's disease and major depressive disorder. Therefore, this rapid, robust quantitative profiling of 15 eicosanoids in plasma could provide a distinct eicosanoid fingerprint for precision medicine in these patients.

Advances in the mechanisms of action of cancer-targeting oncolytic viruses.

Cancer virotherapy mediated by oncolytic viruses (OV), has emerged as a novel and effective strategy in cancer therapeutics. Preclinical models have demonstrated anticancer activity against numerous types of cancer. Currently, a number of recombinant viruses are in late phase clinical trials, many of which have demonstrated promising results regarding the safety and reliability of the treatments, particularly when combined with standard antineoplastic therapies. In addition to molecular-targeted therapeutics, genetic engineering of the viruses allows functional complementation to chemotherapy or radiotherapy agents. Co-administration of chemotherapy or radiotherapy is imperative for an effective treatment regime. Additionally, these approaches may be used in combination with current treatments to assist in cancer management. The near future may reveal whether this renewed interest in oncological virotherapy will result in meaningful therapeutic effects in patients. The aim of the present review was to highlight how the knowledge of oncolytic viral specificity and cytotoxicity has advanced in recent years, with a view to discuss OV in clinical application and the future directions of this field.

A negative feedback regulation of MTORC1 activity by the lysosomal Ca2+ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism.

Macroautophagy/autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. The lysosome plays an essential role in autophagy regulation. For example, the activity of MTORC1, a master regulator of autophagy, is regulated by nutrients within the lysosome. Starvation inhibits MTORC1 causing autophagy induction. Given that MTORC1 is critical for protein synthesis and cellular homeostasis, a feedback regulatory mechanism must exist to restore MTORC1 during starvation. However, the molecular mechanism underlying this feedback regulation is unclear. In this study, we report that starvation activates the lysosomal Ca2+ release channel MCOLN1 (mucolipin 1) by relieving MTORC1's inhibition of the channel. Activated MCOLN1 in turn facilitates MTORC1 activity that requires CALM (calmodulin). Moreover, both MCOLN1 and CALM are necessary for MTORC1 reactivation during prolonged starvation. Our data suggest that lysosomal Ca2+ signaling is an essential component of the canonical MTORC1-dependent autophagy pathway and MCOLN1 provides a negative feedback regulation of MTORC1 to prevent excessive loss of MTORC1 function during starvation. The feedback regulation may be important for maintaining cellular homeostasis during starvation, as well as many other stressful or disease conditions.