TSP50 Attenuates DSS-Induced Colitis by Regulating TGF-ß Signaling Mediated Maintenance of Intestinal Mucosal Barrier Integrity.

The integrity of the intestinal mucosal barrier is crucial for protecting the intestinal epithelium against invasion by commensal bacteria and pathogens, thereby combating colitis. The investigation revealed that the absence of TSP50 compromised the integrity of the intestinal mucosal barrier in murine subjects. This disruption facilitated direct contact between intestinal bacteria and the intestinal epithelium, thereby increasing susceptibility to colitis. Mechanistic analysis indicated that TSP50 deficiency in intestinal stem cells (ISCs) triggered aberrant activation of the TGF-ß signaling pathway and impeded the differentiation of goblet cells in mice, leading to impairment of mucosal permeability. By inhibiting the TGF-ß pathway, the functionality of the intestinal mucosal barrier is successfully restored and mitigated colitis in TSP50-deficient mice. In conclusion, TSP50 played a crucial role in maintaining the intestinal mucosal barrier function and exhibited the preventive effect against the development of colitis by regulating the TGF-ß signaling pathway.

Merits and challenges of iPSC-derived organoids for clinical applications.

Induced pluripotent stem cells (iPSCs) have entered an unprecedented state of development since they were first generated. They have played a critical role in disease modeling, drug discovery, and cell replacement therapy, and have contributed to the evolution of disciplines such as cell biology, pathophysiology of diseases, and regenerative medicine. Organoids, the stem cell-derived 3D culture systems that mimic the structure and function of organs in vitro, have been widely used in developmental research, disease modeling, and drug screening. Recent advances in combining iPSCs with 3D organoids are facilitating further applications of iPSCs in disease research. Organoids derived from embryonic stem cells, iPSCs, and multi-tissue stem/progenitor cells can replicate the processes of developmental differentiation, homeostatic self-renewal, and regeneration due to tissue damage, offering the potential to unravel the regulatory mechanisms of development and regeneration, and elucidate the pathophysiological processes involved in disease mechanisms. Herein, we have summarized the latest research on the production scheme of organ-specific iPSC-derived organoids, the contribution of these organoids in the treatment of various organ-related diseases, in particular their contribution to COVID-19 treatment, and have discussed the unresolved challenges and shortcomings of these models.

Modaline sulfate promotes Oct4 expression and maintains self-renewal and pluripotency of stem cells through JAK/STAT3 and Wnt signaling pathways.

BACKGROUND: Stem cells have been extensively explored for a variety of regenerative medical applications and they play an important role in clinical treatment of many diseases. However, the limited amount of stem cells and their tendency to undergo spontaneous differentiation upon extended propagation in vitro restrict their practical application. Octamer-binding transcription factor-4 (Oct4), a transcription factor belongs to the POU transcription factor family Class V, is fundamental for maintaining self-renewal ability and pluripotency of stem cells. METHODS: In the present study, we used the previously constructed luciferase reporters driven by the promoter and 3'-UTR of Oct4 respectively to screen potential activators of Oct4. Colony formation assay, sphere-forming ability assay, alkaline phosphatase (AP) activity assay and teratoma-formation assay were used to assess the role of modaline sulfate (MDLS) in promoting self-renewal and reinforcing pluripotency of P19 cells. Immunofluorescence, RT-PCR, and western blotting were used to measure expression changes of stem-related genes and activation of related signaling pathways. RESULTS: We screened 480 commercially available small-molecule compounds and discovered that MDLS greatly promoted the expression of Oct4 at both mRNA and protein levels. Moreover, MDLS significantly promoted the self-renewal capacity of P19 cells. Also, we observed that the expression of pluripotency markers and alkaline phosphatase (AP) increased significantly in MDLS-treated colonies. Furthermore, MDLS could promote teratoma formation and enhanced differentiation potential of P19 cells in vivo. In addition, we found that in the presence of LIF, MDLS could replace feeder cells to maintain the undifferentiated state of OG2-mES cells (Oct4-GFP reporter gene mouse embryonic stem cell line), and the MDLS-expanded OG2-mES cells showed an elevated expression levels of pluripotency markers in vitro. Finally, we found that MDLS promoted Oct4 expression by activating JAK/STAT3 and classic Wnt signaling pathways, and these effects were reversed by treatment with inhibitors of corresponding signaling pathways. CONCLUSIONS: These findings demonstrated, for the first time, that MDLS could maintain self-renewal and pluripotency of stem cells.

Transcriptome analysis of the procession from chronic pancreatitis to pancreatic cancer and metastatic pancreatic cancer.

Exploring the underlying mechanisms of cancer development is useful for cancer treatment. In this paper, we analyzed the transcriptome profiles from the human normal pancreas, pancreatitis, pancreatic cancer and metastatic pancreatic cancer to study the intricate associations among pancreatic cancer progression. We clustered the transcriptome data, and analyzed the differential expressed genes. WGCNA was applied to construct co-expression networks and detect important modules. Importantly we selected the module in a different way. As the pancreatic disease deteriorates, the number of differentially expressed genes increases. The gene networks of T cells and interferon are upregulated in stages. In conclusion, the network-based study provides gradually activated gene networks in the disease progression of pancreatitis, pancreatic cancer, and metastatic pancreatic cancer. It may contribute to the rational design of anti-cancer drugs.

A review on extracorporeal membrane oxygenation and kidney injury.

Extracorporeal membrane oxygenation (ECMO) is inevitable external life support in case of cardiac and respiratory failure since the 1970s. Acute kidney injury (AKI) and the requirement of renal replacement therapy (RRT) is a potential risk among these patients. This review aims to give an overview of the risk of AKI, RRT, and associated mortality among the patients who received ECMO for any of its indications. PubMed database was searched to find the relevant literature and the reference list of included studies was also searched for additional studies. The incidence of AKI ranged from 30% to 78% and RRT from 47% to 60% in ECMO patients. The pathophysiology of AKI in ECMO is multifactorial, and includes ischaemia, RBCs breakdown, comorbidity, conversion of zymogen form of pro-inflammatory mediators, structural alteration of the kidney, coadministration of nephrotoxic drugs, coagulation abnormality, and oxidative stress. ECMO was associated with the higher incidence of renal abnormalities, AKI, requirement of RRT, and associated mortality. Patients who underwent RRT had improved renal function and reduced overall mortality compared to the non-RRT group among the ECMO patients. Currently, there is no consensus evidence to support the superior use of the inline hemofilter system over continuous renal replacement therapy among patients who had AKI during ECMO.

CD4+ T cells apoptosis and conversion of Th1/Th2-type cytokines promote the progress of sporotrichosis.

Sporotrichosis is a fungal disease of the human and other mammals, caused by a complex of Sporothrix schenckii. The disease follows the traumatic inoculation to lead to fixed lesions, regional lymphangitic lesions, or even disseminated lesions including internal involvement, which depends on host immunological status and strain virulence. In this work, we observed the role of CD4+ T cells apoptosis and conversion of Th1/Th2-type cytokines in the cellular immunity regulation on mice model sporotrichosis. The experiments showed that there was more CD4+ T cells apoptosis, by endogenous apoptosis signaling pathway (P < .05), and more conversions of Th1/Th2-type cytokines in more severe and longer duration groups (P < .05). Meanwhile, the trends of the conversions of Th1/Th2-type cytokines were almost consistent with the CD4 + T cell's apoptosis in the corresponding groups. These findings suggest that CD4+ T cells apoptosis and conversion of Th1/Th2-type cytokines are contributing to promoting the progress of sporotrichosis.

Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches.

Sepsis-associated cerebral dysfunction is complex pathophysiology, generated from primary infections that are developed elsewhere in the body. The neonates, elderly population and chronically ill and long-term hospitalized patients are predominantly vulnerable to sepsis and related cerebral damage. Generally, electrophysiological recordings, severity and sedation scales, computerized imaging and spectroscopy techniques are used for its detection and diagnosis. About the underlying mechanisms, enhanced blood-brain barrier permeability and metalloprotease activity, tight junction protein loss and endothelial cell degeneration promote the influx of inflammatory and toxic mediators into the brain, triggering cerebrovascular damage. An altered neutrophil count and phenotype further dysregulate the normal neuroimmune responses and neuroendocrine stability via modulated activation of protein kinase C-delta, nuclear factor kappa-B and sphingolipid signaling. Glial activation, together with pro-inflammatory cytokines and chemokines and the Toll-like receptor, destabilize the immune system. Moreover, superoxides and hydroperoxides generate oxidative stress and perturb mitochondrial dynamics and ATP synthesis, propagating neuronal injury cycle. Activated mitochondrial apoptotic pathway, characterized by increased caspase-3 and caspase-9 cleavage and Bax/Bcl2 ratio in the hippocampal and cortical neurons, stimulate neurocognitive impairments. Additionally, altered LC3-II/I and P62/SQSTM1, p-mTOR, p-AMPK1 and p-ULK1 levels and dysregulated autophagosome-lysosome fusion decrease neuronal and glial energy homeostasis. The therapies and procedures for attenuating sepsis-induced brain damage include early resuscitation, cerebral blood flow autoregulation, implantable electric vagus nerve stimulation, antioxidants, statins, glucocorticoids, neuroimmune axis modulators and PKCδ inhibitors. The current review enumerates the pathophysiology of sepsis-induced brain damage, its diagnosis, the role of critical inducers and mediators and, ultimately, therapeutic measures attenuating cerebrovascular degeneration.

Adjuncts to pulsed dye laser for treatment of port wine stains: a literature review.

Noninvasive pulsed dye laser is the current gold standard for the treatment of port wine stains. However, most port wine stains are not completely cleared after pulsed dye laser therapy, owing to insufficient photocoagulation and laser-induced vascular regeneration and reperfusion. Several studies have explored approaches designed to improve treatment efficacy. This integrative literature review summarizes the results of clinical and animal studies published between 2004 and 2021. Pulsed dye laser has been administered in combination with photoelectric devices (the neodymium: yttrium-aluminum-garnet lasers, dual-wavelength 1064-/595-nm laser irradiation, fiberoptic Nd-YAG laser, photodynamic therapy, and radio frequency), and drugs (rapamycin, imiquimod, timolol, axitinib, endothelin receptor antagonist, artificial red blood cells and oxymetazoline). The initial results suggest that combination therapy is a direction worth exploring in the future. Further large prospective, blinded and controlled multicenter clinical trials with longer follow-up period are required to obtain more robust evidence.

Plasticity of Paneth cells and their ability to regulate intestinal stem cells.

Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

Galectins as potential pharmacological targets in renal injuries of diverse etiology.

Galectins are carbohydrate-binding proteins, and their importance in renal diseases of diverse etiology has been documented. Amongst different galectins, the role of galectin-3 in the pathophysiology of renal diseases has been well documented. There is an increase in galectin-3 in the circulation as well as on the kidneys in chronic kidney disease patients. The increase in galectin-3 is negatively correlated with a decrease in renal function and overall survival rate. The preclinical studies also correlate the increase in galectin-3 levels with renal dysfunction. Accordingly, scientists have exploited galectin-3 as a potential pharmacological target to improve renal functions in different preclinical models of renal injury. Apart from galectin-3, there have been few studies documenting the role of galectin-1, 8, and 9 in renal diseases. The role of galectin-1 is not clearly identified, and there have been conflicting reports regarding its role in renal diseases. Galectin-8 and 9 impart renoprotective effects as per clinical and preclinical studies, respectively. The present review discusses the role of different galectins in renal diseases of diverse etiology.

An alternative pathway for cellular protection in BRAF inhibitor resistance in aggressive melanoma type skin cancer.

Oncogenic alterations in the BRAF gene are identified in an estimate of 50% of melanomas and cause melanoma development. BRAF kinase inhibitors (BRAFi), including vemurafenib and dabrafenib, were discovered and used in the clinical treatment of BRAF-mutant metastatic melanoma. Though, BRAFi's therapeutic advantages are short term and short-lived associated with drug resistance. Although a few pathways of developed BRAFi resistance have also been established, in approximately 40% of melanomas, the cause for inherited resistance remains unclear. Recognizing a new process of developed BRAFi resistance might provide new possibilities to successfully treat BRAF mutant melanoma. In this study, we are exploring the compensatory alternative pathway followed by BRAFi/MEKi treated resistant cell for maintaining the long-term integrity and survival.

A secondary discoid lupus erythematosus induced by scald of edible oil: An illustration of Koebner phenomenon.

BACKGROUND: Discoid lupus erythematosus (DLE) is a most well-known clinical variation of chronic cutaneous lupus erythematosus inside the spectrum of lupus erythematosus (LE). Cutaneous trauma remains a significant and peculiar causative factor for DLE. AIMS: We present a case wherein the patient demonstrated unilateral distribution of DLE on a clinically normal appearing occult facial scald of edible oil, representing Koebner phenomenon (KP) i.e. occurrence of a new skin disease at the site of an unrelated and already healed one. PATIENT/METHODS: The 53 years old female patient was unique because she experienced DLE on the nasal back. RESULTS: The injury was totally settled following a month treatment of oral hydroxychloroquine and topical 0.03% tacrolimus ointment. After three months, she encountered an accidental edible oil scald on the right upper cheek. Several small vesicles appeared on a soybean-sized erythema base with a burning sensation. CONCLUSION: We review the literature and conclude by discussing important histologic highlights to think about while endeavoring to perceive the fundamental character and pathogenicity of such sores.

Role of Cellular Biomolecules in Screening, Diagnosis and Treatment of Colorectal Cancer.

BACKGROUND: Prevention is the primary strategy to avoid the occurrence and mortality of colorectal cancer. Generally, the concentrations of tumor markers tested during the diagnosis and believed to assist the detection of disease in the early stages of cancer. Some of the biomarkers are also important during treatment and real-time monitoring of the progress of treatment. METHODS: We considered a rationale search of key references from the database of peer-reviewed research and review literatures of colorectal cancer. The topic of search was focused on the novel methods and modern techniques of Screening, Diagnosis, and Treatment of colorectal cancer. The screened publications were critically analysed using a deductive content analysis and the matter was put in separate headings and sub headings. RESULTS: It was found that endoscopic examination, early detection, and surgery are some of the common strategies to manage colorectal cancer because late stages are difficult to treat due to the high-cost requirement and fewer chances of survival. As far as chemotherapy is concerned, systemic chemotherapy has been shown to offer the maximum benefit to patients with cancer metastasis. Among different chemotherapy measures, primary colorectal cancer prevention agents involve pharmaceuticals, phytochemicals, and dietary supplements are some of the standard options. CONCLUSION: In this review article, we have provided a comprehensive analysis of different biomarkers for the detection of colorectal cancer as well as different formulations developed for efficient treatment of the disease. The use of dietary supplements, the combinatorial approach, and nanotechnology-based strategies for colorectal cancer diagnosis and treatment are some of the recent and modern methods of cancer management.

A huge mediastinal, well-differentiated liposarcoma with heterogenous smooth muscle differentiation: a case report.

Liposarcoma is one of the most common mesenchymal tumors, although liposarcomas that occur in the mediastinum are uncommon. We recently encountered a case of mediastinal well-differentiated liposarcoma with secondary myxoid changes and smooth muscle differentiation in a 54-year-old man. The patient reported a 20-day history of chest pain, and thorax computed tomography revealed a large and multilobulated mass with heterogeneous density in the posterior and anterior mediastinum, which extended to the right hemithorax. Resection was performed and a pathological analysis subsequently confirmed a diagnosis of well-differentiated liposarcoma. The patient experienced recurrence at 15 months after the surgery and subsequently died of heart failure.

Regulatory effects of dermal papillary pluripotent stem cells on polarization of macrophages from M1 to M2 phenotype in vitro.

The M1:M2 macrophage ratio is important for spinal cord injury (SCI) repair. Bone marrow mesenchymal stem cells (BMSCs) can alter macrophage activation, promoting M1 to M2 macrophage conversion and SCI repair; however, clinical BMSC applications have limitations. Previously, we found DPCs to be superior to BMSCs in promoting tissue repair after SCI, which we hypothesized to be mediated by M1 to M2 macrophage conversion. We investigated the regulatory effect of DPCs on M1/M2 macrophage polarization. Dermal papilla cells (DPCs) were isolated from rat vibrissae and characterized. Bone marrow-derived macrophages (BMDMs) were isolated and identified based on specific marker expression, and stimulated to differentiate into M1 macrophages with GM-CSF, IFN-γ, and LPS. These cells were co-cultured with DPCs to evaluate the effect on macrophage differentiation. DPCs expressed dermal papillae-specific markers, including ALP and Sox2, had MSC-expression patterns like those of BMSCs, and were capable of multi-differentiation. BMDMs expressed ANAE and CD68. Three days after induction, differentiated cells exhibited morphology typical of M1-like macrophages and expressed the macrophage marker CD68 and the M1 macrophage markers iNOS, but lacked expression of the M2 macrophage marker CD206. Co-culture with DPCs resulted in a shift to anti-inflammatory M2-like macrophage differentiation, characterized by morphological changes typical of M2 macrophages, downregulation of the characteristic cytokine TNF-α and the proportion of iNOS+ cells, and upregulation of the characteristic cytokine IL-10 and the cell-surface marker CD206. The number of CD206-expressing M2 macrophages also increased. These findings demonstrate that DPCs reprogram macrophages to an anti-inflammatory M2 phenotype, which could improve adverse inflammatory microenvironments and promote tissue repair. Thus, DPCs may be an interesting alternative cell source and merit further investigation in applications for SCI therapy.

Efficient CdTe Nanocrystal/TiO2 Hetero-Junction Solar Cells with Open Circuit Voltage Breaking 0.8 V by Incorporating A Thin Layer of CdS Nanocrystal.

Nanocrystal solar cells (NCs) allow for large scale solution processing under ambient conditions, permitting a promising approach for low-cost photovoltaic products. Although an up to 10% power conversion efficiency (PCE) has been realized with the development of device fabrication technologies, the open circuit voltage (Voc) of CdTe NC solar cells has stagnated below 0.7 V, which is significantly lower than most CdTe thin film solar cells fabricated by vacuum technology (around 0.8 V~0.9 V). To further improve the NC solar cells' performance, an enhancement in the Voc towards 0.8⁻1.0 V is urgently required. Given the unique processing technologies and physical properties in CdTe NC, the design of an optimized band alignment and improved junction quality are important issues to obtain efficient solar cells coupled with high Voc. In this work, an efficient method was developed to improve the performance and Voc of solution-processed CdTe nanocrystal/TiO2 hetero-junction solar cells. A thin layer of solution-processed CdS NC film (~5 nm) as introduced into CdTe NC/TiO2 to construct hetero-junction solar cells with an optimized band alignment and p-n junction quality, which resulted in a low dark current density and reduced carrier recombination. As a result, devices with improved performance (5.16% compared to 2.63% for the control device) and a Voc as high as 0.83 V were obtained; this Voc value is a record for a solution-processed CdTe NC solar cell.

Rat vibrissa dermal papilla cells promote healing of spinal cord injury following transplantation.

Bone marrow mesenchymal stem cell (BMSC) transplantation is effective for repairing spinal cord injuries (SCIs); however, there are limitations of clinical BMSC applications. Previously, we reported that dermal papilla cells (DPCs) secrete brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor more actively than BMSCs. To analyze the therapeutic function of DPCs in SCI, primary DPCs and BMSCs were cultured from the same green fluorescence protein-transgenic rat. The cells were suspended in rat-tail collagen I and transplanted separately into completely transected spinal cord lesion sites. Grafted-cell survival was examined with a small animal in vivo imaging detection system, and lesion sites were examined histochemically. In vivo imaging revealed enhanced lesion filling and survival with DPC grafts compared with BMSC grafts on days 14 and 21 post-transplantation. Hematoxylin and eosin staining demonstrated that lesion area sizes in the two groups were not markedly different. In the DPC transplant group, more axons formed within the lesion sites. CD31-positive vessel-like structures were more abundant in lesion sites near the grafted cells in the DPC group. The results of the present study suggest that DPCs may be a valuable alternative source of stem cells for autologous cell therapy for the treatment of SCI.

Rationally Controlled Synthesis of CdSexTe1-x Alloy Nanocrystals and Their Application in Efficient Graded Bandgap Solar Cells.

CdSexTe1-x semiconductor nanocrystals (NCs), being rod-shaped/irregular dot-shaped in morphology, have been fabricated via a simple hot-injection method. The NCs composition is well controlled through varying molar ratios of Se to Te precursors. Through changing the composition of the CdSexTe1-x NCs, the spectral absorption of the NC thin film between 570-800 nm is proved to be tunable. It is shown that the bandgap of homogeneously alloyed CdSexTe1-x active thin film is nonlinearly correlated with the different compositions, which is perceived as optical bowing. The solar cell devices based on CdSexTe1-x NCs with the structure of ITO/ZnO/CdSe/CdSexTe1-x/MoOx/Au and the graded bandgap ITO/ZnO/CdSe(w/o)/CdSexTe1-x/CdTe/MoOx/Au are systematically evaluated. It was found that the performance of solar cells degrades almost linearly with the increase of alloy NC film thickness with respect to ITO/ZnO/CdSe/CdSe0.2Te0.8/MoOx/Au. From another perspective, in terms of the graded bandgap structure of ITO/ZnO/CdSe/CdSexTe1-x/CdTe/MoOx/Au, the performance is improved in contrast with its single-junction analogues. The graded bandgap structure is proved to be efficient when absorbing spectrum and the solar cells fabricated under the structure of ITO/ZnO/CdSe0.8Te0.2/CdSe0.2Te0.8/CdTe/MoOx/Au indicate power conversion efficiency (PCE) of 6.37%, a value among the highest for solution-processed inversely-structured CdSexTe1-x NC solar cells. As the NC solar cells are solution-processed under environmental conditions, they are promising for fabricating solar cells at low cost, roll by roll and in large area.

A reference human genome dataset of the BGISEQ-500 sequencer.

Background: BGISEQ-500 is a new desktop sequencer developed by BGI. Using DNA nanoball and combinational probe anchor synthesis developed from Complete Genomics™ sequencing technologies, it generates short reads at a large scale. Here, we present the first human whole-genome sequencing dataset of BGISEQ-500. The dataset was generated by sequencing the widely used cell line HG001 (NA12878) in two sequencing runs of paired-end 50 bp (PE50) and two sequencing runs of paired-end 100 bp (PE100). We also include examples of the raw images from the sequencer for reference. Finally, we identified variations using this dataset, estimated the accuracy of the variations, and compared to that of the variations identified from similar amounts of publicly available HiSeq2500 data. We found similar single nucleotide polymorphism (SNP) detection accuracy for the BGISEQ-500 PE100 data (false positive rate [FPR] = 0.00020%, sensitivity = 96.20%) compared to the PE150 HiSeq2500 data (FPR = 0.00017%, sensitivity = 96.60%) better SNP detection accuracy than the PE50 data (FPR = 0.0006%, sensitivity = 94.15%). But for insertions and deletions (indels), we found lower accuracy for BGISEQ-500 data (FPR = 0.00069% and 0.00067% for PE100 and PE50 respectively, sensitivity = 88.52% and 70.93%) than the HiSeq2500 data (FPR = 0.00032%, sensitivity = 96.28%). Our dataset can serve as the reference dataset, providing basic information not just for future development, but also for all research and applications based on the new sequencing platform.