scholarly journals Eradication of Malaria: Present Situations and New Strategies

2021 ◽  
pp. 17-37
Author(s):  
Muslimah N. Alsulami
Keyword(s):  
Drug Targets ◽  
Gene Editing ◽  
Malaria Vaccine ◽  
Treatment Method ◽  
Economic Downturn ◽  
Parasite Plasmodium ◽  
Diagnostic Technology ◽  
Serious Disease ◽  
The Tropics ◽  
New Strategies

Malaria is a serious disease caused by the protozoon parasite Plasmodium and transmitted by the female Anopheles mosquito as a vector.  P. falciparum is the gravest infection for all other species P. ovale, P. vivax, P. Malariae and P. knowlesi in terms of morbidity or mortality, which is why most research focused on P. falciparum. The disease affects about 300-500 million people, mostly in the tropics. In regions with a weak economic downturn in tropical and subtropical capital, morbidity and mortality have elevated. Malaria remains a persistent threat in recent research. At the beginning of the 20th century, scientists tried to describe a successful way of eradicating malaria.  However, the presence of drug resistance and social and environmental problems, no acceptable and positive future solution has been pointed out. Several studies have highlighted the need to establish advanced nano-biotechnology treatment, novel anti-malarial drug targets, an efficient malaria vaccine technique, and Anopheles gene editing, which opened the door to a healthy, environmentally friendly malaria treatment method over the last two decades. In recent years, the use of mosquito microbiota has shown great potential for cutting down the transmission of mosquito-borne pathogens. This review aims to cover important issues in malarial eradication as rapid diagnostic technology, novel anti-malarial drug targets, Anopheles gene editing, use of mosquito microbiota, and recent vaccines.

scholarly journals Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis

2019 ◽  
Vol 78 (5) ◽  
pp. 676-682 ◽  
Author(s):  
Lan Zhao ◽  
Jian Huang ◽  
Yunshan Fan ◽  
Jun Li ◽  
Tianming You ◽  
...  
Keyword(s):  
Structural Damage ◽  
Drug Targets ◽  
Gene Editing ◽  
Joint Damage ◽  
Loss Of Function ◽  
Adeno Associated Virus ◽  
Structural Deterioration ◽  
Efficient Gene ◽  
Genes Encoding ◽  
Surgically Induced

ObjectivesOsteoarthritis (OA) is a painful and debilitating disease and it is associated with aberrant upregulation of multiple factors, including matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β) and nerve growth factor (NGF). In this study, we aimed to use the CRISPR/Cas9 technology, a highly efficient gene-editing tool, to study whether the ablation of OA-associated genes has OA-modifying effects.MethodsWe performed intra-articular injection of adeno-associated virus, which expressed CRISPR/Cas9 components to target each of the genes encoding MMP13, IL-1β and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1β.ResultsLoss-of-function of NGF palliates pain but worsens joint damage in the surgically induced OA model. Ablation of MMP13 or IL-1β reduces the expression of cartilage-degrading enzymes and attenuates structural deterioration. Targeting both MMP13 and IL-1β significantly mitigates the adverse effects of NGF blockade on the joints.ConclusionsCRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1β or IL-1β attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1β provide benefits on both pain management and joint structure maintenance. Our results suggest that CRISPR-based gene editing is useful for the identification of promising drug targets and the development of feasible therapeutic strategies for OA treatment.

scholarly journals Human skin pigmentation, migration and disease susceptibility

2012 ◽  
Vol 367 (1590) ◽  
pp. 785-792 ◽  
Author(s):  
Nina G. Jablonski ◽  
George Chaplin
Keyword(s):  
Vitamin D ◽  
Human Skin ◽  
High Speed ◽  
Homo Sapiens ◽  
Skin Pigmentation ◽  
Disease States ◽  
Disease Risks ◽  
Genetic And Environmental Factors ◽  
Serious Disease ◽  
The Tropics

Human skin pigmentation evolved as a compromise between the conflicting physiological demands of protection against the deleterious effects of ultraviolet radiation (UVR) and photosynthesis of UVB-dependent vitamin D 3 . Living under high UVR near the equator, ancestral Homo sapiens had skin rich in protective eumelanin. Dispersals outside of the tropics were associated with positive selection for depigmentation to maximize cutaneous biosynthesis of pre-vitamin D 3 under low and highly seasonal UVB conditions. In recent centuries, migrations and high-speed transportation have brought many people into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks. These have been increased by urbanization and changes in diet and lifestyle. Three examples—nutritional rickets, multiple sclerosis (MS) and cutaneous malignant melanoma (CMM)—are chosen to illustrate the serious health effects of mismatches between skin pigmentation and UVR. The aetiology of MS in particular provides insight into complex and contingent interactions of genetic and environmental factors necessary to trigger lethal disease states. Low UVB levels and vitamin D deficiencies produced by changes in location and lifestyle pose some of the most serious disease risks of the twenty-first century.

scholarly journals African Swine Fever Virus Induces STAT1 and STAT2 Degradation to Counteract IFN-I Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Riera ◽  
Daniel Pérez-Núñez ◽  
Raquel García-Belmonte ◽  
Lisa Miorin ◽  
Adolfo García-Sastre ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Fever Virus ◽  
Swine Industry ◽  
Inhibitory Mechanisms ◽  
Host Innate Immune Response ◽  
Serious Disease ◽  
New Strategies ◽  
Stat Pathway

African swine fever virus (ASFV) causes a serious disease in domestic pigs and wild boars and is currently expanding worldwide. No safe and efficacious vaccines against ASFV are available, which threats the swine industry worldwide. African swine fever virus (ASFV) is a complex dsDNA virus that displays multiple mechanisms to counteract the host innate immune response, whose efficacy might determine the different degrees of virulence displayed by attenuated and virulent ASFV strains. Here we report that infection with both virulent Arm/07/CBM/c2 and attenuated NH/P68 strains prevents interferon-stimulated gene (ISG) expression in interferon (IFN)-treated cells by counteracting the JAK/STAT pathway. This inhibition results in an impaired nuclear translocation of the interferon-stimulated gene factor 3 (ISGF3) complex, as well as in the proteasome-dependent STAT2 degradation and caspase 3-dependent STAT1 cleavage. The existence of two independent mechanisms of control of the JAK/STAT pathway, suggests the importance of preventing this pathway for successful viral replication. As ASFV virulence is likely associated with the efficacy of the IFN signaling inhibitory mechanisms, a better understanding of these IFN antagonistic properties may lead to new strategies to control this devastating pig disease.

scholarly journals Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies

2019 ◽  
Vol 20 (12) ◽  
pp. 3036 ◽  
Author(s):  
Dario Balestra ◽  
Alessio Branchini
Keyword(s):  
Gene Editing ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Therapeutic Approaches ◽  
Protein Levels ◽  
Functional Factors ◽  
New Strategies ◽  
I Gene

Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition, cleavage, repair/correction or activation of target sequences, even in mutated gene contexts; (ii) the rescue of altered pre-mRNA processing through the engineering of key spliceosome components able to promote correct exon recognition and, in turn, the synthesis and secretion of functional factors, as well as the effects on the splicing of missense changes affecting exonic splicing elements; this section includes antisense oligonucleotide- or siRNA-mediated approaches to down-regulate target genes; (iii) the rescue of protein synthesis/function through the induction of ribosome readthrough targeting nonsense variants or the correction of folding defects caused by amino acid substitutions. Overall, these approaches have shown the ability to rescue the expression and/or function of potentially therapeutic levels of coagulation factors in different disease models, thus supporting further studies in the future aimed at evaluating the clinical translatability of these new strategies.

scholarly journals Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery

2006 ◽  
Vol 399 (1) ◽  
pp. 47-57 ◽  
Author(s):  
Manoj K. Ramjee ◽  
Nicholas S. Flinn ◽  
Tracy P. Pemberton ◽  
Martin Quibell ◽  
Yikang Wang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Specific Substrate ◽  
Rational Drug ◽  
Parasite Plasmodium ◽  
Recognition Motifs ◽  
Synergistic Combinations ◽  
Vitro Data ◽  
In Vitro Data

The Plasmodium falciparum cysteine peptidases FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases and are therefore potential anti-malarial drug targets. To facilitate a rational drug discovery programme, in the current study we analysed the synthetic substrate and model inhibitor profiles of FP-2 and FP-3 as well as BP-2 (berghepain-2), an orthologue from the rodent parasite Plasmodium berghei. With respect to substrate catalysis, FP-2 exhibited a promiscuous substrate profile based around a consensus non-primeside motif, FP-3 was somewhat more restricted and BP-2 was comparatively specific. Substrate turnover for FP-2 was driven by a basic or acidic P1 residue, whereas for FP-3 turnover occurred predominately through a basic P1 residue only, and for BP-2, turnover was again mainly through a basic P1 residue for some motifs and surprisingly a glycine in the P1 position for other motifs. Within these P1 binding elements, additional recognition motifs were observed with subtle nuances that switched substrate turnover on or off through specific synergistic combinations. The peptidases were also profiled against reversible and irreversible cysteine peptidase inhibitors. The results re-iterated the contrasting kinetic behaviour of each peptidase as observed through the substrate screens. The results showed that the substrate and inhibitor preferences of BP-2 were markedly different from those of FP-2 and FP-3. When FP-2 and FP-3 were compared to each other they also displayed similarities and some significant differences. In conclusion, the in vitro data highlights the current difficulties faced by a peptidase directed anti-malarial medicinal chemistry programme where compounds need to be identified with potent activity against at least three peptidases, each of which displays distinct biochemical traits.

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