Aloperine: Comparison
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Aloperine is an alkaloid found in the seeds and leaves of the medicinal plant Sophora alopecuroides L. It has been used as herbal medicine in China for centuries due to its potent anti-inflammatory, antioxidant, antibacterial, and antiviral properties. Recently, aloperine has been widely investigated for its therapeutic activities. Aloperine is proven to be an effective therapeutic agent against many human pathological conditions, including cancer, viral diseases, and cardiovascular and inflammatory disorders. Aloperine is reported to exert therapeutic effects through triggering various biological processes, including cell cycle arrest, apoptosis, autophagy, suppressing cell migration, and invasion. It has also been found to be associated with the modulation of various signaling pathways in different diseases.

  • apoptosis
  • cell cycle
  • autophagy
  • PI3K/Akt
  • NF-κB
  • Nrf2
  • Ras

1. Introduction

For centuries herbal remedies have been employed in therapeutic practices. In recent times, many medicinal plants have been intensively investigated for better understanding of their mechanisms of action and discovery of novel bioactive compounds. Sophora alopecuroides of the sophora genus has remained one of the most popular medicinal plants in eastern Asian countries. It has been utilized to treat dysentery and inflammation [1]. More than 20 bioactive quinolizidine alkaloids have been isolated from Sophora alopecuroides plant [2]. These alkaloids have been categorized into various distinct structural groups: matrine-type, aloperinetype, and cytisine-type [3]. One of the most frequently isolated quinolizidine alkaloids from the Sophora plant is aloperine. The molecular formula of aloperine is C15H24N2 [4]. The investigation to discover its stereochemical structure shows that an octa-hydro quinoline ring partly covered by a quinolizidine ring constitutes its distinctive tetracyclic ring core. Identifying its stereo-chemical structure has enabled the synthesis of its derivatives for therapeutic purposes [5]. In 1992, the Chinese state food and drug administration (SFDA) approved the administration of sophora isolated alkaloids for treating cancer [6]. Aloperine has been widely investigated in a broad range of diseases. A literature review showed that aloperine could produce inflammation and tumor inhibitory effects [7,8][7][8]. It could also alleviate allergies and viral infections [9]. It is well known that most therapeutic agents produce beneficial effects by targeting signaling mechanisms. Investigations to understand the aloperine mediated remedial effects in different diseases revealed that aloperine could modulate various cellular signaling mechanisms to combat disease conditions.
Apoptosis or programmed cell death is a frequent mechanism of action of many drugs. Caspase-dependent and mitochondrial apoptosis pathways are the main types of apoptosis activated by drugs to eradicate harmful effects of disease [10]. Aloperine is capable of activating both types of apoptosis in multiple diseases. Aloperine mediated apoptosis suppressed the growth of various cancer cells, including osteosarcoma, colon cancer, multiple myeloma, pancreatic cancer, breast cancer, liver cancer, hepatoma, and glioma [11,12,13,14][11][12][13][14]. Interestingly, aloperine exhibited anti-apoptotic activity to improve disease conditions. Aloperine attenuated apoptosis to attain curative effects in ischemia and reperfusion (IR) induced renal injury, H2O2 induced injuries to neuronal cells, nucleus pulposus cells, ARPE-19 cells, and cerebral IR injury mice models (Table 1) [15,16,17,18,19][15][16][17][18][19].
Aloperine could stop cell cycle progress to inhibit the growth of tumor cells. The cell cycle is a series of events vital for cell division and the generation of two daughter cells. It mainly has four phases, including G1, S, G2, and M. Cell cycle is targeted by different chemo-preventive drugs to control cancer [20]. Literature review showed that aloperine arrested the cell cycle at different phases to inhibit the growth of multiple tumors, including prostate cancer, lung cancer, thyroid cancer, hepatocellular carcinoma, and colon cancer [14,21,22,23,24][14][21][22][23][24]. Moreover, aloperine can produce anti-invasion and anti-migration effects in different cancers by targeting the protein components of migration and invasion-promoting signaling mechanisms (Table 1) [25,26][25][26].
Autophagy, a degradative process, is responsible for removing abnormal or unnecessary components of cells. Aloperine could also modulate autophagy to improve pathological conditions like leukemia and thyroid cancer (Table 1) [7,27][7][27].
Cellular signaling mechanisms are a series of chemical processes which govern cell growth and survival. A single molecule or a group of molecules (signals) triggers the activation of these chemical reactions. As needed, signaling molecules (hormones and growth factors) are generated in the body, and these attach to a specific receptor on the cell surface to initiate a corresponding signaling cascade to accomplish required functions [28]. Aberrations in signaling mechanisms due to internal or external factors could develop multiple diseases. Many therapeutic strategies target molecules of potentially dysregulated signaling mechanisms to prevent or control disease progression. A literature review showed that aloperine is also one of the potent modulators of signaling mechanisms. Aloperine has been reported to inhibit the PI3K/Akt/mTOR signaling to attenuate the adverse effects of diseases like acute kidney disease, inflammatory diseases, and different types of cancer (Table 2) [11,14,15,29,30][11][14][15][29][30].
Moreover, aloperine altered the levels of components of NF-κB [18[18][31],31], Nrf2 [19[19][32],32], and Ras [33] signaling pathways to produce remedial effects against several diseases (Table 2). In this entreview, wey, researchers summarize the current knowledge on the modulatory effects of aloperine on critical biological processes and signaling mechanisms. This studentry may provide helpful insight into understanding the management of disease-causing aberrations in signaling mechanisms, and it may aid in the development of new molecular mechanisms targeting treatment options in the future.

2. Regulation of Apoptosis

Apoptosis is one of the significant types of cell death [34], mainly directed by caspases (cysteine proteases). Apoptosis occurs by two main pathways: the extrinsic and intrinsic pathways. Apoptosis is complex, energy-dependent process, and it is crucial in removing dying or unwanted cells in normal conditions. Apoptosis is one of many therapeutic agents’ common mechanisms of action [10,35][10][35]. The extrinsic apoptosis or death receptors pathway works by binding death receptors with specific ligands. This binding enables the recruitment of Fas-associated death domain (FADD), which could bind to Fas, TRAIL-R1/2, or TNFR1. This interaction causes the activation of downstream events, which ultimately leads to the activation of caspase 8. Activated caspase 8 brings about apoptosis either by directly activating caspases cascade (Type I) or indirectly by cytochrome c mediated activation of a caspase cascade (Type II) [36]. The intrinsic apoptotic pathway or mitochondrial apoptotic pathway is activated in response to context-dependent stimuli. It causes the release of cytochrome c to the cytosol. Cytochrome c undergoes ATP-dependent binding with protease activating factor-1 (Apaf-1), which results in apoptosome formation. The apoptosome activates Caspase-9, which activates caspases 3,6,7 to carry out apoptosis [12]. Aloperine proved to be a potent inducer of apoptosis. One study reported that aloperine treatment caused apoptosis in U266 and MM.1S myeloma cells by activating the extrinsic apoptosis pathway. Activation of caspases 8/9/3 through aloperine therapy executed apoptosis. In thise study, aloperine was found to activate the caspase by inhibiting the anti-apoptotic cFLIP [22]. The apoptotic role of aloperine is also investigated in prostate cancer cells, which showed that aloperine induced apoptosis by changing the Bax/Bcl-2 ratio. It causes an increase in Bax (pro-apoptotic) and a decrease in Bcl-2 (anti-apoptotic). The change in the concentration of these apoptosis-related proteins activated caspase 3, which ultimately induced apoptosis in PC3, DU45, and LNCaP prostate cancer cells. These findings indicate that aloperine brought about apoptosis through the extrinsic apoptosis pathway [23]. Aloperine executed apoptosis in hepatocellular carcinoma cells. Aloperine treatment augmented cytochrome c level in the cytoplasm of hepatocellular carcinoma cells. Moreover, it caused the cleavage of caspase-9, caspase-3, and PARP and raised the levels of cleaved-caspase-9, cleaved-caspase-3, and cleaved-PARP (poly ADP ribose polymerase). This series of events lead to the apoptosis of liver cancer cells. The outcomes of this sentudry indicate that aloperine promoted apoptosis in HCC cells through the intrinsic apoptotic pathway [11]. The apoptosis induction effects of aloperine in osteosarcoma, colon cancer, breast cancer, glioma, and leukemia cells were determined. In these studies, the outcomes of western blotting and PCR experiments showed that aloperine treatment caused an increase and decrease in the levels of Bax and Bcl-2, respectively, and it also elevated cleaved caspase 3 level [7,11,14,26,37][7][11][14][26][37]. Similarly, aloperine inhibited Bcl-2 activity in bladder and NSCLC cells and caused apoptosis [24,33][24][33]. Since Bcl-2 protein and cleaved caspase-3 are the main components of the intrinsic apoptotic pathway [38[38][39],39], modulations in their levels showed that aloperine brought about apoptosis in OS cells through the intrinsic apoptotic pathway. Aloperine also triggered apoptosis in human thyroid carcinoma. IHH-4 and KMH-2 cells were found more susceptible to aloperine-induced programmed cell death. Aloperine treatment activated caspase-3 and PARP in a dose- and time-dependent manner. It also increased the levels of cleaved caspase-9 in IHH-4 and KMH-2 cells. Additionally, aloperine-treatment activated caspase-8 in KMH-2 cells. These outcomes indicate that aloperine activated intrinsic and extrinsic apoptosis pathways in human thyroid carcinoma cells [30]. The circNSUN2 RNA could promote cancer progression by binding to various RNA binding proteins. Regulation of the formation of circNSUN2 RNA-Protein complex could prevent cancer progression. Aloperine could inhibit the activity of circNSUN2 and counteract the tumor-promoting effects of circNSUN2. These findings suggest that aloperine treatment attenuated cell proliferation and increased the apoptosis in colorectal cancer cells via regulating the circNSUN2/miR-296-5p/STAT3 pathway [40]. Acute kidney disease resulting from renal ischemia and reperfusion (IR) damage is associated with high morbidity and mortality [41]. Tubular cell death frequently occurs in acute renal injury caused by IR [42]. The IR insult could raise caspase-3 levels and induce apoptosis in tubular cells. Interestingly, Hu et al. reported that aloperine treatment reduced tubular cells apoptosis in IR mice models. Protein expression analysis revealed a 1.3-fold reduction in caspase 3 levels in aloperine treated IR mice models compared to untreated mice models. These findings indicate that the treatment of aloperine could reduce apoptosis in tubular cells in IR mice [15]. This conclusion contradicts research in tumor cells where aloperine mainly promotes apoptosis in cancer cells. This variation in the outcome of aloperine treatment might be due to the differing aloperine doses utilized in cancer therapy. Hydrogen peroxide (H2O2) exposure can trigger apoptosis in N2a/Swe.D9 neuronal cells by activating the mitochondrial apoptotic pathway. Zhao et al. reported that aloperine inhibited the H2O2 mediated apoptosis in N2a/Swe.D9 cells. Hydrogen peroxide treatment promoted the release of cytochrome C from mitochondria to cytosol. Additionally, it decreased the Bcl-2 levels and activated caspase 3, but aloperine treatment reversed this apoptosis triggering effects and prevented N2a/Swe.D9 cells death [43]. Moreover, Ren et al. reported the inhibition of H2O2-mediated apoptosis in nucleus pulposus cells by aloperine. Hydrogen peroxide exposure induced apoptosis by increasing the caspase-9 activity in nucleus pulposus cells, but aloperine treatment inhibited the apoptosis of nucleus pulposus cells by attenuating the activity of caspase-9 [44]. Similarly, Zhang et al. also reported the anti-apoptotic effects of aloperine in H2O2 treated ARPE-19 cells. Hydrogen peroxide facilitated a decrease in Bcl-2 levels, and increased caspase 3 activity was mitigated by aloperine [19]. Furthermore, Li et al. evaluated the effects of aloperine in middle cerebral artery occlusion (MCAO)/reperfusion injury rat models. Brain sections of Rats models with cerebral IR injury showed a significant population of apoptotic cells and decreased Bcl-2 protein levels. Interestingly, aloperine treatment inhibited the apoptosis effects in rat models under investigation [16]. This finding shows that aloperine could regulate apoptotic pathways in a context and disease-dependent manner (Figure 1).

3. Modulatory Effects on the Cell Cycle

During the cell growth and division, it undergoes a series of events known as the “cell cycle”. G1, S, G2, and M are the four main cell cycle phases. In the G1 phase, the cellular machinery makes preparation to divide. In cell division, the cell enters the S phase, during which it duplicates all of its genetic material. Hence, the suffix “S” stands for DNA synthesis. During the G2 stage, the arrangement and packaging of already duplicated genetic material are completed. The cell cycle moves to the next phase of the cell cycle. M phase is the next step in which cells physically divide into two daughter cells, and the copies of genetic material are distributed to newly formed daughter cells. At the end of the M phase, the cell cycle completes [45]. Specific serine/threonine-protein kinase regulates each cell cycle phase, known as cyclin-dependent protein kinases (CDKs). Cell cycle phase-specific CDKs make complexes with cyclin regulatory subunits and facilitate the cell cycle progression from one phase to the next [46]. Many drugs achieve their therapeutic effects by targeting the cell cycle. Blocking the cell cycle at different phases results in cell growth inhibition. A review of the literature exhibited that aloperine can effectively block the transition of the cell cycle at different stages. Cell cycle analysis of aloperine treated prostate cancer (PC) cells showed a high proportion of cells at the G1 phase. Further, western blotting analysis revealed increased p53 and p21 proteins, which confirmed that aloperine caused G1 phase cell cycle arrest in PC cells [22]. Previously, ouresearchers' research group conducted a study in NSCLC cells. WeResearchers also found that aloperine could cause G1 phase cell cycle arrest in NSCLC cells. OurResearchers' study showed that aloperine treatment upregulated the p53 and p21 proteins and downregulated the levels of Cyclin E, CDK2, pRb, and E2F1 proteins. By modifying the levels of G1 phase controlling proteins, aloperine achieved G1 phase cell cycle arrest in NSCLC cells [24]. Liu et al. reported that aloperine stopped the G2/M phase transition of the hepatocellular carcinoma cell cycle. Flow cytometry analysis of aloperine treated cells showed a high number of cells at the G2/M phase. Expression analysis exhibited low cdc25C, cdc2, and cyclin B1 proteins in aloperine treated Hep3B and Huh7 cells [23]. Moreover, G2/M phase arrest has also been observed in aloperine treated human colon cancer HCT116 cells. Cell cycle histograms showed elevated peaks at the G2/M phase of the cells cycle. The expression pattern of G2/M phase associated proteins p53, p21, cyclin D1, and B1 confirmed G2/M phase cells cycle arrest in HCT116 cells [14]. Furthermore, a study reported that aloperine executed G2/M phase cell cycle arrest in SNU-182 cancer cells. Propidium Iodide (PI) staining showed a high population of cells at the G2/M phase of the cell cycle. Interestingly, this study reported that overexpression of GRO1 oncogene reversed the cell cycle arresting effects of aloperine in SU-182 liver cancer cells. This finding indicates that aloperine may cause cell cycle arrest in SU-182 cells via downregulating GRO1 oncogene [21]. However, further investigations are needed to affirm this inference. On the contrary, aloperine treatment could not cause cell cycle arrest in IHH-4, 8505c, and KMH-2 thyroid cancer cells. There were no apparent changes in cell cycle histogram patterns [30]. This finding is inconsistent with the findings of studies conducted in other cell types, and this inconsistency might be due to differences in the genetic makeup of different cell types (Figure 1).

4. Modulation of Autophagy

Autophagy is an evolutionarily conserved catabolic process that operates to degrade/remove undesirable cellular components, such as truncated or long-lasting proteins and unnecessary organelles [47,48][47][48]. Macro-autophagy, micro-autophagy, and chaperone-mediated autophagy are the three kinds of autophagy that have been described so far. Among all types, macro-autophagy is perhaps the most well investigated. The first step in autophagy is the formation of phagophores, which encloses truncated proteins/defective organelles. Phagophores undergo elongation and form a double membranous vesicle known as an autophagosome. These double membranous vesicles move towards and fuse with lysosomes to form autolysosomes. Finally, by the action of lysosomal enzymes, unwanted material is degraded, and recycled products are used to form new structures or used as energy sources [49]. Autophagy is a vital degradation process that maintains cellular homeostasis [50,51][50][51]. Many drugs, synthetic or natural, target autophagy to exert their therapeutic effects. Lin et al. conducted a study in HL-60 leukemia cells and evaluated the effects of aloperine treatment on autophagy. They showed that aloperine treatment for 18 h triggered the development of autophagic vacuoles. Acridine orange staining showed that the formation of autophagic vacuoles improved with the increase in the aloperine dosage. These findings demonstrated that aloperine could promote autophagy in HL-60 cells [7]. Moreover, aloperine exerted modulatory effects on autophagy were evaluated in thyroid cancer cells. Three types of thyroid cancer cells, KMH-2, IHH-4, and 8505c cells, were employed in this study. Interestingly, it was observed that aloperine treatment enhanced autophagosome formation and autophagic activity in KMH-2 and IHH-4 cells, but it did not produce such outcomes in 8505c cells. The expression analysis of LC3-II and p62 markers showed that aloperine blocked autophagic flux in 8505c cells [27]. The underlying molecular mechanism for aloperine to exhibit this dual role needs further elucidation (Figure 2).
Table 1.
Aloperine mediated modulations in biological mechanisms.
Apoptosis
Pathological Conditions Cell Lines Animal Model Dosage Regulatory Effects of Aloperine Ref.
In Vitro (µM) In Vivo
Multiple Myeloma U266 and MM.1S SCID NOD mice 50/100/250/500 20 mg/kg Induced Caspase-dependent apoptosis [12]
Prostate cancer PC3, DU145 and LNCaP BALB/C mice 100/200 30 mg/kg Induced Caspase dependent apoptosis [22]
Hepatocellular carcinoma Hep3B and Huh7 Zebrafish embryo 200/350/500 100 µM, 150 µM Induced Mitochondria-dependent apoptosis [23]
Osteosarcoma MG-63 and U2OS ---------
Migration and Invasion
Breast cancer
MCF-7 and MDA-MB-231
---------
100/200/400
---------
Inhibition of Migration and Invasion
[
26
]
Liver cancer
SNU-182
---------
5
--------- Inhibition of Migration and Invasion [21]
Figure 1.
Modulatory effects of aloperine on apoptosis and cell cycle.
Figure 2. Modulatory effects of aloperine on autophagy and tumor cell invasion & migration.
Modulatory effects of aloperine on autophagy and tumor cell invasion & migration.
Table 2. Aloperine mediated modulations in signaling mechanisms.
PI3K/Akt and Other Downstream Molecules Signaling
Pathological ConditionsCell LinesAnimal ModelDosageRegulatory Effects of AloperineRef.
In Vitro (µM)In Vivo
Prostate cancerPC3, DU145 and LNCaPBALB/C mice100/20030 mg/kgInhibition of Akt/ERK signaling[22]
Hepatocellular carcinomaHep3B and Huh7Zebrafish embryo200/350/500100 µM, 150 µMInhibition of PI3K/Akt signaling[23]
OsteosarcomaMG-63 and U2OS---------100/200---------Inhibition of PI3K/Akt signaling[11]100/200 --------- Induced Mitochondria-dependent apoptosis [11]
[14] Colon cancer
Colon cancer HCT116
I/R-Induced Renal Injury--------- 250/500 -------- Induced Mitochondria-dependent apoptosis [RAW264.7 and HK214]
HCT116C57BL/6 mice50050 mg/kgInhibition of PI3K/Akt/mTOR signaling[15] Breast cancer MCF-7 and MDA-MB-231 --------- 100/200/400
Thyroid CancerKMH-2 and IHH-4--------- Induced Mitochondria-dependent apoptosis [---------26]
---------250/500---------Inhibition of PI3K/Akt signaling200---------Inhibition of Akt/mTOR signaling[27] I/R-Induced Renal Injury RAW264.7 and HK2 C57BL/6 mice 500 50 mg/kg Inhibition of Apoptosis
Thyroid CancerIHH-4,8505c and KMH-2[--------15]
100/200-------Inhibition of Akt signaling[30] Thyroid Cancer IHH-4,8505c and KMH-2 --------- 100/200 --------- Induced Caspase-dependent apoptosis [30]
DSS-Induced ColitisJurkat CellsC57BL/6 mice250/50040 mg/kgInhibition of PI3K/Akt/mTOR signaling[29] Leukemia HL-60 --------- 50/100 --------- Induced Mitochondria-dependent apoptosis
Microembolisation-Induced cardiac Injury---------Sprague-Dawley rats---------[200 mg/kg7]
Activation of the PI3K/Akt signaling[54] Alzheimer’s disease N2a/Swe.D9 ---------
I/R-Induced Cerebral injury100 --------- Induced Mitochondria-dependent apoptosis ---------Sprague-Dawley rats---------[43]
2/25/50 mg/kgActivation of the PI3K/Akt signaling[16] Non-small cell lung cancer H1944 and NCI-H1869 BALB/C nude mice 250 30 mg/kg Induced Mitochondria-dependent apoptosis [24]
Intervertebral disc degeneration Nucleus Pulposus cells Sprague-Dawley rats 100 --------- Inhibition of Apoptosis [44]
Bladder Cancer EJ cells --------- 25/50/100 --------- Induced Mitochondria-dependent apoptosis [59][52]
OGD/RP neuronal injury Hippocampal Neuronal cells Sprague-Dawley rats 100/200/400 --------- Inhibition of Apoptosis [60][53]
Colorectal Cancer SW480 and HT29 --------- 200/400/800/1000 ---------
NF-κB Signaling
Allergic airway inflammation---------BALB/c mice---------100/200 mg/kgInhibition of NF-κB signaling[18]Induced Mitochondria-dependent apoptosis [
Neuropathic pain---------ICR mice---------80 mg/kgInhibition of NF-κB signaling[40]
31] Early brain injury ---------
Intervertebral disc degenerationNucleus Pulposus cellsSprague-Dawley rats100-------Inhibition of NF-κB signaling[44]
Pulmonary arterial hypertension---------Sprague-Dawley rats---------25/50/100 mg/kgInhibition of NF-κB signaling[55] Sprague-Dawley rats --------- 75/150 mg/kg Inhibition of Apoptosis [17]
OsteoporosisRAW264.7C57BL/6 mice2030 mg/KgInhibition of NF-κB signaling[56]I/R-Induced Cerebral injury ---------
LPS-induced macrophage activationSprague-Dawley rats --------- 2/25/50 mg/kg Inhibition of Apoptosis [16]
RAW264.7---------50/100---------Inhibition of NF-κB signaling[57] Retinal pigment epithelial cells injury ARPE-19 --------- 6.25/12.5/25 --------- Inhibition of Apoptosis [19]
Nrf2/HO-1 SignalingDSS-Induced Colitis Jurkat Cells C57BL/6 mice
Allergic airway inflammation---------BALB/c mice250/500 40 mg/kg Inhibition of Apoptosis [29]
---------100/200 mg/kgActivation of Nrf2/HO-1 Signaling[18] Microembolisation-Induced cardiac Injury --------- Sprague-Dawley rats --------- 200 mg/kg Inhibition of Apoptosis [61][54]
Retinal pigment epithelial cells injuryARPE-19---------6.25/12.5/25---------Activation of Nrf2/HO-1 Signaling[19] Cell Cycle
High Glucose induced Schwann cells injuryRSC96 cells---------1/10/50---------Activation of Nrf2/HO-1 Signaling[21] Prostate cancer PC3, DU145 and LNCaP BALB/C mice 100/200 30 mg/kg G1 phase arrest [22]
CCl4 induced mouse hepatic injury---------C57BL/6 mice---------50/100 mg/kgActivation of Nrf2/HO-1 Signaling[58] Hepatocellular carcinoma Hep3B and Huh7 Zebrafish embryo 200/350/500 100 µM, 150 µM G2 phase arrest [23]
Ras Signaling Colon cancer HCT116 --------- 250/500 --------- G2 phase arrest [14]
Thyroid Cancer IHH-4,8505c and KMH-2 --------- 100/200 --------- No impact on Cell Cycle [30]
Non-small cell lung cancer H1944 and NCI-H1869 BALB/C nude mice 250 30 mg/kg G1 phase arrest [24]
Liver cancer SNU-182 --------- 5 --------- G2 phase arrest [21]
Autophagy
Breast cancerMCF-7 and MDA-MB-231---------100/200/400---------Inhibition of Ras signaling[26]
Bladder CancerEJ cells----------25/50/100---------Inhibition of Ras signaling[52] Thyroid Cancer KMH-2 and

IHH-4		 --------- 200 --------- Autophagy induction [27]
Thyroid Cancer 8505c --------- 200 --------- Autophagy inhibition [27]
Leukaemia HL-60 --------- 50/100 --------- Autophagy induction [7]

 

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