Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions.

Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.

Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D-Cys6-LHRH vedotin, against ovarian cancer cell lines.

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer.

An overview on the key advantages and limitations of batch and dynamic modes of biosorption of metal ions.

Water purification using adsorption is a crucial process for maintaining human life and preserving the environment. Batch and dynamic adsorption modes are two types of water purification processes that are commonly used in various countries due to their simplicity and feasibility on an industrial scale. However, it is important to understand the advantages and limitations of these two adsorption modes in industrial applications. Also, the possibility of using batch mode in industrial scale was scrutinized, along with the necessity of using dynamic mode in such applications. In addition, the reasons for the necessity of performing batch adsorption studies before starting the treatment on an industrial scale were mentioned and discussed. In fact, this review article attempts to throw light on these subjects by comparing the biosorption efficiency of some metals on utilized biosorbents, using both batch and fixed-bed (column) adsorption modes. The comparison is based on the effectiveness of the two processes and the mechanisms involved in the treatment. Parameters such as biosorption capacity, percentage removal, and isotherm models for both batch and column (fixed bed) studies are compared. The article also explains thermodynamic and kinetic models for batch adsorption and discusses breakthrough evaluations in adsorptive column systems. The review highlights the benefits of using convenient batch-wise biosorption in lab-scale studies and the key advantages of column biosorption in industrial applications.

Influence of Cigarette Aerosol in Alpha-Synuclein Oligomerization and Cell Viability in SH-SY5Y: Implications for Parkinson's Disease.

Although cigarette aerosol exposure is associated with various adverse health issues, its impact on Parkinson's disease (PD) remains elusive. Here, we investigated the effect of cigarette aerosol extract (CAE) on SH-SY5Y cells for the first time, both with and without α-synuclein (α-Syn) overexpression. We found that α-Syn aggravates CAE-induced cell death, oxidative stress, and mitochondrial dysfunction. Fluorescence cross-correlation spectroscopy (FCCS) revealed a dual distribution of α-Syn within the cells, with homogeneous regions indicative of monomeric α-Syn and punctated regions, suggesting the formation of oligomers. Moreover, we observed colocalization of α-Syn oligomers with lysosomes along with a reduction in autophagy activity. These findings suggest that α-Syn overexpression exacerbates CAE-induced intracellular cytotoxicity, mitochondrial dysfunction, and autophagy dysregulation, leading to elevated cell mortality. Our findings provide new insights into the pathogenic mechanisms linking exposure to cigarette aerosols with neurodegenerative diseases.

Exposure to phenols reduces melanogenesis in B16F10 cells and zebrafish.

Phenols, ubiquitous environmental contaminants found in water, soil, and air, pose risks to organisms even at minimal concentrations, and many are classified as hazardous pollutants. Skin pigmentation is a natural shield against ultraviolet-induced DNA damage and oxidative stress, pivotal in reducing skin cancer incidences. Studies on B16F10 melanoma cells and zebrafish offer valuable insights into potential therapeutic avenues for melanoma in the context of phenol exposure. Upon phenol treatment, there was a marked decrease in melanin content and melanogenesis-associated protein expression, such as tyrosinase and the microphthalmia-associated transcription factor (MITF) in these melanoma cells. Additionally, phenols led to diminished p38 phosphorylation, amplified extracellular signal-regulated kinase (ERK) phosphorylation, and curtailed melanin expression in zebrafish. These observations underscore the detrimental impact of phenols on melanogenesis and propose a mechanism of action centered on the ERK/p38 signaling pathway. Consequently, our data spotlight the adverse effects of phenols on melanogenesis."

Obstructive sleep apnea in aboriginal Australians: polysomnographic outcomes and symptom perception post-continuous positive airway pressure implementation.

Study Objectives: Obstructive sleep apnea (OSA) is reported to be highly prevalent among Aboriginal Australians. However, no studies have assessed the implementation and efficacy of continuous positive airway pressure (CPAP) therapy in this population. Hence, we compared the clinical, self-reported perception of sleep quality and polysomnographic (PSG) characteristics among Aboriginal patients with OSA. Methods: Adult Aboriginal Australians who underwent both diagnostic (Type 1 and 2) and in-lab CPAP implementation studies were included. Results: Total of 149 patients were identified (46% female, median age 49 years, body mass index 35 kg/m2). The OSA severity was 6% mild, 26% moderate, and 68% severe on the diagnostic PSG. On application of CPAP, there were significant improvements in; total arousal index (diagnostic 29 to 17/h on CPAP), total apnea-hypopnea index (AHI) (diagnostic 48 to 9/h on CPAP), non-rapid eye movement AHI (diagnostic 47 to 8/h on CPAP), rapid eye movement (REM) AHI (diagnostic 56 to 8/h on CPAP) and oxygen saturation (SpO2) nadir (diagnostic 77% to 85% on CPAP) (p < 0.001 for each). Following a single night of CPAP, 54% of patients reported sleeping "better than normal" compared to 12% following the diagnostic study (p = 0.003). In multivariate regression models, males had a significantly lesser change in REM AHI than females (5.7 events/hour less change (IQR 0.4, 11.1), p = 0.029). Conclusions: There is substantial improvement in several sleep-related domains on the application of CPAP among Aboriginal patients with a good initial acceptance of treatment. Whether the positive impact observed in this study translates to better sleep health outcomes with long-term adherence to CPAP therapy is yet to be assessed.

A Patent Review on SARS Coronavirus Papain-Like Protease (PLpro ) Inhibitors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an unprecedented global health emergency causing more than 6.6 million fatalities by 31 December 2022. So far, only three antiviral drugs have been granted emergency use authorisation or approved by the FDA. The SARS-CoV-2 papain-like protease (PLpro ) is deemed an attractive drug target as it plays an essential role in viral polyprotein processing and pathogenesis although no inhibitors have yet been approved. This patent review discusses coronavirus PLpro inhibitors reported in patents published between 1 January 2003 to 2 March 2023, giving an overview on the inhibitors that have generated commercial interest, especially amongst drug companies.

Water Plays Multifunctional Roles in the Intervening Formation of Secondary Organic Aerosols in Ozonolysis of Limonene: A Valence Photoelectron Spectroscopy and Density Functional Theory Study.

Although water may affect aqueous aerosol chemistry, how it intervenes in the formation of secondary organic aerosols (SOAs) at the molecular level remains elusive. Ozonolysis of limonene is one of the most important sources of indoor SOAs. Here, we report the valence electronic properties of limonene aerosols and SOAs derived from limonene ozonolysis (Lim-SOAs) via aerosol vacuum ultraviolet photoelectron spectroscopy, with a focus on the effects of water on Lim-SOAs. The first vertical ionization energy of limonene aerosols is measured to be 8.79 ± 0.07 eV. While water significantly increases the total photoelectron yield of Lim-SOAs, three photoelectron features attributable to Lim-SOAs each exhibit distinct dependence on the fraction of water in aerosols, implying that different formation pathways and molecular origins are involved in the formation of Lim-SOAs. Combined with density functional theory calculation and mass spectrometry measurements, this study reveals that water, particularly the water dimer, enhances the formation of Lim-SOAs by altering the ozonolysis energetics and pathways by intervening in its Criegee chemistry, acting as both a catalyst and a reactant. The atmospheric implication is discussed.

Frailty and polypharmacy in the community-dwelling elderly with multiple chronic diseases.

BACKGROUND: Both multi-morbidity (MM) and polypharmacy (PP) are common in the elderly and pose a challenge for health and social care systems. However, high-quality patient-centred care requires context-bound understanding of the patterns and use of medications in those with MM. Therefore, the aim of this study was to investigate the prevalence of PP in community-dwelling elderly, and the factors associated with MM, PP, excessive polypharmacy (EPP), and the types of drugs used. METHODS: We analysed data of 164 community-dwelling subjects aged ≥60 years from January to December 2020 at a general hospital in a rural area of Taiwan. MM was defined as >4 diagnoses of chronic health conditions. Non-polypharmacy (NP), PP, and EPP were defined as <5, 5-8, and >8 prescriptions, respectively. Other variables including basic activities of daily living (BADL), severity of frailty, depressive mood, screening for intellectual impairment, and nutritional status were also analysed. RESULTS: Of the 164 participants, 34.8% had >4 diagnoses, 66.5% had PP, and 26.2% had EPP. The patients with >4 diagnoses had worse performance in BADL, higher levels of frailty, and more prescriptions than those with fewer diagnoses. The EPP group had worse performance in BADL, a higher level of frailty, more comorbidities, and higher prevalences of diabetes mellitus and chronic kidney disease compared to the NP and PP groups. After adjusting for covariates, we further found a higher number of medications associated with having more comorbidities, and a higher level of frailty associated with having a greater number of medications. CONCLUSION: We found relationships between frailty and PP, and between PP and MM, but frailty did not associate with MM. Since frailty, PP, and MM may be viewed as an inevitable trinity of ageing, reducing PP could be a method to both prevent frailty and disentangle this trinity in the elderly.

Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer.

Prostate cancer is the third-most commonly diagnosed cancer and is one of the leading causes of cancer-related deaths in men worldwide. Although an armamentarium of approved drugs exists, treatment options become severely limited when resistance develops against last-line taxane chemotherapeutics. In March 2022, the FDA approved a first-in-class targeted radionuclide therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for treating metastatic castration-resistant prostate cancer. The drug constitutes a prostate-specific membrane antigen-targeting peptidomimetic moiety conjugated to a radionuclide chelator via a linker. This Patent Highlight reveals the structure-activity relationship of key compounds against prostate cancer cells.

Oral Nonpeptidic, Noncovalent Triazine Coronavirus Main Protease Inhibitors for Treating COVID-19.

The current COVID-19 global pandemic caused by SARS-CoV-2 has claimed more than 6 million lives since its emergence in December 2019. The first oral coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA in December 2021, with a twice-daily dosing regimen in combination with ritonavir. In March 2022, Shionogi & Co. announced their single-agent, once-daily oral SARS-CoV-2 main protease inhibitor, ensitrelvir, was granted approval for global phase 3 clinical trials. Unlike nirmatrelvir, ensitrelvir is a nonpeptidic, noncovalent, small molecule. This Patent Highlight describes key structures and their inhibitory activities in Shionogi & Co.'s and Hokkaido University's patent WO 2022/138987 A1.

Novel Coronavirus Main Protease Di- and Tripeptide Inhibitors for Treating COVID-19.

COVID-19 is a highly infectious disease caused by SARS-CoV-2. First reported in December 2019, it rapidly escalated into a global pandemic, resulting in over 6.3 million fatalities by July 4, 2022. The first oral coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA in December 2021. It is a tripeptide incorporated with a C-terminal nitrile designed to bind and form a covalent attachment to the SARS-CoV-2 main protease. Shortly after nirmatrelvir's approval, Enanta Pharmaceuticals' peptidomimetic SARS-CoV-2 main protease inhibitor entered clinical trials in February 2022. This patent highlight reports key structures of di- and tripeptide inhibitors described in Enanta Pharmaceuticals' patent WO 2022/020242 A1.

Novel Halomethylketone Azadipeptides for Treating COVID-19.

COVID-19 is a highly infectious disease caused by the SARS-CoV-2 coronavirus. It rapidly escalated into a global pandemic, causing more than 6 million fatalities by March 2022, a little over 2 years since its emergence in December 2019. The first peptidomimetic coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA on Dec 22, 2021. Less than a month after its patent application, Hoffmann La-Roche scientists filed a patent application describing azadipeptide peptidomimetic inhibitors (WO 2022/043374 A1). This patent highlight reveals the structure-activity relationship of key azadipeptide inhibitors described in the patent.

A Patent Review on FDA-Approved Antibody-Drug Conjugates, Their Linkers and Drug Payloads.

Antibody-drug conjugates (ADCs) have emerged as a promising class of biologics since the first approval of Gemtuzumab ozogamicin in 2000. Compared to small molecule drugs, ADCs are structurally much more complex as they comprise of an antibody conjugated to cytotoxic payloads by specially-designed linkers. Correspondingly, the ADC patent landscape is also much more complex. This review collates and discusses the patents protecting ADCs approved by the FDA up to 31 December 2021, with particular emphasis on their linker and cytotoxin payload technologies.

Aerosol emissions and gravity waves of Taal volcano.

The Taal volcano (14.0 N, 121.0 E) in Philippines erupted in January-February 2020, with a part of aerosols drifted northward and detected by a lidar system at Kaohsiung city (22.37 N, 120.15 E), Taiwan. The aerosol observed on Feb 11 is special for its high-altitude distributions at 4-7 km with discrete structures which can be resolved into a sinusoidal oscillation of ~ 30 min period, suggesting a case of wave event caused by the eruptions. We report in this paper the gravity wave generated by the volcanic eruptions and its effects on aerosol emissions. By studying the temperature and pressure data in the Taal region using radiosonde data, we found atmospheric gravity waves with powers correlated with the optical thickness (AOD) at 550 nm measured by the Moderate Resolution Imaging Spectrometer (MODIS) satellite. This study presents the first observation of modulation of the aerosol emissions by the volcanic gravity waves and a case of coupling of dynamics and chemistry.

Novel Nitrile Peptidomimetics for Treating COVID-19.

COVID-19 is a highly infectious disease caused by the viral pathogen SARS-CoV-2, causing an estimated 5.4 million fatalities globally in 2 years since its emergence in December 2019. On December 22, 2021, the U.S. FDA granted Emergency Use Authorization for the oral viral main protease inhibitor, Nirmatrelvir, to treat patients with mild-to-moderate COVID-19. This patent review reveals the structure-activity relationship of key inhibitors described in the patent WO 2021/250648 A1.

A Patent Review on SARS Coronavirus Main Protease (3CLpro ) Inhibitors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an unprecedented global health emergency causing more than 4.2 million fatalities as of 30 July 2021. Only three antiviral therapies have been approved or granted emergency use authorization by the FDA. The SARS-CoV-2 3CL protease (3CLpro ) is deemed an attractive drug target as it plays an essential role in viral polyprotein processing and pathogenesis, although no inhibitors have been approved. This patent review discusses SARS coronavirus 3CLpro inhibitors that have been filed up to 30 July 2021, giving an overview on the types of inhibitors that have generated commercial interest, especially amongst drug companies. Insights into the common structural motifs required for active site binding is also discussed.

Airborne transmission of respiratory viruses.

The COVID-19 pandemic has revealed critical knowledge gaps in our understanding of and a need to update the traditional view of transmission pathways for respiratory viruses. The long-standing definitions of droplet and airborne transmission do not account for the mechanisms by which virus-laden respiratory droplets and aerosols travel through the air and lead to infection. In this Review, we discuss current evidence regarding the transmission of respiratory viruses by aerosols-how they are generated, transported, and deposited, as well as the factors affecting the relative contributions of droplet-spray deposition versus aerosol inhalation as modes of transmission. Improved understanding of aerosol transmission brought about by studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires a reevaluation of the major transmission pathways for other respiratory viruses, which will allow better-informed controls to reduce airborne transmission.

A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors.

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.