EphA2-specific microvesicles derived from tumor cells facilitate the targeted delivery of chemotherapeutic drugs for osteosarcoma therapy.

Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines.

Rutaecarpine ameliorates osteoarthritis by inhibiting PI3K/AKT/NF­κB and MAPK signalling transduction through integrin αVß3.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older­aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti­inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)­1ß­stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY­box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of ß­galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL­1ß­induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide­3­kinase (PI3K)/Akt/nuclear factor­κB (NF­κB) and mitogen­activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL­1ß­stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVß3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF­κB and MAPK pathways. Integrin αVß3 may play a pivotal role in these effects.

Injectable photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered exosomes for osteoarthritis therapy.

Osteoarthritis (OA) is a common degenerative joint disease urgently needing effective treatments. Bone marrow mesenchymal stromal cell-derived exosomes (Exo) are considered good drug carriers whereas they have limitations such as fast clearance and low retention. This study aimed to overcome the limitations of Exo in drug delivery using multiple strategies. Novel photocrosslinking spherical gelatin methacryloyl hydrogel (GelMA)-encapsulated cartilage affinity WYRGRL (W) peptide-modified engineered Exo were developed for OA treatment and the performance of the engineered Exo (W-Exo@GelMA) loaded with a small inhibitor LRRK2-IN-1 (W-Exo-L@GelMA) was investigated in vitro and in vivo. The W-Exo-L@GelMA showed an effective targeting effect on chondrocytes and a pronounced action on suppressing catabolism and promoting anabolism in vitro. Moreover, W-Exo-L@GelMA remarkably inhibited OA-related inflammation and immune gene expression, rescuing the IL-1ß-induced transcriptomic responses. With enhanced retention in the joint, W-Exo-L@GelMA demonstrated superior anti-OA activity and cartilage repair ability in the OA murine model. The therapeutic effect was validated in the cultured human OA cartilage. In conclusion, photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered Exo exhibit notable potential in OA therapy. Engineering Exo by a series of strategies enhanced the targeting ability and retention and cartilage-targeting and Exo-mediated drug delivery may offer a novel strategy for OA treatment.Clinical trial registration: Not applciable.

Stevioside protects primary articular chondrocytes against IL-1ß-induced inflammation and catabolism by targeting integrin.

Osteoarthritis (OA) is a common, progressive, and chronic disorder of the joints that is characterized by the inflammation and degradation of articular cartilage and is known to significantly impair quality of daily life. Stevioside (SVS) is a natural diterpenoid glycoside that has anti-inflammatory benefits. Hence, in the current research, it was hypothesized that SVS might exert anti-inflammatory effects on articular chondrocytes and alleviate cartilage degradation in mice with OA. The expression of inflammatory cytokines, like inducible nitric oxide synthase (iNOS), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in chondrocytes after interleukin-1ß (IL-1ß) exposure, was inhibited by the pretreatment of SVS. As well, SVS inhibited the reduction of collagen II and sry-box transcription factor 9 (SOX9) in chondrocytes stimulated by IL-1ß and suppressed the expression of MMP3 and MMP13. Further, after treatment with SVS, cell cytometry, autophagy flux, and related protein expression showed diminished cell apoptosis and reduced autophagy impairment. Moreover, SVS blocked the activation of phosphoinositide-3-kinase/Akt/nuclear factor-kappa beta (PI3K/Akt/NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways stimulated by IL-1ß. This resulted in decreased cellular inflammation. In vivo experiments with intra-articular injections of SVS in mice with the DMM mouse model demonstrated a decrease in cartilage degradation and an improvement in subchondral bone remodeling. After the integrin αVß3-related knockdown using siRNA, a reversed effect was observed on the anti-inflammatory, anabolic promoting, catabolic blocking, and NF-κB and MAPK signaling pathway inhibition of SVS on chondrocytes treated with IL-1ß. The above findings highlighted that SVS blocked IL-1ß, triggered an inflammatory response in mice chondrocytes, and prevented cartilage degradation in vivo through integrin αVß3. This suggested that SVS might serve as a novel therapeutic option for OA.

Thermosensitive hydrogel for cartilage regeneration via synergistic delivery of SDF-1α like polypeptides and kartogenin.

Regeneration of injured articular cartilage is limited by low early-stage recruitment of stem cells and insufficient chondrogenic differentiation. Hydrogels are widely used to repair cartilage because they have excellent mechanical and biological properties. In this study, a dual drug-loaded thermosensitive hydroxypropyl chitin hydrogel (HPCH) system was prepared to release stromal-derived factor-1α-like polypeptides (SDFP) and kartogenin (KGN) for stem-cell recruitment and chondrogenic differentiation. The hydrogel had a network structure that promoted cell growth and nutrient exchange. Moreover, it was temperature sensitive and suitable for filling irregular defects. The system showed good biocompatibility in vitro and promoted stem-cell recruitment and chondrogenic differentiation. Furthermore, it reduced chondrocyte catabolism under inflammatory conditions. Animal experiments demonstrated that the dual-drug hydrogel systems can promote the regeneration of articular cartilage in rats. This study confirmed that an HPCH system loaded with KGN and SDFP could effectively repair articular cartilage defects and represents a viable treatment strategy.

Decreased Peli1 expression attenuates osteoarthritis by protecting chondrocytes and inhibiting M1-polarization of macrophages.

AIMS: Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA. METHODS: After inhibiting Peli1 expression in chondrocytes with small interfering RNA (siRNA), interleukin (IL)-1ß was used to simulate inflammation, and OA-related indicators such as synthesis, decomposition, inflammation, and apoptosis were detected. Toll-like receptor (TLR) and nuclear factor-kappa B (NF-κB) signalling pathway were detected. After inhibiting the expression of Peli1 in macrophages Raw 264.7 with siRNA and intervening with lipopolysaccharide (LPS), the polarization index of macrophages was detected, and the supernatant of macrophage medium was extracted as conditioned medium to act on chondrocytes and detect the apoptosis index. The OA model of mice was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity to reduce the expression of Peli1. The degree of cartilage destruction and synovitis were evaluated by haematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, and immunohistochemistry. RESULTS: In chondrocytes, knockdown of Peli1 produced anti-inflammatory and anti-apoptotic effects by targeting the TLR and NF-κB signalling pathways. We found that in macrophages, knockdown of Peli1 can inhibit M1-type polarization of macrophages. In addition, the corresponding conditioned culture medium of macrophages applied to chondrocytes can also produce an anti-apoptotic effect. During in vivo experiments, the results have also shown that knockdown Peli1 reduces cartilage destruction and synovial inflammation. CONCLUSION: Knockdown of Peli1 has a therapeutic effect on OA, which therefore makes it a potential therapeutic target for OA.Cite this article: Bone Joint Res 2023;12(2):121-132.

Flavokawain A alleviates the progression of mouse osteoarthritis: An in vitro and in vivo study.

Osteoarthritis (OA) is one of the most prevalent chronic degenerative joint diseases affecting adults in their middle or later years. It is characterized by symptoms such as joint pain, difficulty in movement, disability, and even loss of motion. Moreover, the onset and progression of inflammation are directly associated with OA. In this research, we evaluated the impact of Flavokawain A (FKA) on osteoarthritis. In-vitro effects of FKA on murine chondrocytes have been examined using cell counting kit-8 (CCK-8), safranin o staining, western blot, immunofluorescence staining, senescence ß-galactosidase staining, flow cytometry analysis, and mRFP-GFP-LC3 adenovirus infection. An in-vivo model of destabilization of the medial meniscus (DMM) was employed to investigate FKA's effect on OA mouse. An analysis of bioinformatics was performed on FKA and its potential role in OA. It was observed that FKA blocked interleukin (IL)-1ß-induced expression of inflammatory factors, i.e., cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) in chondrocytes. In addition, FKA also downregulated the catabolic enzyme expression, i.e., aggrecanase-2 (ADAMTS5) and matrix metalloproteinases (MMPs), and helped in the upregulation of the anabolic protein expression, i.e., type II collagen (Col2), Aggrecan, and sry-box transcription factor 9 (SOX9). Moreover, FKA ameliorated IL-1ß-triggered autophagy in chondrocytes, and it was observed that the FKA causes anti-inflammatory effects by the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathways inhibition. The results of immunohistochemical analysis and microcomputed tomography from the in vivo OA mouse model confirmed the therapeutic effect of FKA. Finally, we assessed the anti-arthritic impacts of FKA by conducting in vivo and in vitro analyses. We concluded that FKA can be employed as a useful therapeutic agent for OA therapy, but the findings require needs further clinical investigation.

Epidemiological trends of hand osteoarthritis from 1990 to 2019: Estimates from the 2019 Global Burden of Disease study.

Background: Hand osteoarthritis (OA) is a chronic progressive disease characterized by disabling pain in the hand, with a high clinical burden. This study is designed to assess the epidemiological patterns of hand OA from 1990 to 2019 and analyze its secular trends based on sex, age, and socio-demographic index (SDI) at global, regional, and national levels. Methods: Data on the incidence and disability-adjusted life years (DALYs) of hand OA were extracted from the 2019 Global Burden of Disease (GBD), and their respective age-standardized rates (ASRs) were calculated. The estimated annual percentage changes (EAPCs) in ASR were calculated to assess the prevalent trends of the incidence and DALYs of hand OA over the recent three decades. The relationship between ASR and SDI was analyzed by Pearson's correlation analysis. Results: The incidence of hand OA increased from 371.30 million in 1990 to 676.02 million in 2019, increasing by 82.07%, whereas its age-standardized incidence rate (ASIR) decreased, with a downward trend [EAPC = -0.34; 95% confidence interval: -0.39--0.28]. With the changes in age, the incidence of hand OA exhibited a unimodal distribution before 70 years of age, peaking at 50-54 years, while its incidence had an upward trend in the >70 years age groups. Overall, hand OA-related DALYs increased in the recent 30 years. Meanwhile, its annual age-standardized DALY rate decreased, with EAPCs of -0.35 (95% CI, -0.38 --0.32). The DALYs increased with age. In 2019, the ASIR and age-standardized DALY rate were positively associated with the SDI regions. The incidence and DALYs presented predominance in female patients. The burden of hand OA over the recent three decades displayed obvious geographical diversity. Conclusion: The incident cases of hand OA increased globally from 1990 to 2019, while the ASIR and age-standardized DALY rate decreased. However, in many countries and regions, there was a rising trend of ASR related to incidence and DALYs. In addition, the prevalence revealed geographical, sex, and age diversity. Thus, governments and medical institutions should reallocate medical resources based on the epidemiological characteristics of hand OA.

Oncologic and functional outcomes of different reconstruction modalities after resection of chondrosarcoma of the scapula: a medium- to long-term follow-up study.

OBJECTIVES: To evaluate the oncologic and functional results of scapular reconstruction after partial or total scapulectomy for chondrosarcoma. MATERIALS AND METHODS: Twenty-one patients with chondrosarcoma who underwent partial or total scapulectomy between January 2005 and July 2019 were reviewed retrospectively. RESULTS: At a mean follow-up of 62.6 months (range, 13-123 months), four patients developed local recurrence, and three developed distant metastases, one of which developed both recurrence and metastasis. The overall survival rate of patients at 5 years was 84.6%, the disease-free survival rate was 69.3%, and the complication rate was 19% (4/21). The 1993 American Musculoskeletal Tumor Society (MSTS93) scores of patients in the partial scapulectomy group, total scapulectomy + humeral suspension group and prosthetic reconstruction group were 26.50 ± 1.38, 19.00 ± 2.58, and 21.38 ± 2.62, respectively. There was a statistically significant difference between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group ( P = 0.006 and 0.0336, respectively). The range of motion of the shoulder joint for forward flexion was 80.83° ± 11.14°, 51.25° ± 21.36°, and 52.50° ± 11.02°, respectively. The p-values for the comparison between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group were 0.0493 and 0.0174, respectively. And the range of motion of abduction was 75.00° ± 10.49°, 32.50° ± 11.90°, 41.88° ± 11.63°, respectively. Patients in the partial scapulectomy group had significantly better postoperative shoulder abduction function than the total scapulectomy + humeral suspension or prosthetic reconstruction group (P = 0.0035 and 0.0304, respectively). There was no significant difference in MSTS93 scores and flexion and abduction function of the shoulder joint in the upper extremity after total scapulectomy with humeral suspension or prosthetic reconstruction (P > 0.05). CONCLUSIONS: Surgical treatment of chondrosarcoma of the scapula can achieve a satisfactory prognosis and shoulder function. Total scapulectomy followed by prosthetic reconstruction or humeral suspension are both feasible treatments.

Impact of treatment modalities on prognosis of patients with metastatic renal collecting duct carcinoma.

Although patients with renal collecting duct carcinoma (CDC) benefit from surgery, the value of cytoreductive nephrectomy (CNx) for the prognosis of patients with metastatic CDC remains unclear. Hence, in this study, we used data from Surveillance, Epidemiology, and End Results (SEER) registry to investigate the prognostic factors and the impact of CNx on the outcomes in patients with metastatic CDC. Data of 521 patients, diagnosed with CDC between 2000 and 2018, were retrieved from the SEER database. Kaplan-Meier method and log-rank tests were used to compare the survival differences between the CNx group and non-surgical group. Multivariate Cox regression analysis was used to identify the risk factors associated with overall survival (OS) and cancer-specific survival (CSS) for patients with metastatic CDC. Moreover, multivariate Cox regression analysis guided by directed acyclic graphs (DAG) was used to unfold the impact of CNx and chemotherapy on OS and CSS. 86 patients were identified to have metastatic CDC. The median OS and CSS time were 5 and 6 months, respectively. The OS rates at 1-, 2- and 5-years were 24.4%, 15.1% and 2.3%, respectively. Whereas, the CSS rates at 1-, 2- and 5-years were 27.0%, 17.9% and 2.8%, respectively. Old patients and those receiving CNx or chemotherapy exhibited better survival outcomes. The multivariate regression model identified non-surgical treatment as the only independent prognostic factor for both, OS and CSS. However, DAG-guided multivariate Cox regression model showed that both, CNx and chemotherapy, were associated with both, OS and CSS. Patients with metastatic CDC exhibited worse clinical outcomes. However, CNx improved the prognosis of patients with metastatic CDC. Additionally, surgical resection of visible lesions and suitable chemotherapy were identified as alternative treatment strategies.

Epidemiological Trends of Urolithiasis at the Global, Regional, and National Levels: A Population-Based Study.

Background: Urolithiasis is common worldwide and can predispose to urinary tract infections and renal failure. We aimed to explore the global, regional, and national burden of urolithiasis between 1990 and 2019, stratified by sex, age, and sociodemographic index (SDI). Methods: From 1990 to 2019, data on the number of incident cases of urolithiasis, associated deaths, and disability-adjusted life years (DALYs) were extracted from the 2019 Global Burden of Disease (GBD) study. The trends for the incidence rate, mortality, and DALYs were evaluated using estimated annual percentage changes (EAPCs). Results: The incidence of urolithiasis increased by 48.57%, from 77.78 million incident cases in 1990 to 115.55 million in 2019, while its age-standardized incidence rate (ASIR) decreased. The ASIR increased slightly in the low SDI regions (EAPC = 0.33; 95% confidence interval [CI]: 0.24-0.43), while ASIRs in other SDI regions decreased. The incidence of urolithiasis by age presented a unimodal distribution, with the peak observed in patients aged between 50 years and 70 years. Urolithiasis-related mortality and DALYs also increased over time. Yet, the age-standardized death rate (ASDR) decreased by 2.05% (95% CI, -2.25% to -1.85%) per year, and the annual age-standardized DALY rate decreased by 1.77% (95% CI, -1.92% to -1.63%). The mortality and DALYs increased with age. The incidence, mortality, and DALYs were greater in males than those in females. The burden of urolithiasis showed obvious differences in its regional distribution over the past three decades. Conclusion: From 1990 to 2019, ASIR, ASDR, and age-standardized DALY rate of urolithiasis have decreased. Yet, particularly significant differences exist in the geographic, age, and sex distribution. Thus, medical resources should be rationally allocated and adjusted according to the geographic and demographic distribution of urolithiasis.

Physalin A Inhibits MAPK and NF-κB Signal Transduction Through Integrin αVß3 and Exerts Chondroprotective Effect.

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1ß-induced chondrocyte inflammation response. Moreover, PA reduced IL-1ß-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1ß-induced chondrocytes could be reversed when integrin αVß3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVß3. Thus, PA or integrin αVß3 might be a promising agent or molecular target for the treatment of OA.

Clinicopathological Features and Prognostic Outcomes of Papillary Renal Cell Carcinoma.

PURPOSE: Although papillary renal cell carcinoma (pRCC) is the second common renal malignant tumor, the current understanding of pRCC is poor. This study aims to explore the clinicopathological features and prognostic factors of pRCC. METHODS: From August 2007 and August 2017, 87 patients diagnosed with pRCC by postoperative pathology were enrolled. The clinicopathological features between type1 pRCC and type2 pRCC were compared by Chi-square test, Fisher's exact test, or t-test. The Kaplan-Meier method was performed to estimate progression-free survival (PFS). Univariate and multivariate cox regression models were used to verify the prognostic factors. RESULTS: Of the 87 cases, the median tumor diameter was 5.3cm. Twenty-nine patients were diagnosed with type1 pRCC and 58 patients with type2 pRCC. According pathological stage, 59 (67.8%) cases were in pT1 stage, 19 (21.8%) in pT2 stage, and 9 (10.4%) in pT3 stage. WHO/ISUP pathological grade revealed that 56 (64.4%) patients were in grade I, 17 (19.5%) in grade II, 7 (8.05%) in grade III, and 7 (8.05%) in grade IV. The median follow-up time was 57.0months, and the 1-, 3-year PFS was 95.4%, and 80.8%, respectively. For type1 and type2 pRCC, 3-years PFS was 93.0% and 74.9%, respectively. Survival of type1 pRCC was better than that of type2 (P= 0.027). Patients with late pT stage, lymph node metastasis, distant metastasis, high pathological grade, and large size exhibited worse survival. pTNM stage, pathological grade, and tumor types were potentially related to prognosis for PFS. However, an independent prognostic factor affecting PFS was not found in multivariate regression models. For patients with the pT1 stage, nephron-sparing surgery (NSS) and radical nephrectomy (RN) did not affect the PFS, ignoring tumor types (P=0.45). CONCLUSION: Type2 pRCC is more than type1 pRCC and has an advanced TNM stage and a higher pathological grade. For patients with pRCC with the pT1 stage, the outcome of NSS is not inferior to that of RN.

Single-prolonged stress induce different change in the cell organelle of the hippocampal cells: A study of ultrastructure.

MRI studies have revealed structural and functional changes in the hippocampus of post-traumatic stress disorder (PTSD) patients. Previous studies conducted by us in a PTSD animal model found that single prolonged stress (SPS) induced abnormal morphological changes in hippocampal cells. The effects of SPS on cellular organelles of the hippocampal neurons remain unknown; however, these changes have been involved in SPS-induced abnormal hippocampal function. The aim of the present study is to examine ultrastructural changes in cellular organelles, including the lysosomes, mitochondria (Mit), Golgi apparatus, and endoplasmic reticulum (ER), following SPS exposure using transmission electron microscopy, enzyme histochemistry, and enzyme cytochemistry. First, morphological changes of the hippocampal cells and ultrastructural changes in cellular organelles, including lysosomes, ER, and Mit-induced by SPS were observed. Results from histo- and cytochemistry demonstrated that the Mit marker enzyme, cytochrome c oxidase (COX), and the lysosomal enzyme acid phosphatase, (ACP), increased following exposure to SPS. SPS induced COX release from Mit and led to a wider distribution of ACP in round lysosomes, NLY, and the Golgi. In addition, we found that SPS increased the presence of autophagosomes and induced changes in the autophagy-related protein, Beclin. These results indicated the differential effects of SPS on cellular organelles, that is, a positive effect on lysosomes as well as a negative effect on the Mit and ER. Increased lysosomal function may serve as protection against SPS-induced cell damage. Structural changes in the Mit and ER may be involved in SPS-induced disorders of energy metabolism and protein synthesis and export.