The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein ...response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.
In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or ...bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.
Air pollution is inevitably the result of human civilization, industrialization, and globalization. It is composed of a mixture of gases and particles at harmful levels. Particulate matter (PM), ...nitrogen oxides (NOx), and carbon dioxides (CO
) are mainly generated from vehicle emissions and fuel consumption and are the main materials causing outdoor air pollution. Exposure to polluted outdoor air has been proven to be harmful to human eyes. On the other hand, indoor air pollution from environmental tobacco smoking, heating, cooking, or poor indoor ventilation is also related to several eye diseases, including conjunctivitis, glaucoma, cataracts, and age-related macular degeneration (AMD). In the past 30 years, no updated review has provided an overview of the impact of air pollution on the eye. We reviewed reports on air pollution and eye diseases in the last three decades in the PubMed database, Medline databases, and Google Scholar and discussed the effect of various outdoor and indoor pollutants on human eyes.
Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing ...an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an
-methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.
Animal models are widely used to develop drugs for treating diabetes mellitus (DM). Insulin resistance (IR) is one of the main problems in type-2 DM (T2DM). Streptozotocin (STZ) is used to damage ...pancreatic cells for induction of DM. Many rat models were applied in research as T2DM. However, the degree of IR in each model is unknown. In the present study, IR and insulin signaling were compared in four models of type 2 diabetes: rats fed a fructose-rich chow for 8 weeks, rats feed high-fat chow for 4 weeks followed by injection with streptozotocin (35 mg/kg, i.p.), rats injected with a single low dose streptozotocin (45 mg/kg, i.p.), and rats injected with a single dose of nicotinamide followed by a single high dose of streptozotocin (60 mg/kg, i.p.). Values from these determinations in diabetic rats showing the order that insulin resistance is most marked in rats received fructose-rich chow followed by high-fat diet before STZ injection induced model (HFD/STZ rats), and rats injected with low dose of STZ but it is less marked in rats induced by nicotinamide and STZ. Additionally, insulin secretion was reduced in three rat models except the rats receiving fructose-rich chow. Western blots also showed the same changes in phosphorylation of IRS-1 or Akt using soleus muscle from each model. The obtained data suggest a lack of pronounced IR in the rats with acute diabetes induced by nicotinamide and STZ while IR is markedly identified in rats fed fructose-rich chow. However, the increase of plasma glucose levels in fructose-rich chow-fed rats was not so significant as other groups. Therefore, HFD/STZ rats is an appropriate and stable animal model which is analogous to the human T2DM through a combination of high-fat diet with multiple low-dose STZ injections.
Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse ...chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of ...cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.
Emerging infectious diseases (EIDs), including the latest COVID-19 pandemic, have emerged and raised global public health crises in recent decades. Without existing protective immunity, an EID may ...spread rapidly and cause mass casualties in a very short time. Therefore, it is imperative to identify cases with risk of disease progression for the optimized allocation of medical resources in case medical facilities are overwhelmed with a flood of patients. This study has aimed to cope with this challenge from the aspect of preventive medicine by exploiting machine learning technologies. The study has been based on 83,227 hospital admissions with influenza-like illness and we analysed the risk effects of 19 comorbidities along with age and gender for severe illness or mortality risk. The experimental results revealed that the decision rules derived from the machine learning based prediction models can provide valuable guidelines for the healthcare policy makers to develop an effective vaccination strategy. Furthermore, in case the healthcare facilities are overwhelmed by patients with EID, which frequently occurred in the recent COVID-19 pandemic, the frontline physicians can incorporate the proposed prediction models to triage patients suffering minor symptoms without laboratory tests, which may become scarce during an EID disaster. In conclusion, our study has demonstrated an effective approach to exploit machine learning technologies to cope with the challenges faced during the outbreak of an EID.
Polymers with an abundant amorphous domain should facilitate energy dissipation upon stretching, making near amorphous π-conjugated polymers have immense potential in realizing intrinsically ...stretchable field-effect transistor (FET) devices. In this study, high mobility preservation under the stretched state is attempted by replacing typical alkyl-monothienyl (T-R) on a benzo1,2-b:4,5-b’dithiophene-difluorobenzothiadiazole backbone with three other biaxially extended side-chains, including alkyl-dithienyl (2T-R), branching alkyl-trithienyl (3T-R), and alkyl-benzotrithienyl (B3T-R) groups. Despite showing near amorphous features, the semi-2D BDT-based polymers with bulkier biaxially extended side chains (PBDT-2T, PBDT-3T, and PBDT-B3T) still present comparable mobility to the reference semicrystalline polymer (PBDT-T). Although these four polymers yield comparable mobility, they show distinctly different mobility retention in the stretched state. From the study of their mobility-stretchability relationship, the interdigitating and/or entanglement of these biaxially extended conjugated side chains are shown to play a nontrivial role in the resultant mechanical robustness against the stretching force. Owing to the proper spatial mobility and geometry, the branched 3T-R side chain possesses a more intense interdigitating and/or entanglement capability than the linear 2T-R one and the fused B3T-R one, providing better mechanical strength under stretched states. Meanwhile, it maintains sufficient interchain connectivity for intermittent interchain hopping to compensate for the 1D charge transport along the backbone, ensuring good charge transport even in the stretched state. As a result, the printed PBDT-3T film is demonstrated to deliver a high mobility retention of 73% at a 60% strain exerted parallel to the charge-transporting direction and a very stable mobility retention of 88% after 1000 stretching-releasing cycles at a 60% strain, being one of the best stretchable near amorphous conjugated polymers reported thus far. Our result underlines the effectiveness of using biaxially extended conjugated side chains to realize high-performance stretchable polymers.
The use of Virtual Reality (VR) in health professions education has increased dramatically in recent years, yet there is limited evidence of its impact on educational outcomes. The purpose of the ...study was to assess the impact of VR anatomy instruction on the ultrasound competency of novice learners participating in a ultrasonography workshop.
We designed a VR-enhanced ultrasonography training program and utilized a plane transection tool to interact with a three-dimensional (3D) VR model of the human body which facilitated the 3D conceptualization of the spatial relationship of anatomical structures, leading to faster and better development of ultrasonographic competency. This was a randomized control study which enrolled third-year medical students (n = 101) without previous exposure to formal or informal ultrasonography training. The participants were randomly divided into an intervention and control group. We assessed participants' competency through ultrasound performance stations on live subjects, we also measured anatomical and ultrasound image identification ability using multiple choice tests.
Participants in the intervention group (median = 16; interquartile 13 to 19) had significantly higher scores in ultrasonography task performance tests than the control group (median = 10; interquartile 7 to 14; Mann-Whitney U = 595; P < 0.01). In sub-group analysis, the intervention group performed significantly better in the six out of ten ultrasound tasks. Participants in the intervention group also had greater improvement in ultrasonographic image identification MCQ tests than the control group (Mann-Whitney U = 914; P < 0.05).
This study suggests that VR-enhanced anatomical training could be of significant benefit in ultrasonography training by promoting a better understanding of the spatial relationships of anatomical structures and the development of early psychomotor skills transferable to the handling of ultrasonographic probes.
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