Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics However, such efforts have not yet generated clinically viable interventions In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic

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Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles.

Stroke is the leading cause of adult disability and mortality in most developing and developed countries. The current best practices for patients with acute ischemic stroke include intravenous tissue plasminogen activator and endovascular thrombectomy for large-vessel occlusion to improve clinical outcomes. However, only a limited portion of patients receive thrombolytic therapy or endovascular treatment because the therapeutic time window after ischemic stroke is narrow. To address the current shortage of stroke management approaches, it is critical to identify new potential therapeutic targets. The mitochondrion is an often overlooked target for the clinical treatment of stroke. Early studies of mitochondria focused on their bioenergetic role; however, these organelles are now known to be important in a wide range of cellular functions and signaling events. This review aims to summarize the current knowledge on the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation and scavenging, electron transport chain dysfunction, apoptosis, mitochondrial dynamics and biogenesis, and inflammation. A better understanding of the roles of mitochondria in ischemia-related neuronal death and protection may provide a rationale for the development of innovative therapeutic regimens for ischemic stroke and other stroke syndromes.

Diverse roles of mitochondria in ischemic stroke.

Objective Examine the effectiveness of specific modes of exercise training in non-specific chronic low back pain (NSCLBP). Design Network meta-analysis (NMA). Data sources MEDLINE, CINAHL, SPORTDiscus, EMBASE, CENTRAL. Eligibility criteria Exercise training randomised controlled/clinical trials in adults with NSCLBP. Results Among 9543 records, 89 studies (patients=5578) were eligible for qualitative synthesis and 70 (pain), 63 (physical function), 16 (mental health) and 4 (trunk muscle strength) for NMA. The NMA consistency model revealed that the following exercise training modalities had the highest probability (surface under the cumulative ranking (SUCRA)) of being best when compared with true control: Pilates for pain (SUCRA=100%; pooled standardised mean difference (95% CI): −1.86 (–2.54 to –1.19)), resistance (SUCRA=80%; −1.14 (–1.71 to –0.56)) and stabilisation/motor control (SUCRA=80%; −1.13 (–1.53 to –0.74)) for physical function and resistance (SUCRA=80%; −1.26 (–2.10 to –0.41)) and aerobic (SUCRA=80%; −1.18 (–2.20 to –0.15)) for mental health. True control was most likely (SUCRA≤10%) to be the worst treatment for all outcomes, followed by therapist hands-off control for pain (SUCRA=10%; 0.09 (–0.71 to 0.89)) and physical function (SUCRA=20%; −0.31 (–0.94 to 0.32)) and therapist hands-on control for mental health (SUCRA=20%; −0.31 (–1.31 to 0.70)). Stretching and McKenzie exercise effect sizes did not differ to true control for pain or function (p>0.095; SUCRA Summary/conclusion There is low quality evidence that Pilates, stabilisation/motor control, resistance training and aerobic exercise training are the most effective treatments, pending outcome of interest, for adults with NSCLBP. Exercise training may also be more effective than therapist hands-on treatment. Heterogeneity among studies and the fact that there are few studies with low risk of bias are both limitations.

https://bjsm.bmj.com/content/bjsports/54/21/1279.full.pdf

Which specific modes of exercise training are most effective for treating low back pain? Network meta-analysis

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Guidelines for the use and interpretatoin of assays for monitoring autophagy

Autophagy is an evolutionarily ancient mechanism that ensures the lysosomal degradation of old, supernumerary or ectopic cytoplasmic entities. Most eukaryotic cells, including neurons, rely on proficient autophagic responses for the maintenance of homeostasis in response to stress. Accordingly, autophagy mediates neuroprotective effects following some forms of acute brain damage, including methamphetamine intoxication, spinal cord injury and subarachnoid haemorrhage. In some other circumstances, however, the autophagic machinery precipitates a peculiar form of cell death (known as autosis) that contributes to the aetiology of other types of acute brain damage, such as neonatal asphyxia. Here, we dissect the context-specific impact of autophagy on non-infectious acute brain injury, emphasizing the possible therapeutic application of pharmacological activators and inhibitors of this catabolic process for neuroprotection.

Autophagy in acute brain injury

Apoptosis has been widely reported to be involved in the pathogenesis associated with spinal cord injury (SCI). Recently, autophagy has also been implicated in various neuronal damage models. However, the role of autophagy in SCI is still controversial and its interrelationship with apoptosis remains unclear. Here, we used an in vitro SCI model to observe a time-dependent induction of autophagy and apoptosis. Mechanical injury induced autophagy markers such as LC3 lipidation, LC3II/LC3I conversion, and Beclin-1expression. Injured neurons showed decreased cell viability and increased apoptosis. To elucidate the effect of autophagy on apoptosis, the mechanically-injured neurons were treated with the mTOR inhibitor rapamycin and 3-methyl adenine (3-MA), which are known to regulate autophagy positively and negatively, respectively. Rapamycin-treated neurons showed the highest level of cell viability and lowest level of apoptosis among the injured neurons and those treated with 3-MA showed the reciprocal effect. Notably, rapamycin-treated neurons exhibited slightly reduced Bax expression and significantly increasedBcl-2 expression. Furthermore, by plasmid transfection, we showed that Beclin-1-overexpressing neuronal cells responded to mechanical injury with greater LC3II/LC3I conversion and cell viability, lower levels of apoptosis, higher Bcl-2 expression, and unaltered Bax expression as compared to vector control cells. Beclin-1-knockdown neurons showed almost the opposite effects. Taken together, our results suggest that autophagy may serve as a protection against apoptosis in mechanically-injured spinal cord neurons. Targeting mTOR and/or enhancing Beclin-1 expression might be alternative therapeutic strategies for SCI.

Beclin-1-mediated autophagy protects spinal cord neurons against mechanical injury-induced apoptosis

Background/Aims: To explore the effects of rapamycin-induced autophagy on apoptosis in a rat model of acute spinal cord injury (SCI), and to explore the effect of rapamycin on apoptosis in primary spinal cord cell culture. Methods: SCI was induced at T10 in female adult Sprague-Dawley rats. After injury was induced, the rats were injected with rapamycin and/or methylprednisolone and were sacrificed at various days after injury. Apoptosis and autophagy were examined with TUNEL staining and electron microscopy. Hind limb function was assessed by the Gale scale. Results: The expression of the apoptosis-related protein caspase-3 did not significantly increase until 21 days following injury, while increases in LC3II and LC3I began 10 days after injury, but then declined. TUNEL staining and electron microscopy confirmed that following injury autophagy occurred before apoptosis, but by 14 days after the injury, the level of autophagy had decreased significantly while the level of apoptosis showed a continued increase. Following treatment with rapamycin, apoptosis was significantly higher than in the vehicle control group, but significantly lower than in the sham-operated group, showing a protective effect of rapamycin. Gale scale grades in rats treated with rapamycin were significantly higher compared with the vehicle control group, suggesting a functional effect of rapamycin-induced inhibition of apoptosis. Conclusions: The results indicate that rapamycin significantly improved the prognosis of acute SCI in rats by inhibiting cell apoptosis. Rapamycin might be useful as a therapeutic agent for acute SCI.

Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model.

Shadowboxing for Relief of Chronic Low Back Pain

OBJECTIVE
To analyze the efficacy of percutaneous vertebroplasty for osteoporotic vertebral compression fractures with spinal origin abdominal pain as the main symptom.


METHODS
A retrospective analysis was performed on 37 patients with osteoporotic vertebral compression fractures treated from January 2015 to January 2021, all of whom had spin-derived abdominal pain as the main symptom, and were divided into surgery group(21 cases) and conservative group (16 cases) according to different treatment methods. Patients in the surgery group were treated with percutaneous vertebroplasty, including 7 males and 14 females, with an average age of (75.95±6.84) years old and an average course of disease of (5.26±3.79) days. The conservative group received non-surgical treatment, including 5 males and 11 females, with an average age of (75.50±8.07) years old and an average course of disease of (4.28±3.42) days. Two groups of patients with preoperative mainly characterized by abdominal pain, abdominal distension and constipation, have no obvious chest waist back pain symptoms, the thoracolumbar MRI diagnosed as fresh osteoporotic vertebral compression fractures, record its postoperative abdominal pain visual analogue scale (VAS), medical outcomes study short form-36 (SF-36) score, defecation interval after treatment, etc.


RESULTS
Thirty-seven patients were followed up for (14.90±14.11) months in surgery group and( 21.42±17.53) months in conservative group. Compared with before treatment, the VAS of surgery group at each time period after treatment, VAS of conservative group at 1 month after treatment and SF-36 score between two groups at 3 months after treatment were all improved(P<0.05), while VAS of conservative group at 3 days after treatment showed no statistically significant difference(P>0.05). Compared between two groups, there were no significant differences in VAS and SF-36 scores at 1 day before treatment(P>0.05), but VAS at 3 days after treatment in surgery group, life vitality and social function score at 3 months after treatment, and defecation time after treatment in surgery group were better than those in conservative group(P<0.05). There were no significant differences in other indexes(P>0.05). The incision healing of patients in surgery group was good, and no serious complications occurred in both groups.


CONCLUSION
Percutaneous vertebroplasty is an effective method for the treatment of osteoporotic vertebral compression fractures with spinal origin abdominal pain as the main symptom. Compared with conservative treatment, percutaneous vertebroplasty has more advantages in early relief of abdominal pain and constipation, recovery of vitality and social function.

Zhen-Yu Wang

Papers

Beclin-1-mediated autophagy protects spinal cord neurons against mechanical injury-induced apoptosis

Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model.

Shadowboxing for Relief of Chronic Low Back Pain

[Percutaneous vertebroplasty for the treatment of osteoporotic vertebral compression fractures with spinal origin abdominal pain as the main symptom].