PARK7/DJ-1, a redox-sensitive protein implicated in neurodegeneration, cancer, and inflammation, exhibits increased secretion under stress. We previously demonstrated that, as a leaderless protein, PARK7 relies on an unconventional autophagy pathway for stress-induced secretion. The current study delves deeper into the mechanisms governing PARK7 secretion under oxidative stress triggered by the neurotoxin 6-hydroxydopamine (6-OHDA). Here, we revealed that 6-OHDA-induced autophagic flux is critical for PARK7 secretion. Downregulation of syntaxin 17 (STX17), a SNARE protein crucial for autophagosome-lysosome fusion and cargo degradation, hindered PARK7 secretion. Likewise, impairing lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) diminished PARK7 release, highlighting the importance of functional lysosomes, potentially in the form of secretory autolysosomes, in PARK7 release. We also found that 6-OHDA appeared to promote the unfolding of PARK7, allowing its selective recognition by the chaperone HSPA8 via KFERQ-like motifs, leading to PARK7 translocation to the lysosomal membrane through LAMP2 via chaperone-mediated autophagy (CMA). Additionally, a dedicated SNARE complex comprising Qabc-SNAREs (STX3/4, VTI1B, and STX8) and R-SNARE SEC22B mediates the fusion of PARK7-containing autolysosomes with the plasma membrane, facilitating the extracellular release of PARK7. Hence, this study uncovers a mechanism where 6-OHDA-induced autophagic flux drives the unconventional secretion of PARK7, involving CMA for PARK7 translocation to lysosomes and specialized SNARE complexes for membrane fusion events.

Graphical The highly conserved DJ-1 protein fundamentally acts as a redox sensor conferring antioxidative cytoprotection under oxidative insults. DJ-1 preferentially undergoes oxidation at 106 cysteine residue (C106) under oxidative stress. Although initially identified as an oncogene, emerging evidence suggests the essential roles of DJ-1 in modulating numerous physiological processes involved in cellular growth, development, survival, and death. Compromised DJ-1 expression and function directly or indirectly trigger signaling cascades leading to pathophysiological conditions including neurodegeneration, cancer, stroke, and inflammatory diseases. Besides the intracellular functions, enhanced DJ-1 secretion into the extracellular fluid, including cerebrospinal fluid and blood, is related to Parkinson’s disease (PD) and cancer pathogenesis. Here, we review the current knowledge regarding DJ-1’s roles as a ubiquitous cytoprotective protein controlling numerous signaling pathways, secretion, and therapeutic potentials.

Diagnostic approaches capable of ultrasensitive pathogen detection from low-volume clinical samples, running without any sophisticated instrument and laboratory setup, are easily field-deployable, inexpensive, and rapid, and are considered ideal for monitoring disease progression and surveillance. However, standard pathogen detection methods, including culture and microscopic observation, antibody-based serologic tests, and primarily polymerase chain reaction (PCR)-oriented nucleic acid screening techniques, have shortcomings that limit their widespread use in responding to outbreaks and regular diagnosis, especially in remote resource-limited settings (RLSs). Recently, clustered regularly interspaced short palindromic repeats (CRISPR)-based programmable technology has emerged to challenge the unmet criteria of conventional methods. It consists of CRISPR-associated proteins (Cas) capable of targeting virtually any specific RNA or DNA genome based on the guide RNA (gRNA) sequence. Furthermore, the discovery of programmable trans-cleavage Cas proteins like Cas12a and Cas13 that can collaterally damage reporter-containing single-stranded DNA or RNA upon formation of target Cas-gRNA complex has strengthened this technology with enhanced sensitivity. Current advances, including automated multiplexing, ultrasensitive single nucleotide polymorphism (SNP)-based screening, inexpensive paper-based lateral flow readouts, and ease of use in remote global settings, have attracted the scientific community to introduce this technology in nucleic acid-based precise detection of bacterial and viral pathogens at the point of care (POC). This review highlights CRISPR-Cas-based molecular technologies in diagnosing several tropical diseases, namely malaria, zika, chikungunya, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV-AIDS), tuberculosis (TB), and rabies.

Graphical Schematic representation of lysosomal damage-induced PARK7 secretion. Upon L-leucyl-L-leucine methyl ester (LLOMe)-induced acute lysosomal damage, PARK7 and galectin-3 (LGALS3) are recruited to damaged lysosomes. Following LLOMe washout, lysophagy is activated, during which autophagosomes selectively engulf the damaged lysosomes containing translocated PARK7 and LGALS3. However, instead of fusing with functional lysosomes for degradation, autophagosomes containing SEC22B bypass the degradative route. This process is facilitated by a specific SNARE complex comprising SEC22B, STX3/4 and SNAP23/29, enabling the autophagosomes to fuse with the plasma membrane, producing PARK7 into the extracellular space. Objective: PARK7/DJ-1 is a multifunctional protein and redox sensor essential for cellular survival and oxidative stress defense. PARK7 secretion is linked to pathophysiologies, including neurodegenerative diseases, cancer and inflammation. This study investigates the mechanisms of PARK7 secretion in response to lysosomal membrane permeabilization induced by L-leucyl-L-leucine methyl ester (LLOMe). Methods: HeLa and mouse embryonic fibroblasts cells were treated with LLOMe followed by washout with serum-free Dulbecco’s modified Eagle’s medium. PARK7 secretion was analyzed by assessing the intracellular and extracellular protein levels. Results: Upon LLOMe treatment, PARK7 translocates to damaged lysosomes, colocalizing with galectin-3 (LGALS3), a marker of lysosomal damage. Following LLOMe washout, an increase in lysophagy flux was observed, enhancing the secretion of both PARK7 and LGALS3. The knockdown of TANK-binding kinase 1, a critical lysophagy regulator, suppresses LLOMe-induced PARK7 secretion, confirming a lysophagy-dependent mechanism. Notably, while the inhibition of autophagy initiation blocks PARK7 secretion, the disruption of autophagosome–lysosome fusion does not affect its release. In addition, the SEC22B-mediated SNARE complex, comprising STX3/4 and SNAP23/29, is essential for the fusion of secretory autophagosomes with the plasma membrane during PARK7 secretion. Conclusion: These findings reveal a novel lysophagy-dependent mechanism of PARK7 secretion, where acute lysosomal damage facilitates the recruitment of PARK7 to damaged lysosomes, subsequent autophagosome encapsulation and nondegradative release into the extracellular space through a dedicated SNARE complex. Significance statement: The findings of this study broaden the understanding of unconventional protein secretion under lysosomal stress and highlight the potential therapeutic targets for diseases linked to lysosomal dysfunction, including neurodegeneration and inflammation.

Lack of adequate dietary diversity may contribute to the deterioration of health and nutritional status of newly diagnosed type 2 diabetes mellitus (T2DM) patients. This cross-sectional study was designed to assess the dietary diversity and related health status of 110 newly diagnosed T2DM patients. The diabetes history of the subjects was collected from the hospital’s e-database. IDDS (individual dietary diversity score) was measured based on the FFQ (food frequency questionnaire) according to the FAO guidelines for measuring household and individual dietary diversity. BMI (body mass index), FBG (fasting blood glucose) level, 2h-PG (two-hour plasma glucose) level, serum creatinine level, and any signs of macro and microvascular diseases were recorded. The mean±SD of IDDS was moderate, 5.74±0.85. About half of the newly diagnosed diabetic patients consumed foods with high diversity. All respondents consumed starchy foods and about half of them did not consume any green leafy vegetables. Younger patients had a lower tendency to take high IDDS diets than the older. About half of individuals were overweight or obese. Higher IDDS and lower BMI, hypertension, serum creatinine, FBG, and 2-HPG were found among males than that of the females. Approximately 35% and 20% patients had microvascular and macrovascular complications respectively.The BMI and serum creatinine level of newly diagnosed diabetic patients were negatively affected by the IDDS. Dietary diversity and varied socio-demographic determinants were found to be related to the health status of diabetics.

Street food enterprises are integral to the economies of low‐ and middle‐income countries, providing vital income and employment opportunities due to their low entry barriers and minimal capital investment requirements. Despite their economic significance, concerns have emerged regarding the quality and safety of street‐vended foods, primarily because of knowledge deficits and poor food‐handling practices. This study aimed to assess the food safety knowledge, attitudes, and practices (KAP) of street food vendors while also examining the microbial load present in popular street food items in Jashore. A cross‐sectional analysis involving 129 randomly selected vendors revealed that over 70% possessed adequate basic knowledge of food safety. However, the translation of this knowledge into effective food‐handling practices was found to be limited, significantly influenced by factors such as gender, educational background, and vending experience. The deficiencies in proper food handling practices correlated with elevated microbial hazards in seven common street food items, including the presence of antibiotic‐resistant strains, which pose serious public health risks. These findings underscore the pressing need for comprehensive educational programs and training initiatives that aim to enhance food safety practices among street food vendors, thereby ensuring the provision of safe and high‐quality street foods and safeguarding public health.