Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients' bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins' interactions, offering insights into innovative treatment strategies.

Acute pancreatitis (AP) is an acute inflammation of the pancreas, which is considered a prevalent gastrointestinal emergency characterized by rapid progression and significant mortality. Currently available medications primarily serve as adjunctive therapies, yielding suboptimal therapeutic outcomes. Consequently, there remains a dearth of specific and efficient treatment modalities for AP. In recent years, nanomedicine-based treatment strategies have exhibited significant potential as drug therapy approaches for pancreatitis. The distinctive features of the AP microenvironment encompass aberrant activation of pancreatic enzymes, oxidative stress induced by elevated reactive oxygen species levels, and excessive production of pro-inflammatory cytokines; these factors offer promising targeted sites for early diagnosis and treatment using nanomedicine. This article comprehensively delineates the pathological microenvironmental characteristics associated with AP while highlighting the application of microenvironment-responsive strategies in nanodrug delivery systems for its treatment, thereby providing insights into future prospects.

Defects in the autophagy-lysosomal degradation pathway contribute to neurodegenerative diseases. Cathepsins B (CtsB) and L (CtsL) are major lysosomal cysteine proteases. Mice deficient in both CtsB and CtsL exhibit abnormalities not only in neural tissue but in other organs, such as heart and liver, with most dying at approximately 16 days of age. To investigate the roles of CtsB and CtsL in the nervous system, nervous system-specific CTSB and CTSL double-knockout mice (CtsB/L-NES) were generated. These mice displayed tail elevation, motor dysfunction, and hyperactivity. In adulthood, they developed cerebellar atrophy, with Purkinje cells in the cerebellar cortex showing selective loss of phospholipase C β4-positive and Zebrin II-negative Purkinje cells in a striped pattern. Ubiquitin-positive structures accumulated in the perikarya and axons of Purkinje cells, reflecting impaired autophagy-lysosomal degradation. Activation of astrocytes and microglia was observed in Purkinje cell loss regions. Electron microscopy revealed granular osmiophilic deposit-like structures in perikarya, autophagosome-like accumulations in axons, and a reduction in synaptic vesicles at active regions of swollen axon terminals in Purkinje cells. Additionally, neuronal loss was observed specifically in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus. These findings demonstrate CtsB and CtsL are essential for survival of Purkinje cells in the cerebellum and neurons in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus.

The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However, the mechanistic details of how autophagy influences the immune system and therapy remain inadequately understood. Given this complexity, a deeper understanding of the role of autophagy in the tumor-immune landscape could reveal novel therapeutic avenues. By manipulating autophagy appropriately, it may be possible to overcome immune resistance and enhance the effectiveness of immunotherapeutic strategies. This article summarizes the role of autophagy in tumor immunity, its relationship with immunotherapy, and the potential therapeutic benefits of targeting autophagy to strengthen antitumor immune responses and optimize the outcomes of immunotherapy.

Epilepsy encompasses a spectrum of chronic brain disorders characterized by transient central nervous system dysfunctions induced by recurrent, aberrant, synchronized neuronal discharges. Hippocampal sclerosis (HS) is identified as the predominant pathological alteration in epilepsy, particularly in temporal lobe epilepsy. This study investigates the metabolic profiles of epileptic hippocampal tissues using proteomics and lipidomics techniques. An epilepsy model was established in Sprague-Dawley (SD) rats via intraperitoneal injection of pentylenetetrazole (PTZ), with hippocampal tissue samples subsequently extracted for histopathological examination. Proteomics analysis was conducted using isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), while lipidomics analysis employed ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC Q-TOF/MS). Proteomic analysis identified 144 proteins with significant differential expression in acute epileptic hippocampal tissue and 83 proteins in chronic epileptic hippocampal tissue. Key proteins, including neurofilament heavy (Nefh), vimentin (Vim), gelsolin (Gsn), NAD-dependent protein deacetylase (Sirt2), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (Cnp), myocyte enhancer factor 2D (Mef2d), and Cathepsin D (Ctsd), were pivotal in epileptic hippocampal tissue injury and validated through parallel reaction monitoring (PRM). Concurrently, lipid metabolomics analysis identified 32 metabolites with significant differential expression in acute epileptic hippocampal tissue and 61 metabolites in chronic epileptic hippocampal tissue. Bioinformatics analysis indicated that glycerophospholipid (GP) metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and glycerolipid (GL) metabolism were crucial in epileptic hippocampal tissue injury. Integrated proteomics and lipidomics analysis revealed key protein-lipid interactions in acute and chronic epilepsy and identified critical pathways such as sphingolipid signaling, autophagy, and calcium signaling. These findings provide deeper insights into the pathophysiological mechanisms of epileptic hippocampal tissue damage, potentially unveiling novel therapeutic avenues for clinicians.

Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined.

To investigate the effect of Alox15 expression in cerulein-induced AP in rats.

Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels.

Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15-transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP.

Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.

Cathepsins, a family of lysosomal peptidases, play a crucial role in maintaining cellular homeostasis by regulating protein turnover and degradation as well as many specific regulatory actions that are important for proper cell function and human health. Alterations in the activity and expression of cathepsins have been observed in many diseases such as cancer, inflammation, neurodegenerative disorders, bone remodelling-related conditions and others. These changes are not exclusively harmful, but rather appear to be a compensatory response on the lack of one cathepsin in order to maintain tissue integrity. The upregulation of specific cathepsins in response to the inhibition or dysfunction of other cathepsins suggests a fine-tuned system of proteolytic balance and understanding the compensatory role of cathepsins may improve therapeutic potential of cathepsin's inhibitors. Selectively targeting one cathepsin or modulating their activity could offer new treatment strategies for a number of diseases. This review emphasises the need for comprehensive research into cathepsin biology in the context of disease. The identification of the specific cathepsins involved in compensatory responses, the elucidation of the underlying molecular mechanisms and the development of targeted interventions could lead to innovative therapeutic approaches.

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.

Proteins delivered by endocytosis or autophagy to lysosomes are degraded by exo- and endoproteases. In humans 15 lysosomal cathepsins (CTS) act as important physiological regulators. The cysteine proteases CTSB and CTSL and the aspartic protease CTSD are the most abundant and functional important lysosomal proteinases. Whereas their general functions in proteolysis in the lysosome, their individual substrate, cleavage specificity, and their possible sequential action on substrate proteins have been previously studied, their functional redundancy is still poorly understood. To address a possible common role of highly expressed and functional important CTS proteases, we generated CTSB-, CTSD-, CTSL-, and CTSBDL-triple deficient (KO) human neuroblastoma-derived SH-SY5Y cells and CTSB-, CTSD-, CTSL-, CTSZ and CTSBDLZ-quadruple deficient (KO) HeLa cells. These cells with a combined cathepsin deficiency exhibited enlarged lysosomes and accumulated lipofuscin-like storage material. The lack of the three (SH-SY5Y) or four (HeLa) major CTSs caused an impaired autophagic flux and reduced degradation of endocytosed albumin. Proteome analyses of parental and CTS-depleted cells revealed an enrichment of cleaved peptides, lysosome/autophagy-associated proteins, and potentially endocytosed membrane proteins like the amyloid precursor protein (APP), which can be subject to endocytic degradation. Amino- and carboxyterminal APP fragments accumulated in the multiple CTS-deficient cells, suggesting that multiple CTS-mediated cleavage events regularly process APP. In summary, our analyses support the idea that different lysosomal cathepsins act in concert, have at least partially and functionally redundant substrates, regulate protein degradation in autophagy, and control cellular proteostasis, as exemplified by their involvement in the degradation of APP fragments.

Lysosomes are acidic organelles that mediate the degradation and recycling of cellular waste materials. Damage to lysosomes can cause lysosomal membrane permeabilization (LMP) and trigger different types of cell death, including apoptosis. Newcastle disease virus (NDV) can naturally infect most birds. Additionally, it serves as a promising oncolytic virus known for its effective infection of tumor cells and induction of intensive apoptotic responses. However, the involvement of lysosomes in NDV-induced apoptosis remains poorly understood. Here, we demonstrate that NDV infection profoundly triggers LMP, leading to the translocation of cathepsin B and D and subsequent mitochondria-dependent apoptosis in various tumor and avian cells. Notably, the released cathepsin B and D exacerbate NDV-induced LMP by inducing the generation of reactive oxygen species. Additionally, we uncover that the viral Hemagglutinin neuraminidase (HN) protein induces the deglycosylation and degradation of lysosome-associated membrane protein 1 (LAMP1) and LAMP2 dependent on its sialidase activity, which finally contributes to NDV-induced LMP and cellular apoptosis. Overall, our findings elucidate the role of LMP in NDV-induced cell apoptosis and provide novel insights into the function of HN during NDV-induced LMP, which provide innovative approaches for the development of NDV-based oncolytic agents.

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

In this study, we aimed to combine transcriptomic and network pharmacology to explore the crucial mRNAs and specific regulatory molecules of Buyang Huanwu Decoction (BYHWD) in intracerebral hemorrhage (ICH) treatment.

C57BL/6 mice were randomly divided into three groups: sham, ICH, and BYHWD. BYHWD (43.29 g/kg) was administered once a day for 7 days. An equal volume of double-distilled water was used as a control. Behavioural and histopathological experiments were conducted to confirm the neuroprotective effects of BYHWD. Brain tissues were collected for transcriptomic detection. Bioinformatics analysis were performed to illustrate the target gene functions. Network pharmacology was used to predict potential targets for BYHWD. Next, transcriptomic assays were combined with network pharmacology to identify the potential differentially expressed mRNAs. Immunofluorescence staining, real-time polymerase chain reaction, western blotting, and transmission electron microscopy were performed to elucidate the underlying mechanisms.

BYHWD intervention in ICH reduced neurological deficits. Network pharmacology analysis identified 203 potential therapeutic targets for ICH, whereas transcriptomic assay revealed 109 differentially expressed mRNAs post-ICH. Among these, cathepsin B, ATP binding cassette subfamily B member 1, toll-like receptor 4, chemokine (C-C motif) ligand 12, and baculoviral IAP repeat-containing 5 were identified as potential target mRNAs through the integration of transcriptomics and network pharmacology approaches. Bioinformatics analysis suggested that the beneficial effects of BYHWD in ICH may be associated with apoptosis, animal autophagy signal pathways, and PI3K-Akt and mTOR biological processes. Furthermore, BYHWD intervention decreased Ctsb expression levels and increased autophagy levels in ICH.

Animal experiments in combination with bioinformatics analysis confirmed that BYHWD plays a neuroprotective role in ICH by regulating Ctsb to enhance autophagy.

Significant advances have been made in our understanding of the endolysosomal cycle. Disruption of this cycle leads to cell death. The objective of this study aims to investigate the role of disrupted endolysosomal cycle in brain ischemia-reperfusion injury.

A total of 57 mice were randomly assigned into four experimental groups: (i) wildtype (wt) sham control; (ii) wt middle cerebral artery occlusion (MCAO); (iii) cathepsin B (CTSB) knockout (KO) sham control; and (iv) CTSB KO MCAO. Mice were subjected either to 0 min (sham) or 40 min of MCAO, followed by reperfusion for 1 or 7 days. Physical and behavioral examinations were conducted in the 7-day reperfusion group for 7 consecutive days after MCAO. Confocal microscopy was used to assess the levels, redistributions, and co-localizations of key endolysosomal cycle-related proteins. Histopathology was examined by light microscopy.

Confocal microscopy revealed a significant accumulation of CTSB in post-ischemic penumbral neurons relative to those in the sham group. In addition, N-ethylmaleimide sensitive factor ATPase (NSF) was irreversibly depleted in these neurons. Furthermore, CTSB-immunostained structures were enlarged and diffusely distributed in both the cytoplasm and extracellular space, indicating the release of CTSB from post-ischemic neurons. Compared to wt mice, CTSB KO mice showed a significant decrease in hippocampal injury area, a significant increase in the number of survival neurons in the striatal core area, and a significant improvement in physical and functional performance in post-MCAO mice.

Brain ischemia leads to a cascade of events leading to inactivation of NSF, disruption of the endolysosomal cycle, endolysosomal structural buildup and damage, and the release of CTSB, eventually resulting in brain ischemia reperfusion injury. CTSB KO in mice protected the brain from ischemia-reperfusion injury.

Cathepsin B (CTSB), a lysosomal cysteine protease, plays an important role in human physiology and pathology. CTSB is associated with various human diseases, and its expression level and activity are closely related to disease progression and severity. Physiologically, CTSB is integrated into almost all lysosome-related processes, including protein turnover, degradation, and lysosome-mediated cell death. CTSB can lead to the development of various pathological processes through degradation and remodeling of the extracellular matrix. During tumor development and progression, CTSB has two opposing effects. Its pro-apoptotic properties reduce malignancy, while its proteolytic enzymatic activity promotes invasion and metastasis, thereby inducing malignancy. Here, we discuss the roles of CTSB in tumor and non-tumor disease pathophysiologies. We conclude that targeting the activity or expression of CTSB may be important for treating tumor and non-tumor diseases.

Lysosomes are acidic organelles present in all nucleated mammalian cells [...].

Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airflow limitation, airway inflammation and remodeling. Icariside II (IS), derived from herbal medicine Herba Epimedii, exerts an anti-inflammatory property. However, underlying mechanisms with specifically targeted molecular expression by IS in asthma have not been fully understood, and whether IS could inhibit remodeling and EMT still remains unclear.

The study aimed to clarify therapeutic efficacy of IS for attenuating airway inflammation and remodeling in asthma, and illustrate IS-regulated specific pathway and target proteins through TMT-based quantitative proteomics.

Murine model of chronic asthma was constructed with ovalbumin (OVA) sensitization and then challenge for 8 weeks. Pulmonary function, leukocyte count in bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory and fibrotic cytokines, and markers of epithelial-mesenchymal transition (EMT) were evaluated. TMT-based quantitative proteomics were performed on lung tissues to explore IS-regulated proteins.

IS contributed to alleviative airway hyperresponsiveness (AHR) evidenced by declined R_L and increased Cdyn. After IS treatment, we observed a remarked down-regulation of leukocyte count, inflammatory cytokines in BALF, and peribronchial inflammation infiltration. Goblet cell hyperplasia, mucus secretion and peribronchial collagen deposition were attenuated, with the level of TGF-β and MMP-9 in BALF declined. Furthermore, IS induced a rise of Occludin and E-cadherin and a decline of N-cadherin and α-SMA in lung tissues. These results proved the protective property of IS against airway inflammation, remodeling and EMT. To further investigate underlying mechanisms of IS in asthma treatment, TMT-based quantitative proteomics were performed and 102 overlapped DEPs regulated by IS were identified. KEGG enrichment exhibited these DEPs were enriched in lysosome, phagosome and autophagy, in which LAMP2, CTSD and CTSS were common DEPs. WB, q-PCR and IHC results proofed expressional alteration of these proteins. Besides, IS could decrease Beclin-1 and LC3B expression with increasing p62 expression thus inhibiting autophagy.

The study demonstrated IS could ameliorate AHR, airway inflammation, remodeling and EMT in OVA-induced chronic asthma mice. Our research was the first to reveal that inhibition of LAMP2, CTSD and CTSS expression in autophagy contributed to the therapeutic efficacy of IS to asthma.

Leptin, an adipose tissue-derived hormone, exhibits potent tumor promoting effects through various mechanisms. Cathepsin B, a member of the lysosomal cysteine proteases, has been shown to modulate the growth of cancer cells. In this study, we have investigated the role of cathepsin B signaling in leptin-induced hepatic cancer growth. Leptin treatment caused significant increase in the levels of active cathepsin B through the axis of endoplasmic reticulum stress and autophagy induction without significant effects on pre- and pro-forms of cathepsin B. Interestingly, inhibition of cathepsin B signaling by gene silencing or treatment with a selective pharmacological inhibitor (CA-074) prevented leptin-enhanced viability of hepatic cancer cell and suppressed progression of cell cycle, indicating the critical role of cathepsin B in leptin-induced hepatic cancer growth. We have further observed that maturation of cathepsin B is required for NLRP3 inflammasomes activation, which is implicated in the growth of hepatic cancer cell. The crucial roles of cathepsin B maturation in leptin-induced hepatic cancer growth and NLRP3 inflammasomes activation were confirmed in an in vivo HepG2 tumor xenograft model. Taken together, these results demonstrate that cathepsin B signaling plays a pivotal role in leptin-induced hepatic cancer cell growth by activating NLRP3 inflammasomes.

Both autophagy and glycolysis are essential for pancreatic ductal adenocarcinoma (PDAC) survival due to desmoplasia. We investigated whether targeting a hub gene which participates in both processes could be an efficient strategy for PDAC treatment.

The expression pattern of glycolysis signatures (GS) and autophagy signatures (AS) and their correlation with cystatin B (CSTB) in PDAC were analysed. It was discovered how CSTB affected the growth, glycolysis, and autophagy of PDAC cells. We assessed competitive binding to cathepsin B (CTSB) between CSTB and cystatin C (CSTC) via immunoprecipitation (IP) and immunofluorescence (IF). Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter gene assays were used to unveil the mechanism underlying CSTB upregulation. The expression pattern of CSTB was examined in clinical samples and KrasG12D/+, Trp53R172H/+, Pdx1-Cre (KPC) mice.

GS and AS were enriched and closely associated in PDAC tissues. CSTB increased autophagic flux and provided substrates for glycolysis. CSTB knockdown attenuated the proliferation of PDAC cells and patient-derived xenografts. The liquid chromatography-tandem mass spectrometry assay indicated CSTB interacted with CTSB and contributed to the proteolytic activity of CTSB in lysosomes. IF and IP assays demonstrated that CSTB competed with CSTC to bind to CTSB. Mutation of the key sites of CSTB abolished the interaction between CSTB and CTSB. CSTB was highly expressed in PDAC due to H3K27acetylation and SP1 expression. High expression of CSTB in PDAC was observed in tissue microarray and patients' serum samples.

Our work demonstrated the tumorigenic roles of autophagy and glycolysis in PDAC. CSTB is a key role in orchestrating these processes to ensure energy supply of PDAC cells.

Premature intracellular trypsinogen activation has long been considered a key initiator of acute pancreatitis (AP). Cathepsin B (CTSB) activates trypsinogen, while cathepsin L (CTSL) inactivates trypsin(ogen), and both proteins play a role in the onset of AP.

AP was induced by 7 hourly intraperitoneal injections of cerulein (50 μg/kg) in wild-type and pancreas-specific conditional Ctsb knockout (Ctsb^Δpan), Ctsl knockout (Ctsl^Δpan), and Ctsb;Ctsl double-knockout (Ctsb^Δpan;Ctsl^Δpan) mice. Pancreatic samples were collected and analyzed by histology, immunohistochemistry, real-time PCR, and immunoblots. Trypsin activity was measured in pancreatic homogenates. Peripheral blood was collected, and serum amylase activity was measured.

Double deletion of Ctsb and Cstl did not affect pancreatic development or mouse growth. After 7 times cerulein injections, double Ctsb and Ctsl deficiency in mouse pancreases increased trypsin activity to the same extent as that in Ctsl-deficient mice, while Ctsb deficiency decreased trypsin activity but did not affect the severity of AP. Ctsb^Δpan;Ctsl^Δpan mice had comparable serum amylase activity and histopathological changes and displayed similar levels of proinflammatory cytokines, apoptosis, and autophagy activity compared with wild-type, Ctsb^Δpan, and Ctsl^Δpan mice.

Double deletion of Ctsb and Ctsl in the mouse pancreas altered intrapancreatic trypsin activity but did not affect disease severity and inflammatory response after cerulein-induced AP.

The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a family of neurodegenerative diseases that affect all age groups and ethnicities around the globe. At least a dozen NCL subtypes have been identified that are each linked to a mutation in a distinct ceroid lipofuscinosis neuronal (CLN) gene. Mutations in CLN genes cause the accumulation of autofluorescent lipoprotein aggregates, called ceroid lipofuscin, in neurons and other cell types outside the central nervous system. The mechanisms regulating the accumulation of this material are not entirely known. The CLN genes encode cytosolic, lysosomal, and integral membrane proteins that are associated with a variety of cellular processes, and accumulated evidence suggests they participate in shared or convergent biological pathways. Research across a variety of non-mammalian and mammalian model systems clearly supports an effect of CLN gene mutations on autophagy, suggesting that autophagy plays an essential role in the development and progression of the NCLs. In this review, we summarize research linking the autophagy pathway to the NCLs to guide future work that further elucidates the contribution of altered autophagy to NCL pathology.

Lysosomal proteases play a crucial role in maintaining cell homeostasis. Human cathepsin D manages protein turnover degrading misfolded and aggregated proteins and favors apoptosis in the case of proteostasis disruption. However, when cathepsin D regulation is affected, it can contribute to numerous disorders. The down-regulation of human cathepsin D is associated with neurodegenerative disorders, such as neuronal ceroid lipofuscinosis. On the other hand, its excessive levels outside lysosomes and the cell membrane lead to tumor growth, migration, invasion and angiogenesis. Therefore, targeting cathepsin D could provide significant diagnostic benefits and new avenues of therapy. Herein, we provide a brief overview of cathepsin D structure, regulation, function, and its role in the progression of many diseases and the therapeutic potentialities of natural and synthetic inhibitors and activators of this protease.